Low-Valent Cobalt-Catalyzed C-H Activation: Mechanistic Insight for Synthetic Applications

实用的过渡金属催化的碳氢活化反应的出现，目前是革命性的有机合成。由于它们在有机分子中的普遍存在，碳氢键代表了直接功能化方法的理想目标。合成路线短，效率高，节约资源，减少浪费。同时，由于C-H键的固有反应性较低，难以控制位点选择性，因此C-H功能化具有固有的挑战性。目前大多数方法依赖于四维过渡金属作为催化剂，然而，其高昂的价格严重损害了该方法的可持续性。因此，使用天然丰富的三维过渡金属作为催化剂的实际碳氢官能化具有很高的需求。最近的研究指出，低价钴配合物是特别活跃和有前途的催化剂。由于这些催化剂的分子作用方式几乎是完全未知的，它们的合理和系统的改进在今天是不可能的。目前的建议试图改变这种情况。在第一步，它的目的是充分的机制阐明钴催化碳氢官能化。为此，将采用电喷雾电离质谱法对原位形成的反应中间体进行表征。这种分析方法特别适合于这一目的，因为它可以选择性地检测带电物质，这些带电物质被认为在钴催化的C-H官能化中起着至关重要的作用。初步结果充分证实了这一观点。额外的实验将探索大量选择的钴配合物在气相中的微观反应活性以及溶液中的反应动力学。在第二步中，该项目将建立在获得的机制洞察力的基础上，开发钴催化C-H功能化的新方法。配体的精心设计将使未活化的C(sp3)-H键功能化成为可能。此外，将尝试用较温和的碱基取代目前所需的格氏试剂，从而提高反应的官能团耐受性。因此，新开发的方法将大大提高碳氢官能化反应在有机合成中的应用。

The advent of practical transition metal-catalyzed C-H activation reactions is currently revolutionizing organic synthesis. Thanks to their ubiquity in organic molecules, C-H bonds represent ideal targets for a direct functionalization approach. The resulting synthetic routes are short and efficient, thus saving resources and generating less waste. At the same time, C-H functionalizations are inherently challenging due to the low intrinsic reactivity of the C-H bond and the difficulty to control the site-selectivity. Most current methods rely on 4d transition metals as catalysts, whose high prices severely compromise the sustainability of the approach, however. Therefore, practical C-H functionalizations employing naturally abundant 3d transition metals as catalysts are in high demand. Very recent work points to low-valent cobalt complexes as particularly active and promising catalysts. As the molecular mode of action of these catalysts is almost completely unknown, their rational and systematic improvement today is impossible. The present proposal seeks to change this situation. In the first step, it aims at the full mechanistic elucidation of cobalt-catalyzed C-H functionalizations. To this end, it will characterize the in situ-formed reaction intermediates by electrospray-ionization mass spectrometry. This analytical method is particularly well-suited for this purpose because it selectively detects charged species, which supposedly play a crucial role in cobalt-catalyzed C-H functionalizations. Preliminary results fully confirm this notion. Additional experiments will probe the microscopic reactivity of mass-selected cobalt complexes in the gas phase as well as the reaction kinetics in solution. In the second step, the project will build upon the gained mechanistic insight to develop novel methods for cobalt-catalyzed C-H functionalizations. The careful design of ligands shall make possible the functionalization of unactivated C(sp3)-H bonds. Moreover, it will be attempted to replace the currently required Grignard reagents for milder bases, thereby boosting the functional-group tolerance of the reactions. Thus, the newly developed methods will greatly enhance the utility of C-H functionalization reactions for organic synthesis.