The Rational Development of Organometallic Reagents through Fluorescence Microscopy Experiments

该项目的关键目标是回答关于添加剂如何促进有机金属试剂形成的长期问题。为了实现这一目标，将开发具有灵敏度的荧光显微镜方法，用于检测有机金属中间体的单分子。有机金属试剂对于合成复杂的有机化合物（如天然产物和药物）非常重要。获得这种试剂的一个简单途径是形成金属和有机卤化物。然而，这种简单的方法通常只有使用某些添加剂才能实现。例如，Blum的研究小组最近发现，使用高灵敏度的显微镜方法，氯化锂有助于溶解锌表面的有机锌试剂。关键的实验是通过荧光显微镜显示少量的表面有机金属中间体，并确定观察这些物种的条件。这些中间体的数量太少，传统的分析仪器无法检测到。通过开发用于这种方法的显像剂，我的目标是回答四个问题：(A)锰和铝的有机金属试剂需要催化量的金属盐（钛、铟、铅或铋的氯化物）。然而，这些添加剂的作用机制尚不清楚。荧光显微镜将考虑和研究五种可能的机制。(B)有机金属试剂的另一种替代途径是由所谓的Rieke金属合成-精细分割和高活性的金属粉末。研究表明，雷克金属的合成路线对其反应性有影响；反应性的差异被认为是由每次合成中形成的副产物引起的。在这里，我想通过直接确定副产物的作用来研究为什么来自不同路线的雷克金属具有不同的反应性。(C)将确定有机锌试剂形成过程中明显的溶剂效应的来源。(D)通过合理的反应设计，提出了两个实际应用：1)使有机锡试剂——Stille偶联中的重要试剂——的合成更加简单和安全；2)改进了合成上重要的Ullmann偶联。结论：本研究有助于了解添加剂在有机化学和有机金属化学试剂合成中的作用机理。在未来，这种理解可能使从商业金属粉末中制备有机金属试剂成为可能，用于更大范围的金属。同时，荧光显微技术将作为一种新的分析方法在无机化学中得到发展。

The key objective of the project is to answer long-standing questions about how additives facilitate the formation of organometallic reagents. To achieve this objective, fluorescence microscopy approaches with sensitivity for the detection of single molecules of organometallic intermediates will be developed. Organometallic reagents are important for the synthesis of complex organic compounds, e.g., natural products and pharmaceuticals. A simple route to such reagents is the formation of a metal and an organohalide species. However, this simple route is often only possible using certain additives. For example, Blum's research group has recently discovered that lithium chloride helps to dissolve organozinc reagents from the zinc surface, using a highly sensitive microscopy approach. The key experiment is the visualization of small quantities of surface organometallic intermediates by fluorescence microscopy and the determination of the conditions under which these species are observed. The quantity of these intermediates is too low to be detected by traditional analytical instrumentation. Through the development of imaging agents for this approach, I aim to answer four questions: (A) Organometallic reagents of manganese and aluminum require catalytic amounts of metal salts (chlorides of titanium, indium, lead, or bismuth). However, the mechanism of action of these additives is still unclear. Five mechanistic possibilities will be considered and investigated by fluorescence microscopy.(B) An alternative route to organometallic reagents is the synthesis from so-called Rieke metals – finely divided and highly reactive metal powders. It has been shown that the synthetic route towards Rieke metals has an impact on their reactivity; the difference in reactivity is believed to be caused by by-products formed in each synthesis. Here, I want to investigate why Rieke metals from different routes have different reactivities, by determining the role of the by-products directly.(C) The origin of pronounced solvent effects in the formation of organozinc reagents will be determined.(D) Two practical applications are proposed through rational reaction design: 1) enabling the simple and safer synthesis of organotin reagents – important reagents in the Stille coupling and 2) improvement of the synthetically important Ullmann coupling.Conclusion: The intended research will help to understand the mechanistic role of additives in organometallic reagent synthesis for organic and organometallic chemistry. In the future, this understanding may enable the preparation of organometallic reagents from commercial metal powders for a significantly larger range of metals. At the same time, fluorescence microscopy will be developed as a new analytical method in inorganic chemistry.