Department of Chemistry, Wesleyan University, 52 Lawn Avenue, Middletown, CT, 06459, USA.
Chempluschem. 2020 Nov;85(11):2466-2474. doi: 10.1002/cplu.202000590.
The nucleophile-initiated mechanism of thiol-Michael reactions naturally leads to the formation of undesired nucleophile byproducts. Three aza-Michael compounds representing nucleophile byproducts of thiol-acrylate reactions initiated by 4-dimethylaminopyridine (DMAP), 1-methylimidazole (MIM), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been synthesized and their reactivity in the presence of thiolate has been investigated. Spectroscopic analysis shows that each nucleophile byproduct reacts with thiolate to produce a desired thiol-acrylate product along with liberated aprotic amines DMAP, MIM, or DBU, thus demonstrating that these byproducts are reactive rather than persistent. Density functional theoretical computations support experimental observations and predict that a β-elimination mechanism is favored for converting each nucleophile byproduct into a desired thiol-acrylate product, though an S 2 process can be competitive (i. e. within <2.5 kcal/mol) in less polar solvents.
亲核试剂引发的硫醇-Michael 反应机制自然会导致形成不需要的亲核试剂副产物。本文合成了三种代表由 4-二甲氨基吡啶 (DMAP)、1-甲基咪唑 (MIM) 和 1,8-二氮杂二环[5.4.0]十一碳-7-烯 (DBU)引发的硫醇-丙烯酰反应的亲核试剂副产物，并研究了它们在硫醇存在下的反应活性。光谱分析表明，每种亲核试剂副产物都与硫醇反应，生成所需的硫醇-丙烯酰产物以及释放出的非质子化胺 DMAP、MIM 或 DBU，从而证明这些副产物是反应性的，而不是持久性的。密度泛函理论计算支持实验观察，并预测β-消除机制有利于将每种亲核试剂副产物转化为所需的硫醇-丙烯酰产物，尽管 S 2 过程在极性较小的溶剂中可能具有竞争力（即，在 <2.5 kcal/mol 内）。
