The Rational Development of Organometallic Reagents through Fluorescence Microscopy Experiments

该项目的主要目标是回答长期存在的关于添加剂如何促进有机金属试剂形成的问题。为了实现这一目标，将开发具有灵敏度的荧光显微镜方法来检测有机金属中间体的单分子。有机金属试剂是合成天然产物和药物等复杂有机化合物的重要试剂。获得这种试剂的一个简单途径是形成一种金属和一种有机卤化物。然而，这条简单的路线通常只有使用某些添加剂才能实现。例如，布鲁姆的研究小组最近利用一种高度敏感的显微镜方法，发现氯化锂有助于从锌表面溶解有机锌试剂。关键的实验是用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，无法用传统的分析仪器检测到。通过开发这种方法的显像剂，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理仍不清楚。荧光显微镜将考虑和研究五种机理上的可能性。(B)有机金属试剂的另一种方法是从所谓的Rieke金属合成--精细分散的高活性金属粉末。已经证明，合成Rieke金属的路线对它们的反应性有影响；反应性的差异被认为是由每次合成中形成的副产物造成的。在这里，我想通过直接测定副产物的作用来研究为什么来自不同路线的Rieke金属具有不同的反应性。(C)将确定在有机锌试剂形成中明显的溶剂效应的来源。(D)通过合理的反应设计提出两个实际应用：1)使有机锡试剂的合成变得简单和安全--Stille偶联中的重要试剂；2)改进合成中重要的Ullmann偶合。结论：预期的研究将有助于理解添加剂在有机和有机金属化学合成有机金属试剂中的机理作用。在未来，这一认识可能会使从商业金属粉末中制备有机金属试剂的范围大大扩大。同时，荧光显微镜也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.