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

低价钴催化的 C-H 活化：合成应用的机理洞察

• 批准号: 289205672
• 负责人: Professor Dr. Lutz Ackermann
• 金额: --
• 依托单位: Institut für Organische und Biomolekulare Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/289205672?language=en
• 关键词: Low; Valent; Cobalt; Catalyzed; Activation

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.

过渡金属催化的C-H活化反应的出现，是有机合成的一次革命。由于它们在有机分子中的普遍存在，C-H键代表了直接官能化方法的理想目标。由此产生的合成路线短而高效，从而节省资源并产生更少的废物。同时，由于C-H键的低固有反应性和难以控制位点选择性，C-H官能化固有地具有挑战性。然而，目前大多数方法依赖于4d过渡金属作为催化剂，其高昂的价格严重损害了该方法的可持续性。因此，采用天然丰富的3d过渡金属作为催化剂的实际C-H官能化是高需求的。最近的工作指出，低价钴配合物作为特别活跃和有前途的催化剂。由于这些催化剂的分子作用模式几乎完全未知，因此今天不可能对其进行合理和系统的改进。本提案旨在改变这种情况。在第一步中，它的目的是在钴催化的C-H官能化的完整的机制阐明。为此，它将通过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，因为它选择性地检测带电物种，这被认为在钴催化的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。另外的实验将探测质量选择的钴络合物在气相中的微观反应性以及在溶液中的反应动力学。在第二步中，该项目将建立在所获得的机理洞察力的基础上，开发用于钴催化的C-H官能化的新方法。配体的精心设计将使未活化的C（sp3）-H键的官能化成为可能。此外，它将试图取代目前所需的格氏试剂为温和的碱，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C-H官能化反应在有机合成中的应用。