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

Acylborons, as a growing class of boron reagents, were successfully applied to amide ligation and showed potential in chemoselective bioconjugation reactions in recent years. In this manuscript, a density functional theory (DFT) study was performed to investigate the mechanism of the amide formation between monofluoroacylboronates and hydroxylamines. An updated pathway was clarified herein, including water-assisted hemiaminal formation, pyridine ligand dissociation, elimination via a six-membered-ring transition state, and water-assisted tautomerization. The proposed mechanism was further examined by applying it to investigate the activation barriers of other monofluoroacylboronates, and the related calculations well reproduced the experimentally reported relative reactivities. On the basis of these results, we found that the ortho substitution of the pyridine ligand destabilizes the acylboron substrates and the hemiaminal intermediates by steric effects and thus lowers the energy dema

Cu-catalyzed alkylboration of alkenes with bis- (pinacolato)diboron ((Bpin)2) and alkyl halides provides a ligand-controlled regioselectivity-switchable method for the construction of complex boron-containing compounds. Here, we employed DFT methods to elucidate the mechanistic details of this reaction and the origin of the different regioselectivity induced by Xantphos and Cy-Xantphos. The calculation results reveal that the catalytic cycle mainly proceeds through the migratory insertion of alkenes on Cu-Bpin complex, the oxidative addition of alkyl halides, and the reductive elimination of a C@C bond. Meanwhile, the ratedetermining step is the oxidative addition of alkyl halides and the regioselectivity-determining step is the migratory insertion of alkenes. The bulky cyclohexyl group of Cy-Xantphos facilitates the approach of the substituents of alkenes to Bpin in the migratory insertion step and thus leads to the Markovnikov products. The less bulky phenyl group on Xantphos prefers

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.

A 1,1-hydroboration of alkynylgermanes with unique transGe/B stereochemistry under transition-metal-free conditions is reported. Mechanistic studies suggest that a pathway involving α boration followed by a stepwise 1,2-Ge/H shift on the intermediate structurally lies between an alkyne−Ge+ π complex and a typical vinyl cation. The resulting Ge/B bimetallic modules, along with a Ge*/Ge/B trimetallic variant, can be conveniently transformed into trisubstituted olefins through iterative divergent cross-coupling. This work demonstrates that incorporating metalloids into classical organic reactions may offer unconventional chemical selectivity and efficient synthetic applications.

Nickel/photoredox dual catalyzed cross-coupling of aryl halides with alkylboron compounds is one of the effective methodologies for the construction of C(sp2) C(sp3) bonds. Although elegant results have been achieved by using alkyl trifluoroborates as alkyl radical precursors, the generation of alkyl radicals from readily available alkyl boronic esters is still limited due to their high oxidation potential. We disclosed here that activation of alkyl boronic esters by MeOLi is highly efficient for the generation of alkyl radicals under photocatalysis conditions. The reaction featured with a wide substrate scope, high functional group tolerance, and late-stage modification of bioactive substances. In addition, the method was also successfully extended to alkyl boronic acids. Experimental and computational mechanistic studies indicated that the crosscoupling likely proceeds via a Ni(I)-catalyzed pathway.

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.

A 1,1-hydroboration of alkynylgermanes with unique transGe/B stereochemistry under transition-metal-free conditions is reported. Mechanistic studies suggest that a pathway involving α boration followed by a stepwise 1,2-Ge/H shift on the intermediate structurally lies between an alkyne−Ge+ π complex and a typical vinyl cation. The resulting Ge/B bimetallic modules, along with a Ge*/Ge/B trimetallic variant, can be conveniently transformed into trisubstituted olefins through iterative divergent cross-coupling. This work demonstrates that incorporating metalloids into classical organic reactions may offer unconventional chemical selectivity and efficient synthetic applications.

Nickel/photoredox dual catalyzed cross-coupling of aryl halides with alkylboron compounds is one of the effective methodologies for the construction of C(sp2) C(sp3) bonds. Although elegant results have been achieved by using alkyl trifluoroborates as alkyl radical precursors, the generation of alkyl radicals from readily available alkyl boronic esters is still limited due to their high oxidation potential. We disclosed here that activation of alkyl boronic esters by MeOLi is highly efficient for the generation of alkyl radicals under photocatalysis conditions. The reaction featured with a wide substrate scope, high functional group tolerance, and late-stage modification of bioactive substances. In addition, the method was also successfully extended to alkyl boronic acids. Experimental and computational mechanistic studies indicated that the crosscoupling likely proceeds via a Ni(I)-catalyzed pathway.