Empa, Swiss Federal Laboratories for Materials Science and Technology, Dübendorf, Switzerland.
Department of Chemistry and Applied Bioscience, ETH Zurich, c/o USI Campus, Lugano, Switzerland.
Phys Chem Chem Phys. 2019 Sep 11;21(35):19281-19287. doi: 10.1039/c9cp02386k.
The azide-alkyne Huisgen cycloaddition has a key role in click chemistry and is configured as a powerful tool in pharmaceutical and medicinal chemistry. Although this reaction has already been largely studied, there is an ongoing debate about its mechanism. In this work we study the dynamical aspects of the process using metadynamics computer simulations. We focus on the conformational aspects that determine the course of the reaction and characterize its free energy landscape. To properly capture the thermodynamics of the process we select optimal collective variables using harmonic linear discriminant analysis. The results qualitatively confirm and explain the experimental evidence and give insights into the role of the substituents and the possible transition mechanisms.
叠氮-炔基 Huisgen 环加成反应在点击化学中起着关键作用，并且是药物化学和医药化学中的有力工具。尽管该反应已经得到了广泛的研究，但关于其机制仍存在争议。在这项工作中，我们使用元动力学计算机模拟研究了该过程的动力学方面。我们专注于决定反应进程的构象方面，并对其自由能景观进行了特征描述。为了正确捕捉该过程的热力学性质，我们使用调和线性判别分析选择了最佳的整体变量。结果从定性上证实并解释了实验证据，并深入了解了取代基的作用和可能的过渡机制。
