School of Chemistry and Chemical Engineering, Qufu Normal University , Qufu 273165, People's Republic of China.
J Org Chem. 2018 Mar 2;83(5):2676-2685. doi: 10.1021/acs.joc.7b03107. Epub 2018 Feb 15.
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.
原位生成的混合酸酐的酰基转移是通过短链形成酰胺键的一种重要方法，副产物 CO 很容易去除。为了提高我们对大环应变阻碍的固有困难的酰基转移的理解，进行了密度泛函理论研究。计算表明，活化的α-氨基酸酯和 N-保护的氨基酸的酰胺化更有可能通过两种底物的自催化亲核取代和随后的 1,3-酰基转移进行。相比之下，由于活化的α-氨基酸酯的缓慢同偶联，涉及 1,5-酰基转移的机制在动力学上不太有利。此外，我们发现混合羧酸-氨基甲酸混合酸酐上的 1,3-酰基转移的详细机制取决于催化剂。强酸性催化剂和双功能催化剂都导致分步途径，但它们的基本步骤不同。碱性催化剂导致协同的 C-N 键形成/脱羧途径。计算成功解释了不同 Brønsted 型催化剂和底物的报道性能，验证了所提出的机制，并揭示了反应速率对催化剂的酸碱性质和底物的酸度的依赖性。
