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.
A novel boron ester-catalyzed amidation reaction of carboxylic acids and amines with unprecedented functional group tolerance was recently reported. To gain deeper insights into this reaction, a computational study with density functional theory methods was performed in this manuscript. Calculations indicate that the amidation starts with the condensation of carboxylic acids with the boron ester catalyst. The resulting monoacyloxylated boron species further undergoes the carboxylic acid-assisted nucleophilic addition with amines to generate the amide product and a monohydroxyboron species. The condensation of the carboxylic acid with the monohydroxyboron species with the assistance of an amine regenerates monoacyloxylated boron species to finish the catalytic cycle. The rate-determining step is catalyst regeneration and the amine-coordinated monohydroxyboron species is the resting state in the catalytic cycle. The present results are consistent with the previous NMR study and the observed reaction orders of catalyst and substrates; it is expected to benefit further reaction optimization.
Reactions of thiocarboxylic acids and dithiocarbamate-terminal amines provide a linker-traceless method for amide bond formation under mild conditions, whereas the reaction mechanism is not clear. A systematic study was performed herein with density functional theory (DFT) calculations to elucidate the detailed mechanism, the substitution effect on the proposed CS2-releasing 1,3-acyl transfer and the differences between CS2- and CO2-releasing 1,3-acyl transfer. Relevant results indicate that this type of reaction proceeds via the nucleophilic addition of an in situ generated dithiocarbamic acid on thiocarboxylic acid, H2S elimination, rate-determining 1,3-acyl transfer and CS2 release. For the generation of secondary amides via the 1,3-acyl transfer, a thiocarboxylic acid- or dithiocarbamic acid-assisted pathway, in which both the carbonyl group and amide nitrogen are activated, is the most favored. For the generation of tertiary amides, MeOH-assisted carbonyl-activation is the most favorable pathway. N,N-Dialkyl substitution of the mixed anhydride intermediate promotes the 1,3-acyl transfer by the steric effect. In contrast, N-phenyl substitution and using thiobenzoic acid as a substrate slow down 1,3-acyl transfer by both the conjugation effect and steric effect. Furthermore, CS2-releasing 1,3-acyl transfer was found to be favored over CO2-releasing 1,3-acyl transfer in the aspects of both kinetics and thermodynamics mainly because the S-COR bond is weaker than the O-COR bond.
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