Mechanistic Investigation on the Regioselectivity of Electrochemical Co(II)-Catalyzed [2 + 2 + 2] Cycloaddition of Terminal Acetylenes.

In this paper, the regioselectivity of electrochemical Co(II)-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes was investigated using density functional theory. We explored in detail the energy profiles for both 1,2,4- and 1,3,5-regioselectivity pathways and revealed the origin of the regioselectivity. Two kinds of conformational isomers derived from the different coordination modes of alkynes with cobaltacyclopentadiene have been found, which were formed through electrochemically mediated redox processes. The regioselectivity of the reaction depends on the two coordination modes. When the Co(II) center attacks α-C of the third alkyne, while ß2-C in cyclopentadiene bonds to ß-C of the alkyne, the reaction favors the formation of 1,2,4-products. In contrast, when the Co(II) center connects to ß-C of the alkyne, it forms only the 1,3,5-products via [4 + 2] cycloaddition because of the steric repulsion between the bulky ligand on Co(II) and the phenyl group in the alkyne.

Exploration of Ligand-Centered Hydride Transfer in La/Y-Catalyzed Deoxygenative Reduction of Tertiary Amides with Pinacolborane.

A number of rare-earth metals and actinides have proven to be active in a wide variety of atom-efficient transformations. As compared to the related organometallic catalysts, the detailed mechanisms for the rare-earth metal-catalyzed reactions remain largely unexplored. Herein, the detailed catalyst activation process and reaction mechanisms of deoxygenative reduction of amides with pinacolborane (HBpin) catalyzed by Y[N(TMS)2]3 and La[N(TMS)2]3 complexes as well as a La4(O)acac10 cluster are investigated by density functional theory calculations. The M(III)-hemiaminal complex is disclosed to be the active catalyst for both the complexes and the cluster. During catalyst activation for both the Y and La complexes, the H-B bond polarity results in the formation of a transient M(III)-hydride intermediate, which is converted into an on-cycle M(III)-hemiaminal complex via facile migratory insertion. However, this kind of La(III)-hydride species cannot be formed for the La cluster. Starting from the M(III)-hemiaminal complex, the reaction proceeds via the ligand-centered hydride transfer mechanism that involves B-O bond formation, hydride transfer to B, C-O cleavage within the hemiaminal borane, hydride transfer to C, and σ-bond metathesis. The additional HBpin molecule is vital for the first hydride transfer that leads to the formation of [H2Bpin]- species. Our calculations reveal several important cooperative effects of the HBpin component during the hydride transfer processes. The improved mechanistic insights will be helpful for further development of selective C═O reduction.

Origins of Stereospecificity and Divergent Reactivity of Pd-Catalyzed Cross Coupling with α,α-Disubstituted Alkenyl Hydrazones.

This article presents an exploration of stereospecificity and divergent reactivity of Pd-catalyzed α,α-disubstituted alkenyl hydrazones to synthesize 1,4-dienes in the Z configuration and vinylcyclopropane. We calculated the energy profiles of four α,α-disubstituted alkenyl hydrazones. The results show that the energy profiles of the whole catalytic cycle are basically the same before the syn-carbopalladation step. Subsequent syn-ß-C elimination yields skipping dienes, or direct ß-H elimination yields vinylcyclopropane. Current theoretical calculations reveal that the stereospecificity and the divergent reactivity of reactions result from the competition between syn-ß-C elimination and ß-H elimination. The C-C bond rotation and subsequent syn-ß-C elimination step control the stereospecificity of the reaction by changing the olefin stereostructure from E to Z configuration. The steric factor of α-substituted groups mediates the transformation between syn-ß-C elimination and ß-H elimination. The results are of great significance for the scientific design of substrates to achieve accurate synthesis of target products.

Cation Bridge Mediating Homo- and Cross-Coupling in Copper-Catalyzed Reductive Coupling of Benzaldehyde and Benzophenone.

A novel mechanism of organobase-mediated Brook rearrangement and C-C coupling in the copper-catalyzed reductive coupling of benzaldehyde and benzophenone is proposed. The results demonstrate that this reaction proceeds mainly through five sequential elementary steps: transmetalation, carbonyl addition, σ-bond metathesis, Brook rearrangement, and C-C coupling. The organobases played a significant role not only in forming the active catalyst but also in mediating the Brook rearrangement and chemoselectivity in homo- and cross-coupling. Brook rearrangement mediated by organobases is more favored than that without organobases. In the C-C coupling step, the cation bridge combines two O atoms with the same electronegativity to form a pre-reaction complex. Moreover, a significant charge difference is a major factor in the selectivity of carbonyl addition and C-C coupling.

Single-Atom Ce-Modified α-Fe2O3 for Selective Catalytic Reduction of NO with NH3.

A single-atom Ce-modified α-Fe2O3 catalyst (Fe0.93Ce0.07Ox catalyst with 7% atomic percentage of Ce) was synthesized by a citric acid-assisted sol-gel method, which exhibited excellent performance for selective catalytic reduction of NOx with NH3 (NH3-SCR) over a wide operating temperature window. Remarkably, it maintained ∼93% NO conversion efficiency for 168 h in the presence of 200 ppm SO2 and 5 vol % H2O at 250 °C. The structural characterizations suggested that the introduction of Ce leads to the generation of local Fe-O-Ce sites in the FeOx matrix. Furthermore, it is critical to maintain the atomic dispersion of the Ce species to maximize the amounts of Fe-O-Ce sites in the Ce-doped FeOx catalyst. The formation of CeO2 nanoparticles due to a high doping amount of Ce species leads to a decline in catalytic performance, indicating a size-dependent catalytic behavior. Density functional theory (DFT) calculation results indicate that the formation of oxygen vacancies in the Fe-O-Ce sites is more favorable than that in the Fe-O-Fe sites in the Ce-free α-Fe2O3 catalyst. The Fe-O-Ce sites can promote the oxidation of NO to NO2 on the Fe0.93Ce0.07Ox catalyst and further facilitate the reduction of NOx by NH3. In addition, the decomposition of NH4HSO4 can occur at lower temperatures on the Fe0.93Ce0.07Ox catalyst containing atomically dispersed Ce species than on the α-Fe2O3 reference catalyst, resulting in the good SO2/H2O resistance ability in the NH3-SCR reaction.

Mechanism of iron complexes catalyzed in the N-formylation of amines with CO2 and H2: the superior performance of N-H ligand methylated complexes.

CO2 hydrogenation into value-added chemicals not only offer an economically beneficial outlet but also help reduce the emission of greenhouse gases. Herein, the density functional theory (DFT) studies have been carried out on CO2 hydrogenation reaction for formamide production catalyzed by two different N-H ligand types of PNP iron catalysts. The results suggest that the whole mechanistic pathway has three parts: (i) precatalyst activation, (ii) hydrogenation of CO2 to generate formic acid (HCOOH), and (iii) amine thermal condensation to formamide with HCOOH. The lower turnover number (TON) of a bifunctional catalyst system in hydrogenating CO2 may attribute to the facile side-reaction between CO2 and bifunctional catalyst, which inhibits the generation of active species. Regarding the bifunctional catalyst system addressed in this work, we proposed a ligand participated mechanism due to the low pKa of the ligand N-H functional in the associated stage in the catalytic cycle. Remarkably, catalysts without the N-H ligand exhibit the significant transfer hydrogenation through the metal centered mechanism. Due to the excellent catalytic nature of the N-H ligand methylated catalyst, the N-H bond was not necessary for stabilizing the intermediate. Therefore, we confirmed that N-H ligand methylated catalysts allow for an efficient CO2 hydrogenation reaction compared to the bifunctional catalysts. Furthermore, the influence of Lewis acid and strong base on catalytic N-formylation were considered. Both significantly impact the catalytic performance. Moreover, the catalytic activity of PNMeP-based Mn, Fe and Ru complexes for CO2 hydrogenation to formamides was explored as well. The energetic span of Fe and Mn catalysts are much closer to the precious metal Ru, which indicates that such non-precious metal catalysts have potentially valuable applications.

Effects of electrostatic drag on the velocity of hydrogen migration - pre- and post-transition state enthalpy/entropy compensation.

Ab initio molecular dynamics calculations were used to explore the underlying factors that modulate the velocity of hydrogen migration for 1,2 hydrogen shifts in carbocations in which different groups interact noncovalently with the migrating hydrogen. Our results indicate that stronger electrostatic interactions between the migrating hydrogen and nearby π-systems lead to slower hydrogen migration, an effect tied to entropic contributions from the hydrogen + neighboring group substructures.

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.

Ligands and Bases Mediate Switching between Aminocarbonylations and Alkoxycarbonylations in Coupling of Aminophenols with Iodoarenes.

The mechanisms of aminocarbonylations and alkoxycarbonylations in coupling of aminophenols with iodoarenes catalyzed by the bidentate phosphorus ligand Pd complexes were explored with theoretical calculations. The origins of chemoselective carbonylation mediated by ligands and bases were disclosed. According to our calculations, the bifurcation points of reaction pathways caused by different ligands and bases combinations are L1/L2Int5, a [DPPP/DIBPP]benzoylpalladium(II)iodide complex. The affinity of L1/L2Int5 and adducts (K2CO3 and DBU), as well as the substrate itself, are the predominant factors of switching from aminocarbonylation to alkoxycarbonylation. The results reveal that K2CO3 directly exchanges iodine with L1Int5 and assists in hydrogen transfer in the DPPP-K2CO3 combination, in which alkoxycarbonylation is more favorable than aminocarbonylation, while for the DIBPP-DBU combination, iodine exchange is achieved by means of the hydrogen bond formed between the carbonyl group on L2Int5 and the substrate amino H due to the influence of the ligand, and then iodine exchange occurs; subsequently DBU-assisted amino H transfers to complete the aminocarbonylation. The proton transfer is the step that determines the chemoselectivity in the DPPP-K2CO3 combination. The iodine exchange determines the chemoselectivity between aminocarbonylation and alkoxycarbonylation in the DIBPP-DBU one. These results would be helpful to deeply understand the roles of each component in a chemoselective reaction in a multicomponent complex system.

A rational design of manganese electrocatalysts for Lewis acid-assisted carbon dioxide reduction.

Herein, the mechanisms of Brønsted acid- and Lewis acid-assisted CO2 electroreduction by Mn(mesbpy)(CO)3Br (1) were investigated by density functional theory calculations. Our results indicate that for the Lewis acid-assisted cycle, an energy sink (13) is present owing to the interaction between Mg(OTf)2 and activated CO2, which is disadvantageous to the apparent activation energy (ΔG≠). Moreover, a series of substituted 13 counterparts were investigated to reduce the energy sink and decrease ΔG≠. Based on our study on the substituent effect, an excellent linear relationship was found between 2e reduction potentials and LUMO energies of substituted 1, and a moderate linear relationship was observed between ΔG of substituted 13 and the 2e reduction potential of substituted 1 counterparts. Moreover, for the CO2 reduction assisted by a Lewis acid, the formyl-substituted complex R8 has been predicted to be a more effective catalyst with lower overpotential and higher catalytic activity than its parent complex 1.

Mechanistic Exploration of the Competition Relationship between a Ketone and C═C, C═N, or C═S Bond in the Rh(III)-Catalyzed Carbocyclization Reactions.

The introduction of a C═O, C═C, C═S, or C═N bond has emerged as an effective strategy for carbocycle synthesis. A computational mechanistic study of Rh(III)-catalyzed coupling of alkynes with enaminones, sulfoxonium ylides, or α-carbonyl-nitrones was carried out. Our results uncover the roles of dual directing groups in the three substrates and confirm that the ketone acts as the role of the directing group while the C═C, C═N, or C═S bond serves as the cyclization site. By comparing the coordination of the ketone versus the C═C, C═N, or C═S bond, as well as the chemoselectivity concerning the six- versus five-membered formation, a competition relationship is revealed within the dual directing groups. Furthermore, after the alkyne insertion, instead of the originally proposed direct reductive elimination mechanism, the ketone enolization is found to be essential prior to the reductive elimination. The following C(sp2)-C(sp2) reductive elimination is more favorable than the C(sp3)-C(sp2) formation, which can be explained by the aromaticity difference in the corresponding transition states. The substituent effect on controlling the selectivity was also discussed.

Highly sensitive and selective detection of Pd2+ ions using a ferrocene-rhodamine conjugate triple channel receptor in aqueous medium and living cells.

Herein, a novel ferrocene-rhodamine receptor conjugated with an allylimine bridge was facilely synthesized. This triple channel receptor can selectively and sensitively monitor Pd2+ ions through chromogenic, fluorogenic and electrochemical assays in aqueous medium with a low detection limit (8.46 × 10-9 M) and a fast response (<8 min). It can be applied as a fluorescent probe for effective survey of Pd2+ ions in living cells. Moreover, a plausible recognition mode was proposed and rationalized by theoretical calculations.

Comprehensive Mechanistic Insight into Cooperative Lewis Acid/Cp*CoIII-Catalyzed C-H/N-H Activation for the Synthesis of Isoquinolin-3-ones.

The mechanism of B(C6F5)3 promoted Cp*CoIII-catalyzed C-H functionalization was investigated in detail employing density functional theory (DFT). The formation free energy of every possible species in the multicomponent complex system was explored and the optimal active catalyst was screened out. The results uncover the role of B(C6F5)3 played in forming active catalyst is from the coordination with OAc-, but not from the formation of [I(C6F5)3B]-, and no acceleration effect is found in C-H activation as well as the formation of CoIII-carbene intermediate. Moreover, present theoretical results elucidate the Cp*CoIII-catalyzed C-H activation is mediated by imine N-coordination other than general proposed the sequence of N-deprotonation directed C-H activation. The metal-controlled C-H/N-H selectivity was then elucidated by insighting into [Cp*CoIIIOAc]+/[Cp*RhIIIOAc]+-catalyzed C-H and N-H activations, respectively.

Mechanistic Exploration of Cp*CoIII/RhIII-Catalyzed Carboamination/Olefination of N-Phenoxyacetamides with Alkenes.

A computational study of Cp*CoIII/RhIII-catalyzed carboamination/olefination of N-phenoxyacetamides with alkenes was carried out to elucidate the catalyst-controlled chemoselectivity. The reaction of the two catalysts shares a similar process that involves N-H and C-H activation as well as alkene insertion. Then the reaction bifurcates at the generated seven-membered metallacycle. For Cp*CoIII catalyst, the resulting metallacycle undergoes oxidation addition, reductive elimination, and protonation to yield the carboamination product exclusively. However, the Cp*RhIII catalyst could promote the subsequent olefination pathway via sequential ß-H elimination, reductive elimination, oxidation addition, and protonation, which enables the experimentally observed mixtures of both carboamination and olefination products. Our results uncover that the higher propensity for the ß-H-elimination of the Cp*RhIII than the Cp*CoIII catalyst in the olefination pathway could be responsible for the different selectivity and reactivity of the two catalysts.

O-Phenylenediamine: a privileged pharmacophore of ferrostatins for radical-trapping reactivity in blocking ferroptosis.

Ferroptosis is a non-apoptotic, iron dependent form of regulated cell death that is characterized by the accumulation of lipid hydroperoxides. It has drawn considerable attention owing to its putative involvement in diverse neurodegenerative diseases. Ferrostatins are the first identified inhibitors of ferroptosis and they inhibit ferroptosis by efficiently scavenging free radicals in lipid bilayers. However, their further medicinal application has been limited due to the deficient knowledge of the lipid peroxyl radical-trapping mechanism. In this study, experimental and theoretical methods were performed to illustrate the possible lipid hydroperoxide inhibition mechanism of ferrostatins. The results show that an ortho-amine (-NH) moiety from ferrostatins can simultaneously interact with lipid radicals, and then form a planar seven-membered ring in the transition state, and finally present greater reactivity. NBO analysis shows that the formed planar seven-membered ring forces ortho-amines into better alignment with the aromatic π-system. It significantly increases the magnitudes of amine conjugation and improves spin delocalization in the transition state. Additionally, a classical H-bond type interaction was discovered between a radical and an o-NH group as another transition state stabilizing effect. This type of radical-trapping mechanism is novel and has not been found in diphenylamine or traditional polyphenol antioxidants. It can be said that o-phenylenediamine is a privileged pharmacophore for the design and development of ferroptosis inhibitors.

Theoretical insights into the structural and fluorescence properties of DNA containing fluorescent nucleobases.

Fluorescent base analogues are of great importance as sensitive probes to detect the dynamic structures of DNA. In this research, the structural and photophysical properties of 13-mer oligonucleotides containing 4-aminophthalimide:2,4-diaminopyrimidine (4AP:DAP) (4AP0, 4AP') were characterized using both molecular dynamics simulations and quantum mechanics methods. The results indicate that the 4AP:DAP pair is well adapted to the overall B-DNA structure with higher stability and π-stacking abilities. The structural overlap of 4AP' and 4AP0 with the neighboring adenines only lies in the 5'-direction which results in the structure distortion from native B-DNA. Furthermore, the photophysical properties of the fluorescent base monomers and the B-DNA duplex were explored in detail. A very important result is that the hydrogen bond interaction does not have more effect on the fluorescence band apart from the slight red-shifts. In particular, the identity of the neighboring bases stacked with 4AP has an important effect on the fluorescence band. How the local environment can alter the photophysical features of the nucleobases when they are incorporated into the DNA duplex is elucidated.

Understanding and modulating the high-energy properties of noble-gas hydrides from their long-bonding: an NBO/NRT investigation on HNgCO+/CS+/OSi+ and HNgCN/NC (Ng = He, Ar, Kr, Xe, Rn) molecules.

The noble-gas hydrides, HNgX (X is an electronegative atom or fragment), represent potential high-energy materials because their two-body decomposition process, HNgX → Ng + HX, is strongly exoergic. Our previous studies have shown that each member of the HNgX (X = halogen atom or CN/NC fragment) molecules is composed of three leading resonance structures: two ω-bonding structures (H-Ng+ :X- and H:- Ng+-X) and one long-bonding structure (H∧X). The last one paints a novel [small sigma, Greek, circumflex]-type long-bonding picture. The present study focuses on the relationship between this novel bonding motif and the unusual energetic properties. We chose HNgCO+/CS+/OSi+/CN/NC, with the formula HNgAB (Ng = He, Ar, Kr, Xe, Rn; AB = CO+/CS+/OSi+/CN/NC) as the research system. We first investigated the bonding of HNgCO+ and its analogous HNgCS+/OSi+ species using NBO/NRT methods, and quantitatively compared the bonding with that in HNgCN/NC molecules. NBO/NRT results showed that each of the HNgCO+/CS+/OSi+ molecules could be better represented as a resonance hybrid of ω-bonding and long-bonding structures, but the long-bonding is much weaker than that in HNgCN/NC molecules. Furthermore, we introduced the long-bonding concept into the rationalization of the high-energy properties, and found a good correlation between the highly exothermic two-body dissociation channel and the long-bond order, bH-A. We also found that the long-bond order is highly tunable for these noble-gas hydrides due to its dependence on the nature of the electronegative AB fragments or the central noble-gas atoms, Ng. On the basis of these results, we could optimize the energetic properties by changing the long-bonding motif of our studied molecules. Overall, this study shows that the long-bonding model provides an easy way to rationalize and modulate the unusual energy properties of noble-gas hydrides, and that it is helpful to predict some noble-gas hydrides as potential energetic materials.

A Mechanistic Insight into the Ligand-Controlled Asymmetric Arylation of Aliphatic α-Amino Anion Equivalents: Origin of Regio- and Enantioselectivities.

The reaction mechanism and the origins of regio- and enantioselectivities for Pd-catalyzed asymmetric arylation of aliphatic α-amino anion equivalents were investigated computationally. The results indicate that the reaction proceeds via mainly six sequential steps: deprotonation at α'-site of imine, coordination of α-amino anion to Pd-catalyst, oxidative addition, transmetalation, reductive elimination, as well as the final dissociation to release the product and regenerate the catalyst. The transmetalation is a key step on which both enantioselectivity and regioselectivity depend. The charge inversions of α- and α'-C atoms and the orbital interaction between Pd center and α-C in transmetalation step are responsible for the regioselectivity. Additionally, the intermediates before the dissociation step are critical in controlling the enantioselectivity. Noncovalent interactions analyses indicate that the enantioselectivity primarily arises from the CH···π interactions of isopropyl (iPr) groups with the fluorene and the benzene rings for PdL1-catalyzed reaction.

Solvent Mediating a Switch in the Mechanism for Rhodium(III)-Catalyzed Carboamination/Cyclopropanation Reactions between N-Enoxyphthalimides and Alkenes.

Recently, a new synthetic methodology of rhodium-catalyzed carboamination/cyclopropanation from the same starting materials at different reaction conditions has been reported. It provides an efficient strategy for the stereospecific formation of both carbon- and nitrogen-based functionalities across an alkene. Herein we carried out a detailed theoretical mechanistic exploration for the reactions to elucidate the switch between carboamination and cyclopropanation as well as the origin of the chemoselectivity. Instead of the experimentally proposed RhIII-RhI-RhIII catalytic mechanism, our results reveal that the RhIII-RhV-RhIII mechanism is much more favorable in the two reactions. The chemoselectivity is attributed to a combination of electronic and steric effects in the reductive elimination step. The interactions between alkene and the rhodacycle during the alkene migration insertion control the stereoselectivity in the carboamination reactions. The present results disclose a dual role of the methanol solvent in controlling the chemoselectivity.

Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical by liproxstatin-1.

Ferroptosis is a recently discovered iron-dependent form of non-apoptotic cell death caused by the accumulation of membrane lipid peroxidation products, which is involved in various pathological conditions of the brain, kidney, liver and heart. A potent spiroquinoxalinamine derivative named liproxstatin-1 is discovered by high-throughput screening, which is able to suppress ferroptosis via lipid peroxide scavenging in vivo. Thus, molecular simulations, density functional theory (DFT) and variational transition-state theory with a small-curvature tunneling (SCT) coefficient are utilized to elucidate the detailed mechanisms of inactivation of a lipid peroxide radical by liproxstatin-1. H-atom abstracted from liproxstatin-1 by a CH3OO˙ radical occurs preferentially at the aromatic amine site (1'-NH) under thermodynamic and frontier molecular orbital analysis. The value of a calculated rate constant at 300 K is up to 6.38 × 103 M-1 S-1, indicating that the quantum tunneling effect is responsible for making a free radical trapping reaction more efficient by liproxstatin-1. The production of a liproxstatin-1 radical is easily regenerated to the active reduced form by ubiquinol in the body to avoid secondary damage by free radicals. A benzene ring and the higher HOMO energy are beneficial to enhance the lipid radical scavenging activity based on the structure-activity relationship study. Overall, the present results provide theoretical insights into the exploration of novel ferroptosis inhibitors.