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Issue 32, 2018
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Computational study of the mechanism of amide bond formation via CS2-releasing 1,3-acyl transfer

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Abstract

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.

Graphical abstract: Computational study of the mechanism of amide bond formation via CS2-releasing 1,3-acyl transfer

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Supplementary files

Article information


Submitted
07 Jun 2018
Accepted
24 Jul 2018
First published
25 Jul 2018

Org. Biomol. Chem., 2018,16, 5808-5815
Article type
Paper

Computational study of the mechanism of amide bond formation via CS2-releasing 1,3-acyl transfer

Y. Jiang, T. Liu, X. Sun, Z. Xu, X. Fan, L. Zhu and S. Bi, Org. Biomol. Chem., 2018, 16, 5808
DOI: 10.1039/C8OB01338A

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