Theoretical Insights into N-Glycoside Bond Cleavage of 5-Carboxycytosine by Thymine DNA Glycosylase: A QM/MM Study.

Thymine DNA glycosylase (TDG)-mediated excision of 5-formylcytosine and 5-carboxylcytosine (5-caC) is a critical step in active DNA demethylation. Herein, we employed a combined quantum mechanics/molecular mechanics approach to investigate the reaction mechanism of TDG-catalyzed N-glycosidic bond cleavage of 5-caC. The calculated results show that TDG-catalyzed 5-caC excision follows a concerted (SN2) mechanism in which glycosidic bond dissociation is coupled with nucleophile attack. Protonation of the 5-caC anion contributes to the cleavage of the N-glycoside bond, in which the N3-protonated zwitterion and imino tautomers are more favorable than carboxyl-protonated amino tautomers. This is consistent with the experimental data. Furthermore, our results reveal that the configuration rearrangement process of the protonated 5-caC would lower the stability of the N-glycoside bond and substantially reduce the barrier height for the subsequent C1'-N1 bond cleavage. This should be attributed to the smaller electrostatic repulsion between the leaving base and the negative phosphate group as a result of the structural rearrangement.

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.

Cobalt-catalyzed radical-mediated carbon-carbon scission via a radical-type migratory insertion.

Migratory insertions of alkenes into metal-carbon (M-C) bonds are elementary steps in diverse catalytic processes. In the present work, a radical-type migratory insertion that involves concerted but asynchronous M-C homolysis and radical attack was revealed by computations. Inspired by the radical nature of the proposed migratory insertion, a distinct cobalt-catalyzed radical-mediated carbon-carbon (C-C) cleavage mechanism was proposed for alkylidenecyclopropanes (ACPs). This unique C-C activation is key to rationalizing the experimentally observed selectivity for the coupling between benzamides and ACPs. Furthermore, the C(sp2)-H activation in the coupling reaction occurs via the proton-coupled electron transfer (PCET) mechanism rather than the originally proposed concerted metalation-deprotonation (CMD) pathway. The ring opening strategy may stimulate further development and discovery of novel radical transformations.

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.

Charge-Shift Bonding in Xenon Hydrides: An NBO/NRT Investigation on HXeY···HX (Y = Cl, Br, I; X = OH, Cl, Br, I, CCH, CN) via H-Xe Blue-Shift Phenomena.

Noble-gas bonding represents curiosity. Some xenon hydrides, such as HXeY (Y = Cl, Br, I) and their hydrogen-bonded complexes HXeY···HX (Y = Cl, Br, I; X = OH, Cl, Br, I, CN, CCH), have been identified in matrixes by observing H-Xe frequencies or its monomer-to-complex blue shifts. However, the H-Xe bonding in HXeY is not yet completely understood. Previous theoretical studies provide two answers. The first one holds that it is a classical covalent bond, based on a single ionic structure H-Xe+ Y-. The second one holds that it is resonance bonding between H-Xe+ Y- and H- Xe+-Y. This study investigates the H-Xe bonding, via unusual blue-shifted phenomena, combined with some NBO/NRT calculations for chosen hydrogen-bonded complexes HXeY···HX (Y = Cl, Br, I; X = OH, Cl, Br, I, CN, CCH). This study provides new insights into the H-Xe bonding in HXeY. The H-Xe bond in HXeY is not a classical covalent bond. It is a charge-shift (CS) bond, a new class of electron-pair bonds, which is proposed by Shaik and Hiberty et al. The unusual blue shift in studied hydrogen-bonded complexes is its H-Xe CS bonding character in IR spectroscopy. It is expected that these studies on the H-Xe bonding and its IR spectroscopic property might assist the chemical community in accepting this new-class electron-pair bond concept.

Understanding the unique reactivity patterns of nickel/JoSPOphos manifold in the nickel-catalyzed enantioselective C-H cyclization of imidazoles.

The 3d transition metal-catalyzed enantioselective C-H functionalization provides a sustainable strategy for the construction of chiral molecules. A better understanding of the catalytic nature of the reactions and the factors controlling the enantioselectivity is important for rational design of more efficient systems. Herein, the mechanisms of Ni-catalyzed enantioselective C-H cyclization of imidazoles are investigated by density functional theory (DFT) calculations. Both the π-allyl nickel(ii)-promoted σ-complex-assisted metathesis (σ-CAM) and the nickel(0)-catalyzed oxidative addition (OA) mechanisms are disfavored. In addition to the typically proposed ligand-to-ligand hydrogen transfer (LLHT) mechanism, the reaction can also proceed via an unconventional σ-CAM mechanism that involves hydrogen transfer from the JoSPOphos ligand to the alkene through P-H oxidative addition/migratory insertion, C(sp2)-H activation via σ-CAM, and C-C reductive elimination. Importantly, computational results based on this new mechanism can indeed reproduce the experimentally observed enantioselectivities. Further, the catalytic activity of the π-allyl nickel(ii) complex can be rationalized by the regeneration of the active nickel(0) catalyst via a stepwise hydrogen transfer, which was confirmed by experimental studies. The calculations reveal several significant roles of the secondary phosphine oxide (SPO) unit in JoSPOphos during the reaction. The improved mechanistic understanding will enable design of novel enantioselective C-H transformations.

Mechanism and origins of ligand-controlled Pd(ii)-catalyzed regiodivergent carbonylation of alkynes.

Transition-metal-catalyzed carbonylation provides a useful approach to synthesize carbonyl-containing compounds and their derivatives. Controlling the regio-, chemo-, and stereoselectivity remains a significant challenge and is the key to the success of transformation. In the present study, we explored the mechanism and origins of the ligand-controlled regiodivergent carbonylation of alkynes with competitive nucleophilic amino and hydroxy groups by density functional theory (DFT) calculations. The proposed mechanism involves O(N)-cyclization, CO insertion, N-H(O-H) cleavage, C-N(C-O) reductive elimination and regeneration of the catalyst. The chemoselectivity is determined by cyclization. Instead of the originally proposed switch of competitive coordination sites, a new type of concerted deprotonation/cyclization model was proposed to rationalize the ligand-tuned chemoselectivity. The electron-deficient nitrogen-containing ligand promotes the flow of electrons during cyclization, and so it favors the O-cyclization/N-carbonylation pathway. However, sterically bulky and electron-rich phosphine controls the selectivity by a combination of electronic and steric effects. The improved mechanistic understanding will enable further design of selective transition-metal-catalyzed carbonylation.

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.

Fragment-centric topographic mapping method guides the understanding of ABCG2-inhibitor interactions.

Understanding protein-ligand interactions is crucial to drug discovery and design. However, it would be extremely difficult for the proteins which only have one available apo structure but multiple binding sites. To address this constraint, a fragment-centric topographic mapping method (AlphaSpace software) was employed to map out concave interaction pockets at the assigned protein region. These pockets are used as complementary spaces to screen the known inhibitors for this specific binding site and to guide the molecular docking pose selection as well as protein-ligand interaction analysis. By mapping the shape of central cavity surface, we have tested the strategy against a multi-drug resistant transmembrane protein-ABCG2 to assist in generating a pharmacophore model for its inhibitors that is based on the structure of apo. Classical molecular simulation and accelerated molecular simulation are used to verify the accuracy of inhibitor screening and binding pose selection. Our study not only has gained insight for the development of novel specific ABCG2 inhibitors, but also has provided a general strategy in describing protein-ligand interactions.

Reactions of the Lipid Hydroperoxides With Aminic Antioxidants: The Influence of Stereoelectronic and Resonance Effects on Hydrogen Atom Transfer.

Aminic radical-trapping antioxidants (RTAs), as one of the most important antioxidants, have not received sufficient attention yet. But, an increasing number of aminic RTAs have been identified as ferroptosis inhibitors in recent years, which can potentially mediate many pathological states including inflammation, cancer, neurodegenerative disease, as well as ocular and kidney degeneration. This highlights the importance of aminic RTAs in the field of medicine. Herein, we systematically explored the radical scavenging mechanism of aminic RTAs with a quantum chemical method, particularly emphasizing the role of stereoelectronic factors and resonance factors on the transfer of H-atom and the stability to one-electron oxidation. These theoretical results elucidate the diversity of free radical scavenging mechanisms for aminic RTAs, and has significant implications for the rational design of new aminic RTAs.

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.

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.

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.