Mechanism and Rate-Determining Factors of Amide Bond Formation through Acyl Transfer of Mixed Carboxylic–Carbamic Anhydrides: A Computational Study

Abstract

Acyl transfer of in situ-generated mixed anhydrides is an important method for amide bond formation from short linkages with the easily removed byproduct CO. To improve our understanding of the inherently difficult acyl transfer hindered by the large ring strain, a density functional theory study was performed. The calculations indicate that the amidation of activated α-aminoesters and N-protected amino acids is more likely to proceed via the self-catalytic nucleophilic substitution of the two substrates and the subsequent 1,3-acyl transfer. By comparison, the mechanism involving 1,5-acyl transfer is less kinetically favored because of the slow homocoupling of activated α-aminoesters. Furthermore, we found that the detailed mechanism of 1,3-acyl transfer on the mixed carboxylic-carbamic anhydrides depends on the catalysts. Strong acidic catalysts and bifunctional catalysts both lead to stepwise pathways, but their elementary steps are different. Basic catalysts cause a concerted C-N bond formation/decarboxylation pathway. The calculations successfully explain the reported performances of different Brønsted-type catalysts and substrates, which validates the proposed mechanism and reveals the dependence of the reaction rates on the acid-base property of catalysts and the acidity of substrates.

Insights into the N-Heterocyclic Carbene (NHC)-Catalyzed Oxidative γ-C(sp3)–H Deprotonation of Alkylenals and Cascade [4 + 2] Cycloaddition with Alkenylisoxazoles

“…All calculations were performed by Gaussian 09 using density functional theory, which has been widely used to clarify the detailed mechanisms of the enzyme-catalyzed, organocatalytic, and transition metal-catalyzed reactions and other theoretical studies . The more successful applications can be found in the references reported by Houk, Tantillo, Sunoj, and so on. , The calculations were performed at the M06-2X level of DFT using the appropriate integral equation formalism polarizable continuum model (IEF-PCM) in a toluene or THF solvent.…”

Chemoselective N-acylation of indoles using thioesters as acyl source

“…As shown in Scheme 5 , the reaction starts with a base-promoted deprotonation of indole forming intermediate A . In the next step nucleophilic substitution between intermediate A and 2a occurs to give the desired N -acylindole product and CsSCH 3 as byproduct [ 19 – 21 ] ( Scheme 5 ).…”

N-Vinyl and N-Aryl Hydroxypyridinium Ions: Charge-Activated Catalysts with Electron-Withdrawing Groups

“…This led us to hypothesize that for the stronger acids the carbon–carbon bond-forming step in the Friedel–Crafts alkylation may no longer be rate-determining and that deprotonation at C3 to aromatize the indole and reform the catalyst could become the slow step (Scheme ). Such variations with changing pH are well-known and have been reported with organocatalysts but not for the Friedel–Crafts reaction of N -methylindole with trans -β-nitrostyrene even though it has been extensively used for benchmarking purposes.…”