Catalytic activation of oxygen-containing functional groups

化学合成是一项费力的实践，但在提供获取分子的途径方面却是无价的，这些分子对社会有益，并有助于回答科学问题。虽然任何分子都可以用现有的技术来制备，但对时间和资源的要求往往是不合理的。使有机分子变得复杂或引入重要官能团的化学反应是最可取的。相比之下，非建设性的氧化还原操作、官能团相互转化和保护/去保护步骤仅用于为关键键的形成准备分子。为了使合成更高效、更环保，我们需要新的化学反应能够直接利用大量天然氧化态的原料分子中普遍存在的未受保护的官能团。过渡金属催化，特别是交叉偶联反应，已被证明是建立与更传统的亲核/亲核反应垂直的分子复杂性的强大工具。因此，虽然格氏反应是形成C-C键的最常见的非催化方法，但与Pd和Ni催化的偶联相比，它们的使用现在相形见绌。考虑到醇、酚、酮和羧酸等丰富的含氧官能团，在催化偶联反应中使用这些底物的策略令人惊讶。这项研究提案的首要目标是通过实施利用这些官能团的自然行为的激活策略来改变这一点。特别是，人们寻求的是“捷径”反应。这些直接的单步反应旨在取代通常使用的多步骤合成过程，这些过程需要非复杂的构建预活化步骤。这一研究目标将通过利用含碳-氧键分子的动力学行为来实现。六名研究生和十名本科生HQP将通过三个目标来解决这个问题。寻求削弱原位C-O键的活化途径，使醇、烯醇和羧酸像烷基卤化物、三氟乙烯和酸性氯化物一样容易参与偶联化学。在开发类似格利纳德的1，2加成反应时，将利用温和的方法来操纵醇/酮的氧化态(“借氢”)，而不需要化学计量的金属。最后，将探索使烯酮和非含氧的聚酰亚胺体系瞬时亲核的策略，为正式的C-H官能化提供一种独特的方法。在解决这些问题时，HQP将接受在有机合成、催化和现代化学技术方面的世界级培训。在发现的道路上获得的见解将被推广到为化学家提供新的工具，以更好地获取加拿大人依赖于他们的生活质量的当前和未来的药物、材料和高性能化学品。

Chemical synthesis is a laborious practice but is invaluable in providing access to molecules that provide benefits to society and help answer scientific questions. While any molecule can be prepared with existing technology, the demand of time and resources is often unreasonable. Chemical reactions that build complexity or introduce important functionality into an organic molecule are most desirable. In contrast, non-constructive redox manipulation, functional group interconversion, and protection/deprotection steps serve only to prepare a molecule for key bond formations. To make synthesis a more efficient and environmentally friendly practice, we need new chemical reactions that are able to directly harness the unprotected functional groups that are prevalent in abundant feedstock molecules in their native oxidation state. Transition metal catalysis, and cross-coupling reactions in particular, has proven itself to be powerful tool for building molecular complexity that is orthogonal to more traditional nucleophile/electrophile reactions. Thus, while Grignard reactions are the single most common non-catalytic method used to form C-C bonds, their use is now dwarfed by Pd & Ni-catalyzed couplings. Given the abundance of oxygen-containing functional groups like alcohols, phenols, ketones, and carboxylic acids, there are surprisingly few strategies for using these substrates in catalytic coupling reactions. The overarching goal of this research proposal is to change this by implementing activation strategies that exploit the natural behaviour of these functional groups. In particular, 'shortcut' reactions are sought. These direct, single step reactions are designed to replace commonly employed multi-step synthetic procedures that require non-complexity building pre-activation steps. This research goal will be achieved by exploiting the dynamic behaviour of carbon-oxygen bond containing molecules. Six graduate students and ten undergraduate HQP will tackle this problem across three objectives. Activation pathways that weaken C-O bonds in situ are sought to enable alcohols, enols, and carboxylic acids to participate in coupling chemistry as readily as alkyl halides, vinyl triflates, and acid chlorides. Mild methods to manipulate the alcohol/ketone oxidation state (`borrowing hydrogen') will be exploited in the development of Grignard-like 1,2 additions without the requirement of stoichiometric metals. Lastly, strategies to render enones and non-oxygenated pi-systems transiently nucleophilic will be explored, providing a unique approach to formal C-H functionalizations. In solving these problems, HQP will receive world-class training in organic synthesis, catalysis, and modern chemistry technologies. Insights gained along the path to discovery will be generalized to arm chemists with new tools to better access the current and future medicines, materials, and performance chemicals Canadians rely on for their quality of life.