Center for Molecular Modeling, Ghent University, Member of QCMM-Alliance Ghent-Brussels, Technologiepark 903, B-9052 Zwijnaarde, Belgium.
J Org Chem. 2011 Nov 4;76(21):8698-709. doi: 10.1021/jo201255z. Epub 2011 Oct 10.
The difference in reactivity between the activated 2-bromomethyl-1-tosylaziridine and the nonactivated 1-benzyl-2-(bromomethyl)aziridine with respect to sodium methoxide was analyzed by means of DFT calculations within the supermolecule approach, taking into account explicit solvent molecules. In addition, the reactivity of epibromohydrin with regard to sodium methoxide was assessed as well. The barriers for direct displacement of bromide by methoxide in methanol are comparable for all three heterocyclic species under study. However, ring opening was found to be only feasible for the epoxide and the activated aziridine, and not for the nonactivated aziridine. According to these computational analyses, the synthesis of chiral 2-substituted 1-tosylaziridines can take place with inversion (through ring opening/ring closure) or retention (through direct bromide displacement) of configuration upon treatment of the corresponding 2-(bromomethyl)aziridines with 1 equiv of a nucleophile, whereas chiral 2-substituted 1-benzylaziridines are selectively obtained with retention of configuration (via direct bromide displacement). Furthermore, the computational results showed that explicit accounting for solvent molecules is required to describe the free energy profile correctly. To verify the computational findings experimentally, chiral 1-benzyl-2-(bromomethyl)aziridines and 2-bromomethyl-1-tosylaziridines were treated with sodium methoxide in methanol. The presented work concerning the reactivity of 2-bromomethyl-1-tosylaziridine stands in contrast to the behavior of the corresponding 1-tosyl-2-(tosyloxymethyl)aziridine with respect to nucleophiles, which undergoes a clean ring-opening/ring-closure process with inversion of configuration at the asymmetric aziridine carbon atom.
在超分子方法中，通过 DFT 计算并考虑到显式溶剂分子，分析了活化的 2-溴甲基-1-对甲苯磺酰基氮丙啶与非活化的 1-苄基-2-(溴甲基)氮丙啶相对于甲醇钠的反应性差异。此外，还评估了环氧溴丙烷相对于甲醇钠的反应性。对于在甲醇中直接用甲氧基取代溴化物，所有三种研究的杂环物种的势垒是相当的。然而，发现只有环氧化物和活化的氮丙啶可以开环，而非活化的氮丙啶则不行。根据这些计算分析，通过用 1 当量亲核试剂处理相应的 2-(溴甲基)氮丙啶，可以通过开环/闭环（构型反转）或通过直接溴化物取代（构型保留）来合成手性 2-取代的 1-对甲苯磺酰基氮丙啶，而手性 2-取代的 1-苄基氮丙啶则通过构型保留（通过直接溴化物取代）选择性得到。此外，计算结果表明，需要显式考虑溶剂分子才能正确描述自由能曲线。为了实验验证计算结果，用甲醇钠处理手性 1-苄基-2-(溴甲基)氮丙啶和 2-溴甲基-1-对甲苯磺酰基氮丙啶。与相应的 1-对甲苯磺酰基-2-(对甲苯磺酰氧基甲基)氮丙啶相比，2-溴甲基-1-对甲苯磺酰基氮丙啶的反应性研究与亲核试剂的行为形成对比，后者在手性氮丙啶碳原子上通过构型反转的开环/闭环过程进行，并且发生了干净的开环/闭环过程。
