A DFT Study on the Binuclear CuAAC Reaction: Mechanism in Light of New Experiments

In this DFT study, the mechanism of the copper­(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction is revisited in light of recent experimental findings that made significant contributions to unraveling this challenging and important reaction. The generally accepted binuclear mechanism was used as a framework to investigate two inquiries raised by new experiments. First, Fokin et al. have proposed ligand exchanges that can take place as possible alternative pathways to the generic path and in that way they have proved the binuclear nature of the CuAAC mechanism. In this study, the experimentally proposed ligand exchanges which deviate from the generic path were modeled with NHC as the ligand and the electronic nature of the mechanism was also investigated with the NBO analyses. The results in this study are compatible with the experimental proposals, since the ligand exchange and the generic pathways’ calculated energies are on the same order. Second, possible pathways for the formation of a recently isolated bis-copper triazolide intermediate were considered by DFT calculations to explain this mechanism thoroughly. It was shown that its formation is energetically highly unfavorable during the cycloaddition step, whereas it can be facile after the formation of the mononuclear triazolide. The calculations were performed at the M06-L/6-31+G­(d,p) level with the LANL2TZ+ effective core potential for copper atoms.本项密度泛函理论（DFT, Density Functional Theory）研究中，结合近期为阐明这一兼具挑战性与重要性的反应而取得的关键实验进展，重新探讨了铜(I)催化叠氮-炔环加成（CuAAC, Copper-Catalyzed Azide-Alkyne Cycloaddition）反应的机理。本研究以学界普遍认可的双核机理作为研究框架，针对新实验提出的两个核心问题展开探究。其一，福金等人（Fokin et al.）提出配体交换路径可作为通用路径的潜在替代途径，并以此证实了CuAAC反应机理的双核本质。本研究以氮杂环卡宾（NHC, N-Heterocyclic Carbene）为配体，对实验提出的偏离通用路径的配体交换过程进行了建模，并通过自然键轨道（NBO, Natural Bond Orbital）分析探究了该机理的电子结构本质。本研究结果与实验提议相符，因配体交换路径与通用路径的计算能量处于同一数量级。其二，为全面阐明该反应机理，本研究通过DFT计算探究了近期分离得到的双核铜三唑鎓中间体的可能形成路径。计算结果表明，该中间体在环加成步骤中生成的热力学能垒极高，极为不利；但在单核三唑鎓中间体生成后，其形成过程则较为容易。所有计算均采用M06-L/6-31+G(d,p)理论水平，并对铜原子使用LANL2TZ+有效核势（ECP, Effective Core Potential）进行处理。