Mechanism of Amide Bond Formation from Carboxylic Acids and Amines Promoted by 9-Silafluorenyl Dichloride Derivatives

5 years ago

Mechanism of Amide Bond Formation from Carboxylic Acids and Amines Promoted by 9-Silafluorenyl Dichloride Derivatives

Ling Zhu, Yuan-Ye Jiang, Xiaoping Man, Yujie Liang, Siwei Bi

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 favorable. Finally, we found that the intermolecular nucleophilic addition on the AcO-Si(L)(L′)-Cl intermediate is the most favorable mechanism among all the candidates considered. In this mechanism, carboxylic acids or bases can act as self-catalysts to promote the amide bond formation via hydrogen bonding, and the formation of the unstable silanone or anhydride is avoided.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b01637

DOI: 10.1021/acs.joc.7b01637