羧酸和胺类酰胺形成的酰胺键形成机理的计算研究,Organic & Biomolecular Chemistry

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羧酸和胺类酰胺形成的酰胺键形成机理的计算研究
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2017-07-07 00:00:00 , DOI: 10.1039/c7ob01378g
Song-Lin Zhang _{1,

2,

3,

4,

5} , Hai-Xing Wan _{1,

2,

3,

4,

5} , Zhu-Qin Deng _{1,

2,

3,

4,

5}

Affiliation

本文报道了一项计算研究，阐明了由羧酸和胺形成酰胺反应介导的酰胺键的反应机理。已经详细研究了用于酰胺酰胺加氢羧化以及随后的胺加成胺加成胺解的机理。亚酰胺加氢羧化在动力学上是有利的，并且在热力学上是不可逆的，从而导致形成关键的低洼中间体CP1，该中间体具有双乙烯基乙烯基酰氧基和磺酰胺基团。提出了由胺对CP1进行氨解的方法是通过羧酸本身来催化的，该羧酸本身具有有利的双功能作用。在拟议的关键过渡态TS^氨解酸-iso2，胺在CP1的酰基上经历直接的亲核取代，以一致的方式取代烯醇盐基团，这是由于羧酸与胺和CP1两者的二次氢键结合而促进的。这些次级相互作用被认为可以增加胺的亲核性，并激活要被裂解的C_酰基-O键，从而稳定氨解的过渡态。协同的氨解机制与经典的逐步亲核酰基取代机制具有竞争性，后者的特征是依次加成胺来进行酰基/分子内质子转移/ C-O键裂解和关键的四面体中间体。基于机理模型，羧酸底物效应和更酸性CF的研究_以3 SO₃ H为催化剂与实验结果吻合良好，为机理模型提供了进一步的支持。羧酸底物的双功能催化作用可能在相关的酰胺键形成反应和肽形成化学中广泛发挥作用。

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A computational study on the mechanism of ynamide-mediated amide bond formation from carboxylic acids and amines

This paper reports a computational study elucidating the reaction mechanism for ynamide-mediated amide bond formation from carboxylic acids and amines. The mechanisms have been studied in detail for ynamide hydrocarboxylation and the subsequent aminolysis of the resulting adduct by an amine. Ynamide hydrocarboxylation is kinetically favorable and thermodynamically irreversible, resulting in the formation of a key low-lying intermediate CP1 featuring geminal vinylic acyloxy and sulfonamide groups. The aminolysis of CP1 by the amine is proposed to be catalyzed by the carboxylic acid itself that imparts favourable bifunctional effects. In the proposed key transition state TS^{aminolysis-acid}-iso2, the amine undergoes direct nucleophilic substitution at the acyl of CP1 to replace the enolate group in a concerted way, which is promoted by secondary hydrogen bonding of carboxylic acid with both the amine and CP1. These secondary interactions are suggested to increase the nucleophilicity of the amine and to activate the C_acyl–O bond to be cleaved, thereby stabilizing the aminolysis transition state. The concerted aminolysis mechanism is competitive with the classic stepwise nucleophilic acyl substitution mechanism that features sequential amine addition to acyl/intramolecular proton transfer/C–O bond cleavage and a key tetrahedral intermediate. Based on the mechanistic model, the carboxylic acid substrate effect and studies of more acidic CF₃SO₃H as the catalyst are in good agreement with the experimental observations, lending further support for the mechanistic model. The bifunctional catalytic effect of the carboxylic acid substrate may widely play a role in related amide bond-forming reactions and peptide formation chemistry.

更新日期：2017-08-02

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