Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Lynnwood Road, Hatfield, Pretoria 0002, South Africa.
Department of Chemistry, Faculty of Science and Agriculture, University of Limpopo, Private Bag X1106, Sovenga 0727, South Africa.
Molecules. 2021 Mar 12;26(6):1570. doi: 10.3390/molecules26061570.
In search for the cause leading to low reaction yields, each step along the reaction energy profile computed for the assumed oxidative nucleophilic substitution of hydrogen (ONSH) reaction between 2-phenylquinoxaline and lithium phenylacetylide was modelled computationally. Intermolecular and intramolecular interaction energies and their changes between consecutive steps of ONSH were quantified for molecular fragments playing leading roles in driving the reaction to completion. This revealed that the two reactants have a strong affinity for each other, driven by the strong attractive interactions between Li and two N-atoms, leading to four possible reaction pathways (RP-C2, RP-C3, RP-C5, and RP-C10). Four comparable in energy and stabilizing molecular system adducts were formed, each well prepared for the subsequent formation of a C-C bond at either one of the four identified sites. However, as the reaction proceeded through the TS to form the intermediates (-), very high energy barriers were observed for RP-C5 and RP-C10. The data obtained at the nucleophilic addition stage indicated that RP-C3 was both kinetically and thermodynamically favored over RP-C2. However, the energy barriers observed at this stage were very comparable for both RPs, indicating that they both can progress to form intermediates and . Interestingly, the phenyl substituent (Ph1) on the quinoxaline guided the nucleophile towards both RP-C2 and RP-C3, indicating that the preferred RP cannot be attributed to the steric hindrance caused by Ph1. Upon the introduction of HO to the system, both RPs were nearly spontaneous towards their respective hydrolysis products ( and ), although only can proceed to the final oxidation stage of the ONSH reaction mechanism. The results suggest that RP-C2 competes with RP-C3, which may lead to a possible mixture of their respective products. Furthermore, an alternative, viable, and irreversible reaction path was discovered for the RP-C2 that might lead to substantial waste. Finally, the modified experimental protocol is suggested to increase the yield of the desired product.
为了寻找导致低反应产率的原因，我们对假定的 2-苯基喹喔啉与锂苯乙炔之间的氧化亲核取代反应（ONSH）的反应能量曲线进行了计算，对每个步骤进行了建模。我们对在推动反应完成中起主导作用的分子片段之间的分子间和分子内相互作用能及其在 ONSH 连续步骤之间的变化进行了量化。这表明，两种反应物彼此之间具有很强的亲和力，这是由 Li 与两个 N 原子之间的强烈吸引相互作用驱动的，导致存在四种可能的反应途径（RP-C2、RP-C3、RP-C5 和 RP-C10）。形成了四个能量相当且稳定的分子体系加合物，每个加合物都为随后在四个确定的位置之一形成 C-C 键做好了充分的准备。然而，当反应通过 TS 进行以形成中间体 (-) 时，对于 RP-C5 和 RP-C10，观察到非常高的能垒。在亲核加成阶段获得的数据表明，RP-C3 在动力学和热力学上都优于 RP-C2。然而，在这一阶段观察到的能垒对于两种 RP 都非常相似，这表明它们都可以进一步形成中间体和。有趣的是，喹喔啉上的苯基取代基（Ph1）将亲核试剂引导至 RP-C2 和 RP-C3，这表明首选的 RP 不能归因于 Ph1 引起的空间位阻。当向体系中引入 HO 时，两种 RP 都几乎自发地转化为它们各自的水解产物（和），尽管只有可以进一步进行 ONSH 反应机制的最终氧化阶段。结果表明，RP-C2 与 RP-C3 竞争，这可能导致它们各自产物的混合物。此外，还发现了一种替代的、可行的、不可逆的 RP-C2 反应途径，这可能会导致大量浪费。最后，建议修改实验方案以提高所需产物的产率。
