The Cl-initiated atmospheric oxidation mechanism of methyl isopropenyl ketone (MIK) has been investigated at the CCSD(T)/6-311++G(d,p)//MP2/6-311G(d,p) level of theory. Two reaction types initiated from Cl-addition and H-abstraction, respectively, and the key intermediates involved, IM1, IM2 (obtained from Cl-addition) and IM6 (obtained from H-abstraction), are presented and discussed. The calculated results supported the experimental results that Cl addition dominates the initial reactions of MIK with Cl atoms, and the most energetically favorable pathway is the Cl addition to the terminal carbon of C]C bond. Among the four proposed H abstraction processes, our study clearly indicated that the H-abstraction by Cl only takes place at the methyl linking to the internal alkenfinic carbon rather than the one at the methyl linking to the carbonyl carbon, which resolves the uncertainty of Habstraction encountered in experiment. In addition, the isomerization processes involved in the Cl add

Three new arylboronate ester protected amino acids and their on-resin deprotection methods have been developed. These useful building blocks were found to exhibit favorable chemical properties that are fully compatible with Fmoc strategy solid-phase peptide synthesis. Furthermore, the formation of over-oxidation side-product methionine was minimized by using N-methyl-N-phenylaniline N-oxide as the oxidizing reagent. Effective application of the three new amino acids for the synthesis of different types of peptidomimetics has been demonstrated by high-quality preparation of lipidated peptide MP-196 C-C8, on-resin head-to-tail cyclization of desotamide B, and lactam bridging of hPTHrP-(11–19) through a facile and metal-free procedure by standard Fmoc solid-phase peptide synthesis.

Oxaziridine-based redox sulfur imidation provides a breakthrough strategy for selective modification at methionine in proteins. The chemoselectivity of imidization (N-transfer) over oxidation (O-transfer) of the thioether functionality of methionine, and the modification selectivity of methionine over other amino acids, are the key features of this strategy. To elucidate the detailed reaction mechanism and the origin of the reported chemoselectivity, a theoretical investigation on the oxaziridine-based methionine modification reaction is reported. It is found that both the N-transfer and O-transfer pathways occur in a concerted mechanism. Distortion/interaction−activation strain model analysis indicates that the N-transfer chemoselectivity is mainly controlled by the interaction energy. Orbital and charge analysis further supports that the interaction energy resulting from the orbital interaction favors the N-transfer pathway at the early stage of the reaction. The calculated reactivit

Benzene ring functionalization provides useful alternatives to access indole derivatives and has received much attention in recent years. In this work, the mechanism of Pt(II)-catalyzed cyclization/alkynylation of benziodoxole with pyrrole homopropargylic ethers to generate C5-alkenylated indole derivatives has been studied with the aid of density functional theory (DFT) calculations. We found that fivemembered-ring cyclization/six-membered-ring cyclization is competitive in the formation of an indole skeleton. The following aromatization stage prefers the reaction sequence bicarbonate-assisted deprotonation at the C3a position, H2CO3-promoted methoxy elimination at the C7 position, and bicarbonate-assisted deprotonation at the C6 position. In the last alkynylation stage, the oxidative substitution mechanism assisted by H2CO3 is found to be favored over the previously proposed 1,2-iodo shift and oxidative addition. The overall ratedetermining step is oxidative substitution. Additionall

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.