Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, Vienna, 1090, Austria.
Department of Chemistry, University of Torino, Via P. Giuria 7, Torino, 10125, Italy.
Chemistry. 2020 Dec 9;26(69):16246-16250. doi: 10.1002/chem.202003213. Epub 2020 Nov 11.
The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to n →π* conjugation. In this study, we report electrophilicity scale by exploiting O NMR and N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.
酰胺的结构和性质在有机合成和生物化学中具有巨大的研究价值。传统的酰胺是平面的，由于 n→π* 共轭，羰基是非亲电性的。在这项研究中，我们通过利用 O NMR 和 N NMR 化学位移来报告亲电性标度，这些化学位移来自于最近受到广泛关注的非循环扭曲和非循环去稳定酰胺，它们作为 N-C(O) 交叉偶联反应中选择性氧化加成的前体以及 N-C(O) 键的亲电活化前体。最重要的是，我们证明非循环扭曲酰胺的羰基亲电性在酸酐和酰氯之间。此外，通过酰胺键性质的空间位阻和电子调谐，可以实现具有逐渐变化的羰基亲电性的广泛的亲电酰胺。总的来说，该研究首次定量表明，常见非环酰胺中酰胺键的空间位阻和电子去稳定化使酰胺键具有与酸酐和氯化物一样的亲电性。这些发现应该对酰胺键的基本性质产生重大影响。
