The recognition of the biological activity of H2S has drawn much attention to the development of biocompatible H2S release reactions. Thiol-, particularly cysteine-triggered systems which mimic the enzymatic conversion of cysteine or homocysteine to H2S have been intensively reported recently. Herein, a density functional theory (DFT) study was performed to address the reaction mechanism of H2S release and potential amide bond formation from thionoesters and cysteine to gain deeper mechanistic insights. Three possible mechanisms were considered and we found that the one starting from the nucleophilic addition of the ionized mercapto of cysteine on thionoester to generate a dithioester intermediate (Path A) is kinetically favored over the others starting from the nucleophilic addition of the amine of cysteine to generate thionoamide intermediates (Paths B and C). Dithioester then undergoes intramolecular nucleophilic addition of an amine group and the rate-limiting water-assisted proton

The mechanism of ruthenium-catalyzed [4 + 1] annulation of benzamide and propargyl alcohol has been investigated by density functional theory calculations. The reaction undergoes N−H and C−H deprotonations by a concerted metalation-deprotonation mechanism to afford a 5- membered ruthenacyclic species, which then undergoes ring expansion by alkyne insertion to deliver a 7-membered ring intermediate. Our study focused on how the successive hydrogen migrations take place that remains unclear. The 1,2- proton migration and 1,3-proton transfer from O to C are successively finished by using acetate anion as a shuttle (a stepwise process). In contrast to the experimental proposal that the reaction experiences a Ru(II)−Ru(0)−Ru(II) transformation, our study unveiled a Ru(II)−Ru(IV)−Ru(II) transformation in the reaction. In addition, our calculations suggested that the EtO−N bond cleavage rather than the C−H activation is likely to be the rate-determining step for the entire reaction, which is

The combination of carbon monoxide with palladium chemistry has been demonstrated to be a promising tool for the synthesis of carbonyl compounds, and relative mechanistic studies are desirable to take this field one step further. In this manuscript, density functional theory calculations were performed to investigate the mechanism and origin of stereoselectivity of Pd-catalyzed cascade annulation of aryl iodide, alkene, and carbon monoxide to access the core of cephanolides B and C. It was found that the favorable mechanism proceeds via oxidative addition of Ar−I bond, migratory insertion of the CC bond, CO insertion into the Pd−(sp3) bond, Ar−H activation, and C(sp2)− C(sp2) reductive elimination. The Ar−H activation is the ratedetermining step and goes through an I-assisted outer-sphere concerted metalation−deprotonation mechanism. The CC bond insertion is irreversible and controls the stereoselectivity. In contrast, other two pathways involving the direct Ar−H activation after the

We discovered a cooperative gold/silver catalysis mechanism in the oxidative cross-coupling reaction between 1,2,4,5-tetrafluorobenzene and N-TIPS-indole, using DFT calculations. A silver(I)- catalyzed CMD mechanism is responsible for the C−H activation of 1,2,4,5-tetrafluorobenzene, and C−H acidity determines the chemoselectivity. A gold(III)-catalyzed SE2Ar mechanism is responsible for the C3−H activation of N-TIPS-indole, and arene nucleophilicity determines the chemo- and regioselectivity. The orthogonal chemoselectivity control provides a mechanistic guide for dual C−H activation reactions.

Cu-catalyzed aerobic epoxidation offers cost-effective access to epoxides, a class of versatile chemical building blocks. Herein, a computational mechanistic study was performed to investigate Cu-catalyzed aerobic epoxidation of tertiary allylic alcohols and ethers. In contrast to the previously proposed solvent−O2 cascade activation and the O2-activation mechanisms, a substrate− O2−solvent cascade activation mechanism was revealed for not only high-strained substrates but also low- and nonstrained substrates tested herein. Specifically, it involves an induction period for the in situ generation of the actual catalyst, a Cu(II)- alkylperoxide complex derived from solvent 1,4-dioxane. Three substrate-activation pathways, depending on the substrate strain and the presence or absence of an allylic hydroxyl group, were found to be operative in this period. For the actual catalytic epoxidation, the mononuclear Cu(II) pathway was found to be favored over the dinuclear Cu(III)-oxo pathway and

1,4-Dicarbonyl motifs are notoriously difficult to synthesize, yet the mechanistic underpinnings of conventional electron donor– acceptor (EDA) strategies remain contentious. Here, we unambiguously resolve this debate and disprove the hydrogenbonding EDA (H-EDA) mechanism for decarboxylative acylation of activated alkenes with α-keto acids, establishing a concerted proton-coupled electron transfer (PCET) pathway as the exclusive operative mechanism. A combination of spectroscopic, electrochemical, photophysical, and computational studies provides definitive evidence against EDA/H-EDA formation and electron transfer, while DFT calculations revealed an exceptionally low activation barrier for concerted PCET (ΔG‡/ΔE‡ = 5.1–11.6 kcal mol-1), consistent with high efficiency under mild conditions. This photocatalyst- and base-free visible-light protocol enables rapid assembly of diverse 1,4-dicarbonyl compounds, with broad substrate scope, exceptional functional group compatibility, and reli

Here, an unpresented non-C1 synthon function of CO2 is reported to facilitate electrochemical defluorination. The introduction of CO2 modulates the electron distribution of the radical anion intermediate generated through one-electron reduction, thereby weakening the reduction potential and facilitating reduction and defluorination. CO2 is released subsequently via spontaneous decarboxylation to complete its promotion role. The presented results shed light on a distinctive utilization of CO2, which may stimulate interest in developing non-C1 synthon functions of CO2.

A KOtBu-mediated C2-benzylation of quinoline N-oxides with benzylboronates under mild reaction conditions has been developed. The reaction shows broad scope for both of the quinoline N-oxides and benzylboronates, especially, secondary and tertiary benzylboronates are also compatible with this reaction. DFT calculations indicate that the reaction is promoted by the nucleophilic addition of KOtBu to boronate rather than the deprotonation of benzylic C−H bond with KOtBu.

Cu-catalyzed aerobic epoxidation offers cost-effective access to epoxides, a class of versatile chemical building blocks. Herein, a computational mechanistic study was performed to investigate Cu-catalyzed aerobic epoxidation of tertiary allylic alcohols and ethers. In contrast to the previously proposed solvent−O2 cascade activation and the O2-activation mechanisms, a substrate− O2−solvent cascade activation mechanism was revealed for not only high-strained substrates but also low- and nonstrained substrates tested herein. Specifically, it involves an induction period for the in situ generation of the actual catalyst, a Cu(II)- alkylperoxide complex derived from solvent 1,4-dioxane. Three substrate-activation pathways, depending on the substrate strain and the presence or absence of an allylic hydroxyl group, were found to be operative in this period. For the actual catalytic epoxidation, the mononuclear Cu(II) pathway was found to be favored over the dinuclear Cu(III)-oxo pathway and

1,4-Dicarbonyl motifs are notoriously difficult to synthesize, yet the mechanistic underpinnings of conventional electron donor– acceptor (EDA) strategies remain contentious. Here, we unambiguously resolve this debate and disprove the hydrogenbonding EDA (H-EDA) mechanism for decarboxylative acylation of activated alkenes with α-keto acids, establishing a concerted proton-coupled electron transfer (PCET) pathway as the exclusive operative mechanism. A combination of spectroscopic, electrochemical, photophysical, and computational studies provides definitive evidence against EDA/H-EDA formation and electron transfer, while DFT calculations revealed an exceptionally low activation barrier for concerted PCET (ΔG‡/ΔE‡ = 5.1–11.6 kcal mol-1), consistent with high efficiency under mild conditions. This photocatalyst- and base-free visible-light protocol enables rapid assembly of diverse 1,4-dicarbonyl compounds, with broad substrate scope, exceptional functional group compatibility, and reli

Here, an unpresented non-C1 synthon function of CO2 is reported to facilitate electrochemical defluorination. The introduction of CO2 modulates the electron distribution of the radical anion intermediate generated through one-electron reduction, thereby weakening the reduction potential and facilitating reduction and defluorination. CO2 is released subsequently via spontaneous decarboxylation to complete its promotion role. The presented results shed light on a distinctive utilization of CO2, which may stimulate interest in developing non-C1 synthon functions of CO2.

A KOtBu-mediated C2-benzylation of quinoline N-oxides with benzylboronates under mild reaction conditions has been developed. The reaction shows broad scope for both of the quinoline N-oxides and benzylboronates, especially, secondary and tertiary benzylboronates are also compatible with this reaction. DFT calculations indicate that the reaction is promoted by the nucleophilic addition of KOtBu to boronate rather than the deprotonation of benzylic C−H bond with KOtBu.