Elementary Steps of Silver- and Gold-Mediated Trifluoromethylation Reactions

Due to the importance of the trifluoromethyl group in medicinal chemistry, trifluoromethylation reactions are in high demand. Most of the reported trifluoromethylation protocols rely on copper complexes, whose mechanistic role in these transformations has been analyzed extensively. First evidence also points to the potential of silver and gold complexes for enabling trifluoromethylation reactions, but a more detailed mechanistic understanding of these processes is still lacking. Here, we use electrospray-ionization mass spectrometry to study the formation of [Ag(R)(CF3)3]− and [Au(R)(CF3)3]− (R = Me, Et, nBu, sBu, allyl, aryl) in solution and characterize their unimolecular reactivity by gas-phase fragmentation experiments and quantum chemical calculations. The argentate complexes undergo both concerted reductive eliminations of RCF3 and 2-fold radical losses of R• and CF3•. Like in the case of the analogous cuprate complexes, the branching ratio between the two competing fragmentation channels is controlled by the stability of the R• radicals. In contrast, the calculated barriers of the corresponding fragmentation reactions of the aurates are much higher, for which reason these complexes dissociate by alternative pathways and do not afford the RCF3 products.

鉴于三氟甲基基团在药物化学中的重要性，三氟甲基化反应需求旺盛。目前已报道的三氟甲基化反应方案大多依赖铜配合物，其在这类转化中的机理作用已得到广泛分析。已有初步证据表明，银和金配合物在实现三氟甲基化反应方面具备潜力，但目前对这些过程的机理仍缺乏更深入的理解。本研究采用电喷雾电离质谱（electrospray-ionization mass spectrometry）技术，在溶液中研究了[Ag(R)(CF₃)₃]⁻与[Au(R)(CF₃)₃]⁻（其中R为甲基（Me）、乙基（Et）、正丁基（nBu）、仲丁基（sBu）、烯丙基（allyl）、芳基（aryl））的生成过程，并通过气相碎裂实验与量子化学计算对其单分子反应性进行了表征。该银酸盐配合物既可发生RCF₃的协同还原消除，也可发生R·与CF₃·的双自由基解离。与类似的铜酸盐配合物体系一致，这两种竞争性碎裂通道间的分支比由R·自由基的稳定性决定。与之形成鲜明对比的是，金酸盐配合物对应碎裂反应的计算能垒要高得多，因此这类配合物会通过其他途径解离，无法生成RCF₃产物。