AstraZeneca, S-151 85 Södertälje, Sweden.
Beilstein J Org Chem. 2013 Apr 23;9:791-9. doi: 10.3762/bjoc.9.90. Print 2013.
A computational approach using density functional theory to compute the energies of the possible σ-complex reaction intermediates, the "σ-complex approach", has been shown to be very useful in predicting regioselectivity, in electrophilic as well as nucleophilic aromatic substitution. In this article we give a short overview of the background for these investigations and the general requirements for predictive reactivity models for the pharmaceutical industry. We also present new results regarding the reaction rates and regioselectivities in nucleophilic substitution of fluorinated aromatics. They were rationalized by investigating linear correlations between experimental rate constants (k) from the literature with a theoretical quantity, which we call the sigma stability (SS). The SS is the energy change associated with formation of the intermediate σ-complex by attachment of the nucleophile to the aromatic ring. The correlations, which include both neutral (NH3) and anionic (MeO(-)) nucleophiles are quite satisfactory (r = 0.93 to r = 0.99), and SS is thus useful for quantifying both global (substrate) and local (positional) reactivity in SNAr reactions of fluorinated aromatic substrates. A mechanistic analysis shows that the geometric structure of the σ-complex resembles the rate-limiting transition state and that this provides a rationale for the observed correlations between the SS and the reaction rate.
使用密度泛函理论计算可能的σ-配合物反应中间体能量的计算方法，即“σ-配合物方法”，已被证明在预测区域选择性方面非常有用，无论是在亲电芳香取代还是亲核芳香取代中。在本文中，我们将简要概述这些研究的背景以及制药行业预测反应性模型的一般要求。我们还介绍了关于亲核取代氟化芳烃的反应速率和区域选择性的新结果。我们通过研究实验速率常数（k）与我们称之为σ-稳定性（SS）的理论量之间的线性相关关系来合理化这些结果。SS 是指亲核试剂与芳环结合形成中间体σ-配合物时的能量变化。这些相关性包括中性（NH3）和阴离子（MeO(-)）亲核试剂，非常令人满意（r = 0.93 到 r = 0.99），因此 SS 可用于量化氟化芳基底物的 SNAr 反应中的全局（底物）和局部（位置）反应性。机理分析表明，σ-配合物的几何结构类似于速率限制过渡态，这为观察到的 SS 与反应速率之间的相关性提供了依据。
