The couplings of carboxylic acids and amines promoted by dichlorosilane derivatives provide a promising tool for amide synthesis and peptide coupling, in which an unprecedented mechanism was proposed for the amide bond formation process. To investigate this mechanistic proposal and enrich the understanding of this novel reaction, a theoretical study was conducted herein. The formation and interconversion of silylamine and silyl ester intermediates were calculated to be kinetically feasible under the experiment conditions. However, the subsequent amidation via direct elimination on the AcO-Si(L)(L′)-NHMe intermediate was found to involve a high energy barrier due to the formation of an unstable silanone. By contrast, the in situ generated salts can promote the amidation process by generating a silanol as the temporary product. Similarly, the anhydride formation mechanism can proceed via direct elimination or salt-assisted elimination on the AcO-Si(L)(L′)-OAc intermediate but is less fav

The Pd-catalyzed cross-coupling of aryl iodide, benzoic anhydride and ethyl acrylate provided a useful alternative to synthesize alkenylated aryl ketones with good selectivity and functional-group tolerance. In this manuscript, density functional theory (DFT) calculations were performed to address the detailed reaction mechanism. Computational results support the experimentally proposed Pd(0)–Pd(II)–Pd(IV) catalytic cycle and further clarify that the rate-determining step is the oxidative addition of benzoic anhydride, the regioselectivity-determining step is the migratory insertion of ethyl acrylate and the following β-H elimination determines the stereoselectivity. The regioselectivity can be attributed to the steric and electronic effect of ethyl acrylate and the stereoselectivity can be explained by the steric repulsion between the toluene moiety and the CO2Et moiety. Furthermore, we found that norbornene not only acts as the removable scaffold in Catellani–Lautens type reactions,

An enamide-based 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis (SPPS) method was recently disclosed for the synthesis of peptide thioesters. In this manuscript, density functional theory (DFT) calculations were performed to provide deeper mechanistic insights into this reaction. The calculation results clarified the detailed mechanisms of the relevant N-to-S acyl transfer and hydrolysis, the overall rate-determining step, the role of trifluoroacetic acid (TFA), as well as the influence of the stereo-configuration of amide bond and C]C bond on reaction rate.

Density functional theory (DFT) calculations have been performed to unravel the mechanism of Lewis-acid-induced Ni(cod)2-catalyzed selective coupling reactions of one diketene and two alkynes. Complex mixtures (unsymmetrical phenylacetic acid P1, symmetrical phenylacetic acid P2 and (3E)-4-ethyl-5-methylene-3- heptenoic acid P3) were obtained in the absence of Et2Al(OEt). P1 formation involves C(sp2)-O oxidative addition of diketene, twice alkyne insertion, intramolecular C=C insertion, acidolysis, and β-H elimination. For P2/P3 formation, the common key issue related to the C=C double bond cleavage of the substrate diketene was explored and found that it was accomplished via a four-membered-ring-closure/ four-membered-ring-opening process. And then, P2 was produced via the second alkyne insertion while P3 was accessed by a stoichiometric reaction with HCl. The Et2Al(OEt)-induced chemoselectivity was also probed. It is found that the Ni−O (from Al reagent) bonding facilitates the secon

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 thio-esters 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)

DFT calculations are carried out to investigate the hydroacylation mechanism based on copper-catalyzed A3- coupling tandem reaction of terminal alkynes, aldehydes and amines. The study reveals significant mechanistic differences between copper(I) and copper(II) catalysts. In the Cu(II)-catalyzed system, incorporation of a ligand is deemed necessary for facilitating reactivity, whereas no ancillary ligand is required in Cu(I) system. The ligand, through coordination with the Cu(II) center, stabilizes the key transition states and intermediates, resulting in a substantial reduction in the activation barrier. The ligand exhibits varying effect, with the order of activity being piperidine > pyridine > DMSO, correlating positively with the interaction energy between ligand and Cu complex. Additionally, the study sheds light on the pivotal roles played by the catalyst, ligand, base, and solvent DMSO in the reaction.

Developing applicable methods to forge linkages between sp3 and sp2-hydridized carbons is of great significance in drug discovery. We show here a new, Ni-catalyzed reductive crosscoupling reaction that forms Csp3−Csp2 bonds from aryl iodides and cyclic sulfonium salts. Notably, Csp3−Csp2 bonds can be forged selectively at the iodine-bearing carbon of bromo(iodo)arenes which is usually recognized as a huge challenge under the catalytic reductive cross-coupling (CRCC) conditions. Experimental and computational mechanistic studies support LNiIAr as an active species, while the untraditional anti-Markovnikov selective alkylation of asymmetric sulfonium salts is determined by the oxidative S-substitution of sulfonium salts with LNiIAr. This protocol further expands the range of alkyl electrophiles under the CRCC conditions and provides a new strategy for the construction of Csp3−Csp2 bonds.

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.

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 thio-esters 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)

DFT calculations are carried out to investigate the hydroacylation mechanism based on copper-catalyzed A3- coupling tandem reaction of terminal alkynes, aldehydes and amines. The study reveals significant mechanistic differences between copper(I) and copper(II) catalysts. In the Cu(II)-catalyzed system, incorporation of a ligand is deemed necessary for facilitating reactivity, whereas no ancillary ligand is required in Cu(I) system. The ligand, through coordination with the Cu(II) center, stabilizes the key transition states and intermediates, resulting in a substantial reduction in the activation barrier. The ligand exhibits varying effect, with the order of activity being piperidine > pyridine > DMSO, correlating positively with the interaction energy between ligand and Cu complex. Additionally, the study sheds light on the pivotal roles played by the catalyst, ligand, base, and solvent DMSO in the reaction.

Developing applicable methods to forge linkages between sp3 and sp2-hydridized carbons is of great significance in drug discovery. We show here a new, Ni-catalyzed reductive crosscoupling reaction that forms Csp3−Csp2 bonds from aryl iodides and cyclic sulfonium salts. Notably, Csp3−Csp2 bonds can be forged selectively at the iodine-bearing carbon of bromo(iodo)arenes which is usually recognized as a huge challenge under the catalytic reductive cross-coupling (CRCC) conditions. Experimental and computational mechanistic studies support LNiIAr as an active species, while the untraditional anti-Markovnikov selective alkylation of asymmetric sulfonium salts is determined by the oxidative S-substitution of sulfonium salts with LNiIAr. This protocol further expands the range of alkyl electrophiles under the CRCC conditions and provides a new strategy for the construction of Csp3−Csp2 bonds.

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.