Computational Study on Flavin-Catalyzed Aerobic Dioxygenation of Alkenyl Thioesters: Decomposition of Anionic Peroxides.

Flavin-dependent catalysts are widely applied to aerobic monooxygenation/oxidation reactions. In contrast, flavin-catalyzed aerobic dioxygenation reactions exhibit higher atomic economy but are less reported, not to mention the relevant mechanistic studies. Herein, a density functional theory study on flavin-catalyzed aerobic epoxidation-oxygenolysis of alkenyl thioesters was performed for the first time. Different from the previous mechanistic proposal, a pathway featuring two catalytic stages, monoanionic flavin-C(4a)-peroxide/oxide intermediates, and a reverse reaction sequence (epoxidation goes prior to oxygenolysis) was revealed. In comparison, the pathways involving dianionic flavin catalysts, monoanionic flavin-N(5)-(hydro)peroxide/C(10a)-peroxide, or neutral flavin-C(4a)-hydroperoxide/hydroxide/N(5)-oxide, and the pathways where oxygenolysis goes prior to epoxidation are less favored. Epoxidation goes through intramolecular substitution of the O-O bond of anionic flavin-C(4a)-peroxide by ß-carbon, while the resulting flavin-C(4a)-oxide accomplishes the oxygenolysis. Furthermore, two other reaction modes, i.e., concerted O-O cleavage/1,2-shift of α-substituents and dyotropic rearrangement were discovered for the decomposition of other anionic peroxides, and preliminary rules were summarized for understanding the chemoselectivity for this process. This study sheds light on the different reaction features of numerous flavin-dioxygen derivatives, providing deeper insights into flavin-catalyzed dioxygenation reactions, and is expected to inspire experimental design based on unconventional anionic peroxides.

Targeted metabolomics study of fatty-acid metabolism in lean metabolic-associated fatty liver disease patients.

BACKGROUND: The annual incidence of metabolic-associated fatty liver disease (MAFLD) in China has been increasing and is often overlooked owing to its insidious characteristics. Approximately 50% of the patients have a normal weight or are not obese. They are said to have lean-type MAFLD, and few studies of such patients are available. Because MAFLD is associated with abnormal lipid metabolism, lipid-targeted metabolomics was used in this study to provide experimental evidence for early diagnosis and pathogenesis. AIM: To investigate the serum fatty-acid metabolic characteristics in lean-type MAFLD patients using targeted serum metabolomic technology. METHODS: Between January and June 2022, serum samples were collected from MAFLD patients and healthy individuals who were treated at Shanghai Putuo District Central Hospital for serum metabolomics analysis. Principal component analysis and orthogonal partial least squares-discriminant analysis models were developed, and univariate analysis was used to screen for biomarkers of lean-type MAFLD and analyze metabolic pathways. UPLC-Q-Orbitrap/MS content determination was used to determine serum palmitic acid (PA), oleic acid (OA), linoleic acid (LA), and arachidonic acid (AA) levels in lean-type MAFLD patients. RESULTS: Urea nitrogen and uric acid levels were higher in lean-type MAFLD patients than in healthy individuals (P < 0.05). Alanine transaminase and cholinesterase levels were higher in lean-type MAFLD patients than in healthy individuals (P < 0.01). The expression of high-density lipoprotein and apolipoprotein A-1 were lower in lean-type MAFLD patients than in healthy individuals (P < 0.05) and the expression of triglycerides and fasting blood glucose were increased (P < 0.01). A total of 65 biomarkers that affected the synthesis and metabolism of fatty acids were found with P < 0.05 and variable importance in projection > 1". The levels of PA, OA, LA, and AA were significantly increased compared with healthy individuals. CONCLUSION: The metabolic profiles of lean-type MAFLD patients and healthy participants differed significantly, yielding 65 identified biomarkers. PA, OA, LA, and AA exhibited the most significant changes, offering valuable clinical guidance for prevention and treatment of lean-type MAFLD.

CO2 Transient Promotion Function Enabled the Selective Electrochemical Transformation of Imines.

An unprecedented transient promotion function (TPF) of CO2 in the electrochemical hydrogenation/deuteration of imines (especially α-iminonitriles) is reported. The TPF influence of CO2 results from the introduction of CO2 that disperses the negative charges of the imine radical anion intermediate. The resulting redistribution of electrons leads to a lower reduction potential of the CO2-substituted imine radical anion and thus facilitates the succeeding one-electron reduction. CO2 is finally released via spontaneous decarboxylation to complete the transient promotion process.

Highly active, ultra-low loading single-atom iron catalysts for catalytic transfer hydrogenation.

Highly effective and selective noble metal-free catalysts attract significant attention. Here, a single-atom iron catalyst is fabricated by saturated adsorption of trace iron onto zeolitic imidazolate framework-8 (ZIF-8) followed by pyrolysis. Its performance toward catalytic transfer hydrogenation of furfural is comparable to state-of-the-art catalysts and up to four orders higher than other Fe catalysts. Isotopic labeling experiments demonstrate an intermolecular hydride transfer mechanism. First principles simulations, spectroscopic calculations and experiments, and kinetic correlations reveal that the synthesis creates pyrrolic Fe(II)-plN3 as the active center whose flexibility manifested by being pulled out of the plane, enabled by defects, is crucial for collocating the reagents and allowing the chemistry to proceed. The catalyst catalyzes chemoselectively several substrates and possesses a unique trait whereby the chemistry is hindered for more acidic substrates than the hydrogen donors. This work paves the way toward noble-metal free single-atom catalysts for important chemical reactions.

Recent advances in computational studies on Cu-catalyzed aerobic reactions: cooperation of copper catalysts and dioxygen.

O2, one of the ideal oxidants, suffers from low solubility, low oxidizability, low selectivity and a triplet ground state when applied in organic synthesis. Biomimetic copper catalysis has been demonstrated to be a powerful method for activating and transforming O2 to conduct aerobic reactions for a long time. On the other hand, the structures of Cu-O2 complexes are complex with diverse downstream reactions, whereas active copper intermediates were rarely identified by experimental methods, making the mechanisms of many Cu-catalyzed aerobic reactions far from clear. In this context, computational studies emerged as an effective alternative to mechanistic studies on Cu-catalyzed aerobic reactions. This review introduces the relevant computational studies since 2012, focusing on showing the cooperation of copper catalysts and O2 in dehydrogenation, oxygenation and coupling reactions.

Late-Stage Diversification of Peptides via Pd-Catalyzed Site-Selective δ-C(sp2)-H Fluorination and Amination.

Site-selective C-H fluorination is an attractive strategy for directly transforming inert C-H bonds into C-F bonds, yet it remains a significant challenge. Herein, we have developed an efficient and versatile strategy for site-selective fluorination and amination of phenylalanine-containing peptides via late-stage Pd-catalyzed δ-C(sp2)-H activation, providing a valuable tool for the in situ synthesis of fluorinated indoline scaffolds within peptides.

Mechanistic Insights Into the Rhodium-Catalyzed C-H Alkenylation/Directing Group Migration and [3+2] Annulation: A DFT Study.

The mechanism of the rhodium-catalyzed C-H alkenylation/directing group migration and [3+2] annulation of N-aminocarbonylindoles with 1,3-diynes has been investigated with DFT calculations. On the basis of mechanistic studies, we mainly focus on the regioselectivity of 1,3-diyne inserting into the Rh-C bond and the N-aminocarbonyl directing group migration involved in the reactions. Our theoretical study uncovers that the directing group migration undergoes a stepwise ß-N elimination and isocyanate reinsertion process. As studied in this work, this finding is also applicable to other relevant reactions. Additionally, the role of Na+ versus Cs+ involved in the [3+2] cyclization reaction is also probed.

Transient Stabilization Effect of CO2 in the Electrochemical Hydrogenation of Azo Compounds and the Reductive Coupling of α-Ketoesters.

The carbon dioxide (CO2 ) capture and utilization has attracted a great attention in organic synthesis. Herein, an unpresented transient stabilization effect (TSE) of CO2 is disclosed and well applied to the electrochemical hydrogenation of azo compounds to hydrazine derivatives. Mechanistic experiments and computational studies imply that CO2 can capture azo radical anion intermediates to protect the hydrogenation from potential degradation reactions, and is finally released through decarboxylation. The promotion effect of CO2 was further demonstrated to work in the preliminary study of electrochemical reductive coupling of α-ketoesters to vicinal diol derivatives. For the electrochemical reductive reactions mentioned above, CO2 is indispensable. The presented results shed light on a different usage of CO2 and could inspire novel experimental design by using CO2 as a transient protecting group.

Computational Study Revealing the Mechanistic Origin of Distinct Performances of P(O)-H/OH Compounds in Palladium-Catalyzed Hydrophosphorylation of Terminal Alkynes: Switchable Mechanisms and Potential Side Reactions.

Pd-catalyzed hydrophosphorylation of alkynes with P(O)-H compounds provided atom-economical and oxidant-free access to alkenylphosphoryl compounds. Nevertheless, the applicable P(O)-H substrates were limited to those without a hydroxyl group except H2P(O)OH. It is also puzzling that Ph2P(O)OH could co-catalyze the reaction to improve Markovnikov selectivity. Herein, a computational study was conducted to elucidate the mechanistic origin of the phenomena described above. It was found that switchable mechanisms influenced by the acidity of substrates and co-catalysts operate in hydrophosphorylation. In addition, potential side reactions caused by the protonation of PdII-alkenyl intermediates with P(O)-OH species were revealed. The regeneration of an active Pd(0) catalyst from the resulting Pd(II) complexes is remarkably slower than the hydrophosphonylation, while the downstream reactions, if possible, would lead to phosphorus 2-pyrone. Further analysis indicated that the side reactions could be suppressed by utilizing bulky substrates or ligands or by decreasing the concentration of P(O)-OH species. The presented switchable mechanisms and side reactions shed light on the co-transformations of P(O)-H and P-OH compounds in the Pd-catalyzed hydrophosphorylation of alkynes, clarify the origin of the distinct performances of P(O)-H/OH compounds, and provide theoretical clues for expanding the applicable substrate scope of hydrophosphorylation and synthesizing cyclic alkenylphosphoryl compounds.

Ligand-Controlled Regiodivergent Cyanoboration of Internal Allenes by Copper Catalysis.

The first copper-catalyzed regiodivergent cyanoboration of internal allenes with B2 pin2 (bis(pinacolato)diboron) and NCTS (N-cyano-N-phenyl-p-toluenesulfonamide) derivatives is reported. The ß,γ- and α,ß-cyanoborylated products were synthesized with high regio- and stereo-selectivity. Computational studies revealed that nucleophilic addition of allylcopper or related intermediates on cyanation reagent is the regio- and stereo-determining step, while transmetalation with B2 pin2 is the rate-determining step. The nucleophilic addition step proceeds via inner-sphere mechanism in the CuI /P(o-tol)3 and CuI /Xantphos (P(o-tol)3 =tris(o-methylphenyl)phosphine, Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) catalytic systems and via outer-sphere mechanism in the CuII /Xantphos catalytic system, respectively.

Insights into α-Alkynylation and α-Allenylation of Aldehydes under the Synergisitic Catalysis of Gold/Amine: A DFT Study.

A mechanistic investigation of α-alkynylation and α-allenylation of aldehydes under the synergistic catalysis of AuCl/amine was performed using density functional theory (DFT) calculations. For such a reaction that delivers two products, this study reveals that the reaction undergoes such a mechanistic mode: reactants → alkynyl product → allenyl product, implying that the allenyl product cannot be obtained directly from reactants. The product ratio obtained experimentally was rationalized based on the computed results that both products can reversibly interconvert with AuCl as the catalyst and with N-containing Lewis bases as additives such as 4,5-diazafluorenone. For the relative stability of alkynyl versus allenyl compounds, unsaturated substituents are found to favor the allenyl compounds.

Distinctive Mechanistic Scenarios and Substituent Effects of Gold(I) versus Copper(I) Catalysis for Hydroacylation of Terminal Alkynes with Glyoxal Derivatives.

Density functional theory (DFT) calculations have been conducted to study the mechanisms, substituent effects, and the role of bases in Au- and Cu-catalyzed hydroacylation of terminal alkyne with glyoxal derivatives. The two reactions, despite being catalyzed by the same group of transition metals, follow distinctive reaction mechanisms. Through the detailed DFT calculations, insights into the mechanisms are obtained, and the substituent effects and the role of the bases are understood.

Noncovalent Interaction- and Steric Effect-Controlled Regiodivergent Selectivity in Dimeric Manganese-Catalyzed Hydroarylation of Internal Alkynes: A Computational Study.

Selective hydroarylation of internal alkynes catalyzed by a dimeric manganese complex provides a powerful strategy for the construction of multisubstituted alkenes. In this work, density functional theory (DFT) calculations and experimental studies were carried out to explore the mechanism and origin of regiodivergent hydroarylation of internal alkynes reported by our group. The results demonstrate that this reaction first proceeds via a bimetallic mechanism to generate the active catalyst that subsequently undergoes a monometallic mechanism to run the three-stage catalytic cycle: alkyne migratory insertion, protonation, and active catalyst regeneration. Alkyne migratory insertion is considered as the regioselectivity-determining step. Energy decomposition analyses on insertion transition states suggest that the interaction between the substrate and catalyst is mainly responsible for the observed exclusive γ-selectivity of 1a, while the deformation of these two sections induced by the sterically hindered phenyl group and aryl group accounts for the complete ß-position arylation of 1e. The decrease of γ-selectivity with the regulation of a tertiary alcohol motif in 1a originates from the reduced noncovalent interaction. The computational results provide important insights into the origin of regiodivergent selectivities and useful information for further designing and adjusting the strategy in Mn-catalyzed alkyne hydroarylation.

Palladium-Catalyzed Regioselective B(3,4)-H Acyloxylation of o-Carboranes.

We disclose herein an efficient regioselective B(3,4)-H activation via a ligand strategy, affording B(3)-monoacyloxylated and B(3,4)-diacyloxylated o-carboranes. The identification of amino acid and phosphoric acid ligands is crucial for the success of B(3)-mono- and B(3,4)-diacyloxylation, respectively. This ligand approach is compatible with a broad range of carboxylic acids. The functionalization of complex drug molecules is demonstrated. Other acyloxyl sources, including sodium benzoate, benzoic anhydride, and iodobenzene diacetate, are also tolerated.

Regioselective Synthesis of Tetrasubstituted Benzenes via Co-Catalyzed Cycloaddition of Alkynyl Ketones and 2-Acetylpyridines.

A Co(II)-catalyzed cycloaddition reaction of alkynyl ketones and 2-acetylpyridines using 2,2'-bipyridine as the ligand has been developed. These reactions have been realized through Co-catalyzed reductive coupling of two molecules of 2-acetylpyridine followed by regioselective insertion of the alkynone. It is the first example of regioselective cyclotrimerization of one molecule of alkyne and two molecules of monoketone to polysubstituted benzene derivatives in good to excellent yields. A mechanism involving the formation of a cobaltacyclopentane via homocoupling of 2-acetylpyridines is proposed, and it is supported by the DFT calculations.

Double-Regiodetermining-Stages Mechanistic Model Explaining the Regioselectivity of Pd-Catalyzed Hydroaminocarbonylation of Alkenes with Carbon Monoxide and Ammonium Chloride.

Pd-catalyzed hydroaminocarbonylation (HAC) of alkenes with CO and NH4Cl enables atom-economic and regiodivergent synthesis of primary amides, but the origin of regioselectivity was incorrectly interpreted in previous computational studies. A density functional theory study was performed herein to investigate the mechanism. Different from the previous proposals, both alkene insertion and aminolysis were found to be potential regioselectivity-determining stages. In the alkene insertion stage, 2,1-insertion is generally faster than 1,2-insertion irrespective of neutral or cationic pathways for both P(tBu)3 and xantphos. Such selectivity results from the unconventional proton-like hydrogen of the Pd-H bond in alkene insertion transition states. For less bulky alkenes, aminolysis with P(tBu)3 shows low selectivity, while linear selectivity dominates in this stage with xantphos due to a stronger repulsion between xantphos and branched acyl ligands. It was further revealed that the less-mentioned CO concentration and solvents also influence the regioselectivity by adjusting the relative feasibilities of CO-involved steps and NH3 release from ammonium chloride, respectively. The presented double-regiodetermining-stages mechanistic model associated with the effects of ligands, CO concentration, and solvents well reproduced the experimental selectivity to prove its validity and illuminated new perspectives for the regioselectivity control of HAC reactions.

Mechanism and Origin of Chemoselectivity of Ru-Catalyzed Cross-Coupling of Secondary Alcohols to ß-Disubstituted Ketones.

Ru-catalyzed cross-coupling of secondary alcohols with only byproducts H2 and H2O provides a green synthetic strategy to prepare ß-disubstituted ketones. Density functional theory (DFT) calculations were performed with the coupling of 1-phenylethanol and cyclohexanol as a model reaction to gain deeper mechanistic insights herein. The mechanistic details of the main reaction and the key steps of possible side reactions were clarified, and the obtained results are consistent with reported selectivity. Hydrogenation of α,ß-unsaturated ketones and dehydrogenation of ruthenium hydride intermediate are direct chemoselectivity-determining stages. The hydrogenation via 1,4-addition generates more stable intermediates, being favored over that via 1,2-addition, and thus avoids the formation of alkene products. The conjugation and π-π stacking effects of phenyl and the weak electronic effect of alkyls explain the dominance of specific ketone products in the hydrogenation stage. Hydrogenation of ketone products is kinetically operative but not exergonic enough to stop the irreversible dihydrogen release in an open reaction system, and thus alcohol products are absent. Furthermore, water evaporation in aldol condensation is found to be a double-edged sword, as it can accelerate the hydrogenation stage to prevent α,ß-unsaturated ketones from being the main products but decrease the selectivity therein from thermodynamics overall.

Density Functional Theory Study on the Mechanism of Iridium-Catalyzed Benzylamine ortho C-H Alkenylation with Ethyl Acrylate.

Iridium-catalyzed oxidative o-alkenylation of benzylamines with acrylates was enabled by the directing group pentafluorobenzoyl (PFB). Density functional theory calculations were performed to explore the detailed reaction mechanism. The calculated results reveal that N-deprotonation prior to C-H activation is favored over direct C-H activation. Moreover, C-H activation is reversible and not the rate-determining step, which has been supported by the experimental observation. The regio- and stereoselectivity of ethyl acrylate insertion are controlled by the steric effect and the carbon atom with a larger orbital coefficient of the π* antibonding orbital in the nucleophilic attack, respectively. The migratory insertion of ethyl acrylate is computationally found to be rate-determining for the whole catalytic cycle. Finally, the seven-membered ring intermediate IM11 undergoes a sequential N-protonation and ß-H elimination with the assistance of AcOH, rather than ß-H elimination and reductive elimination proposed experimentally, to afford the o-alkenylated product. IM11 is unable to directly cyclize through C-N reductive elimination because both sp3-hybridized N and C atoms are unfavorable for N-C reductive elimination. The origin of the directing group PFB preventing the product and intermediates undergoing aza-Michael addition has been explained.

Mechanism and Origin of Ligand-Controlled Chemo- and Regioselectivities in Palladium-Catalyzed Methoxycarbonylation of Alkynes.

Pd-catalyzed alkoxycarbonylation of alkynes provided a redox-neutral method to selectively access branched/linear α,ß-unsaturated monoesters and 1,4-dicarboxylic acid diesters. Herein, a systematic computational study was performed to elucidate the mechanism and origin of ligand-controlled chemo- and regioselectivities. It is found that the catalytic cycle, including hydrometallation, carbon monoxide insertion, and methanolysis, is more likely than that involving palladium alkoxycarbonyl intermediates. Both hydrometallation and methanolysis stages are important to determine the chemo- and regioselectivities. Hydrometallation proceeds via anti-Markovnikov-selective migratory insertion or Markovnikov-selective ligand-participated electrophilic addition. A flexible bidentate phosphine ligand slows down migratory insertion due to the stronger trans effect of the CO ligand but accelerates the ligand-participated electrophilic addition by adopting better orbital orientations. On the other hand, a ligand-participated mechanism and an unrevealed mechanism involving ketene intermediates can promote methanolysis, whereas ligands with large bite angles or bulky substituents are detrimental to methanolysis. On the basis of these mechanistic foundations, the influence of the flexibility, basicity, bite angle, and steric hindrance of ligands on chemo- and regioselectivities was clarified. The present study provided more universal and deeper mechanistic insights into Pd-catalyzed alkoxycarbonylation reactions and shed light on the superior regulation performance of the bifunctional pyridyl-containing phosphine ligands.

Mechanistic Insights into the Chemo- and Regio-Selective B(C6F5)3 Catalyzed C-H Functionalization of Phenols with Diazoesters.

The Lewis acidic B(C6F5)3 was recently demonstrated to be effective for the C-H alkylation of phenols with diazoesters. The method avoids the general hydroxyl activation in transition-metal catalysis. Ortho-selective C-H alkylation occurs regardless of potential para-selective C-H alkylation and O-H alkylation. In the present study, a theoretical calculation was carried out to elucidate the reaction mechanism and the origin of chemo- and regio-selectivity. It is found that the previously proposed B(C6F5)3/N or B(C6F5)3/C bonding-involved mechanisms are not favorable, and a more favored one involves the B(C6F5)3/C═O bonding, rate-determining N2 elimination, selectivity-determining electrophilic attack, and proton transfer steps. Meanwhile, the new mechanism is consistent with KIE and competition experiments. The facility of the mechanism is attributed to two factors. First, the B(C6F5)3/C═O bonding reduces the steric hindrance during electrophilic attack. Second, the bonding forms the conjugated system by which the LUMO energy is reduced via the electron-withdrawing B(C6F5)3. The ortho-selectivity resulted from the greater ortho-C-C (than para-C-C) interaction and the O-H···O and O-H···F hydrogen-bond interaction during electrophilic attack. The greater C-C (than C-O) interaction and the π-π stacking between the benzene rings of phenol and diazoester concerted contribute to the chemo-selective C-H alkylation.