Catalytic Functionalisation of Aromatic Fluorocarbons

世界十大畅销药物中的三种-立普妥（用于控制血液胆固醇水平），舒利迭（哮喘）和可定（胆固醇和心血管疾病）-是选择性氟化的芳香族有机分子。总体而言，目前市场上高达20%的所有药物和40%的所有农用化学品都含有至少一个氟取代基。这些产品对现代社会的福祉至关重要，在经济上也是巨大的参与者，仅制药行业每年就能产生超过250亿美元的氟化芳烃。在健康/福祉和经济繁荣方面的这种巨大价值意味着，使其更有效的生产手段的新方法是非常可取的。然而，目前用于制备此类物质的方法在范围和选择性方面受到限制。在本论文中，我们的目标是开发一种新的方法来利用过渡金属催化合成这些重要的化合物，我们的想法是基于最近的实验工作，其中我们之一（Whittlesey）制备了新的钌（Ru）基催化剂用于含几个氟取代基的芳族碳氟化合物的加氢脱氢（HDF）。这允许氟基团被另一个基团（在这种情况下，氢）选择性地取代，从而以特定的模式留下剩余的氟（邻位选择性）。这种选择性对于过渡金属催化剂来说是前所未有的。至关重要的是，该团队的另一名成员（Macgregor）已经能够使用计算建模来证明这种不寻常的选择性来自一种新的反应模式，其中Ru催化剂以非常高的区域选择性将氢化物配体传递到氟化底物。能够实现这种氢化物亲核攻击的关键设计特征是使用N-杂环卡宾（NHC）配体，其不仅增强催化剂的活性，而且还负责控制该过程的选择性。我们现在的目标是联合收割机结合我们在实验和计算化学方面的专业知识，采用支撑我们HDF工作的原则，为更一般的XDF反应开发新的催化剂，其中F取代基可以被其他亲核基团取代，从而选择性地形成新的C-O和C-N键。我们将通过（i）使用计算模型来阐明这些因素（立体/电子），支撑Ru-NHC HDF催化剂，以显示如何使它们更有效，（ii）实验建立完整的底物范围（化学选择性，低含氟底物等），（iii）采用计算方法来探测XDF与M-OR，-OH，- NR 2，SH和-烃基催化剂，（iv）进行催化XDF的全面实验研究，以确定区域选择性，化学选择性和底物范围和（v）结合计算和实验研究，以完善和改进我们的XDF催化剂。我们的工作成果将是一系列新的XDF催化剂，将能够合成新的氟化芳烃。这类化合物的全部潜力尚未完全实现，成功的XDF催化剂将为各种新的氟化物质开辟道路，为健康和福祉带来无数的可能性。

Three of the top 10 selling pharmaceuticals in the world Lipitor (used for controlling blood cholesterol levels), Seretide (asthma) and Crestor (cholesterol and cadiovascular disease), are selectively fluorinated aromatic organic molecules. Overall, up to 20% of all pharmaceuticals in the current market and 40% of all agrochemicals bear at least one fluorine substituent. These products are central to the well-being of modern society and economically they are also huge players, with fluorinated aromatics typically generating over $25 billion per annum to the pharmaceutical industry alone. This immense value in terms of health/well-being and economic prosperity means that new methods enabling their more efficient means of production are highly desirable. However, current methods for the preparation of such species are limited in scope and selectivity. In this proposal, we aim to devlop a new approach to the synthesis of these vital compounds using transition metal catalysis.Our ideas are based on recent experimental work where one of us (Whittlesey) prepared new ruthenium (Ru)-based catalysts for the hydrodefluorination (HDF) of aromatic fluorocarbons containing several fluorine substituents. This allows the selective replacement of a fluorine group by another group - in this case, hydrogen - leaving the remaining fluorines in a specific pattern (ortho-selectivity). This selectivity is unprecdented for for transition metal catalysts. Crucially, the other member of the team (Macgregor) has been able to use computational modelling to demonstrate that this that this unusual selectivity arises from a novel mode of reaction, where the Ru catalyst delivers a hydride ligand to the fluorinated substrates with a remarkably high level of regioselectivity. A key design feature that enables this hydride nucleophilic attack is the use of N-heterocyclic carbene (NHC) ligands, which not only enhance the activity of the catalysts, but are also responsible for controlling the selectivity of the process. We now aim to combine our expertise in experimental and computational chemistry to take the principles underpinning our HDF work to develop new catalysts for more general XDF reactions in which F substituents can be replaced by other nucleophilic groups resulting in the selective formation of new C-O and C-N bonds. We will achieve this by (i) using computational modelling to elucidate the factors (sterics/electronics) that underpin the Ru-NHC HDF catalysts to show how they can be made more efficient, (ii) establishing experimentally the full substrate scope (chemoselectivity, low fluorine containing substrates etc) of the system for hydrodefluorination, (iii) employing computational methods to probe the mechanism of XDF with M-OR, -OH, -NR2, SH and -hydrocarbyl catalysts, (iv) undertaking a full experimental study of catalytic XDF to determine regioselectivity, chemoselectivity and substrate scope and (v) combining computational and experimental studies to refine and improve our XDF catalysts.The outcome of our work will be a range of new XDF catalysts that will enable the synthesis of new fluorinated aromatics. The full potential of this class of compound has yet to be fully realised and a successful XDF catalyst would open up pathways to a wide array of new fluorinated species, with untold possibilities for health and well-being.