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.

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.

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.

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.

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.

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.

A computational mechanistic study of Pd(ii)-catalyzed γ-C(sp3)-H olefination/cyclization of amines: the roles of bicarbonate and ligand effect.

The detailed mechanism of palladium-catalyzed γ-C(sp3)-H olefination/cyclization of triflyl-protected amines was investigated by density functional theory (DFT) calculations. The olefinated intermediate was initially formed in the first catalytic cycle involving ligand exchange, bicarbonate-assisted C(sp3)-H bond cleavage, alkene insertion and 'reductive ß-hydride elimination'. The following syn-addition and reductive elimination furnish the aza-Wacker product. The first step of reductive elimination is the rate-determining step. The mechanism unveils the important roles of bicarbonate: aiding the C-H activation and abstracting the ß-proton in the second step of reductive elimination. The parallel bridging mode in the metal-olefin intermediate facilitates the syn-addition, explaining the experimentally observed stereoselectivity. The effect of the monodentate pyridine-based ligands is also discussed.

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.

Tandem Synthesis of Pyrrolo[2,3-b]quinolones via Cadogen-Type Reaction.

A tandem [3 + 2] cycloaddition/reductive cyclization of nitrochalcones with activated methylene isocyanides for the efficient synthesis of pyrrolo[2,3-b]quinolones is reported. In this reaction, the in situ generated dihydropyrroline acts as the internal reductant to convert the nitro into an electrophilic nitroso group, which undergoes subsequent C-N bond formation. Transition-metal-free, simple experimental procedure and ready accessibility of starting materials characterize the present transformation.

The underlying factors controlling the Pd-catalyzed site-selective alkenylation of aliphatic amines.

The Pd(ii)-catalyzed site-selective δ-C(sp3)-H alkenylation in the presence of more accessible γ-C(sp3)-H bonds is investigated by DFT calculations. Migratory insertion is found to be both the rate-limiting and the selectivity-determining step. The origin of the unusual site-selectivity is originally attributed to the different steric repulsion between the alkyne and palladacycle; however, our theoretical results reveal that the inherent electronic effect instead of steric repulsion determines the site-selectivity. The proposal is further validated by model calculations involving the less sterically hindered 1,2-dimethyl acetylene and acetylene. In addition, a novel HCO3--assisted N-H activation mechanism is reported, and the origin of the regioselectivity of an unsymmetrical alkyne is also studied.

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.

Computational Mechanistic Study of Redox-Neutral Rh(III)-Catalyzed C-H Activation Reactions of Arylnitrones with Alkynes: Role of Noncovalent Interactions in Controlling Selectivity.

The mechanism of redox-neutral Rh(III)-catalyzed coupling reactions of arylnitrones with alkynes was investigated by density functional theory (DFT) calculations. The free energy profiles associated with the catalytic cycle, involving C(sp2)-H activation, insertion of alkyne, transfer of O atom, cyclization and protodemetalation, are presented and analyzed. An overwhelming preference for alkyne insertion into Rh-C over Rh-O is observed among all pathways, and the most favorable route is determined. The pivalate-assisted C-H activation step is turnover-limiting, and the cyclization step determines the diastereoselectivity of the reaction, with the stereoselectivity arising mainly from the difference of noncovalent interactions in key transition states. The detailed mechanism of O atom transfer, RhIII-RhI-RhIII versus RhIII-RhV-RhIII cycle, is discussed.

Organometallic coordination polymers generated from bent Bis(acetylenylphenyl)oxadiazole ligands and Ag(I) salts.

Two new bent oxadiazole bridging benzoacetylene ligands 2,5-bis(4-ethynylphenyl)-1,3,4-oxadiazole (L9) and 2,5-bis(3-ethynylphenyl)-1,3,4-oxadiazole (L10) were synthesized. The coordination chemistry of them with various inorganic Ag(I) salts has been investigated. Seven new coordination polymers were prepared by solution reactions and fully characterized by infrared spectroscopy, elemental analysis, and single-crystal X-ray diffraction. [Ag2(L9)](SO3CF3)2 (1) (triclinic, P; a =10.292(4), b = 10.794(4), c = 11.399(5) A; alpha = 98.894(5), beta = 102.360(6), gamma = 90.319(5) degrees ; Z = 2), [Ag(L9)]SbF6 (2) (orthorhombic, Cmca; a = 19.059(9), b = 12.922(6), c = 15.609(7) A; Z = 8), [Ag(L9)]BF4 (3) (orthorhombic, Cmca; a = 19.128(3), b = 12.6042(18), c = 28.003(4) A; Z = 16), [Ag(L9)]ClO4 (4) (monoclinic, P2(1)/c; a = 8.5153(16), b = 19.722(4), c = 10.320(2) A; beta = 105.307(3) degrees ; Z = 4), [Ag(L10)]SO3CF3 (5) (triclinic, P; a = 9.0605(13), b = 10.4956(15), c = 10.8085(16) A; alpha = 101.666(2), beta = 109.269(2), gamma = 100.944(2) degrees ; Z = 2), [Ag(L10)(H2O)(0.5)]BF4.0.5H2O (6) (monoclinic, C2/m; a = 32.180(6), b = 17.027(3), c = 8.1453(15) A; beta = 102.541(3) degrees ; Z = 8), and {[Ag2(L10)2(H2O)](ClO4)2}.o-xylene (7) (monoclinic, P2(1)/c; a = 8.1460(10), b = 17.326(2), c = 30.345(4) A; beta = 97.71 degrees ; Z = 4) were obtained by the combination of L9 and L10 with various Ag(I) salts in a benzene/methylene chloride mixed solvent system. In addition, the luminescent and electrical conductive properties of these new compounds were investigated.