New Catalytic Methodologies for the Synthesis of Organofluorine Compounds

氟在有机化合物中的掺入对空间位阻的限制很小，但其强大的吸电子能力会引起邻近官能团的pKa或前线轨道能量的调节。氟还可以加强或参与关键的分子内和分子间静电相互作用。由于氟掺入所产生的效应，它已成为药物、农用化学品和先进材料等领域设计的关键。这一点值得注意，因为自然产生的有机化合物几乎不含氟，而且现在越来越需要强有力的方法来获取有机氟化合物并将其复杂化。此外，可持续的合成是非常可取的，可能来自于最大限度地减少化学废物的反应条件的改善，以及能够进行短合成的新颖的断开。过渡金属催化可能是使有机化合物进入新的反应模式的关键工具，通过可靠和步骤高效的过程简化氟化分子的合成。因此，这一研究计划的总体目标将是(1)操纵C-H和C-C键，以更好地获取和衍生化有机氟化合物；(2)建立制备应变或融合的含氟环化合物的工艺，并研究它们在新的含氟基序中的新应用；以及(3)探索新的含氟基序的生物等价性及其作为分子探针的潜力。在接下来的五年里，根据这项发现助学金，参与我研究活动的研究生和本科生将通过利用C-H和C-C键作为官能化处理来开发合成氟化分子的新途径，并将扩展应变氟化碳环的反应性、安装和应用，特别是双环[1.1.1]戊基衍生物和宝石-二氟环丙烷。整个研究计划将带来重大进展，这些进展将影响我们如何构建和操作有机氟化合物，使学术界、加拿大工业(例如制药、农用化学品)以及整个研发工作受益。

Fluorine incorporation into organic compounds poses minimal steric constraints, but its strong electron-withdrawing ability can cause a modulation of the pKa of neighbouring functional groups or the energy of frontier orbitals. Fluorine can also strengthen or participate in key intra- and intermolecular electrostatic interactions. As a result of the effects caused by fluorine incorporation, it has become key to the design of drugs, agrochemical agents, and advanced materials among other areas. This is remarkable as fluorine is virtually absent from naturally occurring organic compounds, and there is now a growing need for robust methods to access and build complexity into organofluorine compounds. Furthermore, sustainable syntheses are highly desirable and may come from improved reaction conditions minimizing chemical wastes, and from novel disconnections enabling short syntheses. Transition-metal catalysis may be a key tool to engage organic compounds into new reactivity patterns, streamlining the synthesis of fluorinated molecules via reliable and step-efficient processes. Thus, the overarching goals of this research program will be (1) to manipulate C-H and C-C bonds to better access and derivatize organofluorine compounds; (2) to establish processes for preparing strained or fused, fluorinated cyclic compounds, and investigate their novel applications towards new fluorinated motifs; and (3) to explore the bioisosterism of new fluorinated motifs and their potential as molecular probes. Over the next five years, under this Discovery Grant, graduate and undergraduate students involved in my research activities will develop new synthetic routes to fluorinated molecules by exploiting C-H and C-C bonds as handles for functionalization, and will expand on the reactivity, installation, and applications of strained fluorinated carbocycles, particularly bicyclo[1.1.1]pentanyl derivatives and gem-difluorocyclopropanes. The overall research program will result in major advances that will influence how we construct and manipulate organofluorine compound, benefiting academia, the Canadian industry (e.g. pharmaceutical, agrochemical), and efforts in R&D at large.