Concerted Cycloaddition Mechanism in the CuAAC Reaction Catalyzed by 1,8-Naphthyridine Dicopper Complexes

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most versatile reactions in the “click chemistry” toolbox, and its development has made the synthesis of 1,4-triazole derivatives robust and efficient. In this work, we present a density functional theory (DFT) study on the mechanism of the CuAAC reaction catalyzed by a dicopper complex supported by a nonsymmetric 1,8-naphtyridine ligand bearing two different metal-coordinating substituents (i.e., −P­(tBu)2 and −C­(Me)­(Py)2). The calculations showed that the cycloaddition of the azide to the alkyne occurs in a single concerted step, in contrast with the two-step mechanism proposed in the literature. The energies predicted for this step indicated that the 1,4-triazole isomer of the product is formed in a selective manner, in agreement with experiments. Further, the DFT results showed that there is a subtle and complex interplay between several variables, including the relative orientation of the two substrates, the position of the counter-anion, and the partial decoordination of the 1,8-naphtyridine ligand. A series of 90 transition state calculations showed that, on average, the impact of these variables is strong on the structures but soft on the energy barriers, highlighting the flexible nature of the bonding within the coordination sphere of the bimetallic core of the catalyst. The insight provided by this study will be valuable for the further development of dicopper catalysts for the CuAAC reaction.铜催化叠氮-炔环加成（Copper-catalyzed azide-alkyne cycloaddition, CuAAC）是“点击化学（click chemistry）”工具库中通用性最强的反应之一，其发展使得1,4-三唑衍生物的合成变得稳健高效。在本研究中，我们开展了一项密度泛函理论（density functional theory, DFT）研究，针对由非对称1,8-萘啶配体（该配体带有两种不同的金属配位取代基：−P(tBu)₂与−C(Me)(Py)₂）配位的双核铜配合物催化的CuAAC反应机理展开探究。计算结果表明，叠氮与炔烃的环加成以协同单步过程进行，这与文献中提出的两步反应机理相悖。该步骤的能垒计算结果显示，产物以1,4-三唑异构体的形式选择性生成，与实验观测结果一致。进一步的DFT计算结果表明，多个变量之间存在微妙且复杂的相互作用，包括两种底物的相对取向、抗衡阴离子的位置，以及1,8-萘啶配体的部分脱配位行为。我们开展了共计90组过渡态计算，结果显示，平均而言，这些变量对反应结构的影响较为显著，但对能垒的影响相对温和，这凸显了催化剂双金属核配位球内成键的柔性特性。本研究提供的理论见解，将为用于CuAAC反应的双核铜催化剂的后续开发提供重要参考。