The synthesis of new arene and heteroarene scaffolds of therapeutic interest has generated a renewed interest in the domino radical cyclisation–Smiles. In this work we present a detailed mechanistic investigation of the radical version of a cascade involving a desulfonative Smiles rearrangement on an aromatic ring bearing a sulfonamide linker. Competing routes have been explored to characterize the molecular mechanism of the studied reaction. The knowledge gained from previous experimental observations is explained through the energy profile obtained by means of quantum mechanical calculations. This study answers questions about the rate determining step and the type of mechanism involved (two-step or concerted). Supplementary rate constant calculations as well as quantum molecular dynamics support experimental observations. An IGM-δg analysis performed along the reaction path unveils and quantifies an intramolecular π–π stacking interaction accelerating the reaction. This novel post processing IGM-δg tool based on the electron density, turns out to be useful to monitor and quantify specific intramolecular weak interactions along a reaction path from wave functions. From this mechanistic investigation it turns out that Smiles rearrangement here takes place in two steps rather than in a direct intramolecular radical substitution. Furthermore, we show that chain length effects must be taken into account in the functionalization of new sulfonylated derivatives subjected to this radical cascade, given their influence in the reaction rate.

中文翻译：

---

对微笑重排的机械见解。关注自由基级联的 π-π 堆叠相互作用。

具有治疗意义的新芳烃和杂芳烃支架的合成引起了人们对多米诺自由基环化-Smiles 的新兴趣。在这项工作中，我们对带有磺酰胺接头的芳环上的脱磺化微笑重排级联反应的自由基形式进行了详细的机械研究。已经探索了竞争路线来表征所研究反应的分子机制。从先前的实验观察中获得的知识是通过量子力学计算获得的能量分布来解释的。本研究回答了有关速率确定步骤和所涉及机制类型（两步或协同）的问题。补充速率常数计算以及量子分子动力学支持实验观察。IGM-δ沿反应路径进行的g分析揭示并量化了加速反应的分子内 π-π 堆积相互作用。这种基于电子密度的新型后处理 IGM-δ g工具被证明可用于监测和量化波函数沿反应路径的特定分子内弱相互作用。从这个机制研究结果表明，微笑重排在这里发生在两个步骤中，而不是在直接的分子内自由基取代中。此外，我们表明，考虑到它们对反应速率的影响，在进行这种自由基级联的新磺酰化衍生物的官能化中必须考虑链长效应。