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Catalytic Functionalisation of Aromatic Fluorocarbons

芳香族氟碳化合物的催化官能化

基本信息

批准号：
EP/J009962/1
负责人：
Mike Whittlesey
金额：
$ 39.17万
依托单位：
University of Bath
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FJ009962%2F1
关键词：
Catalytic Functionalisation Aromatic Fluorocarbons

项目摘要

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.

全球十大畅销药物中的三种，立普妥（用于控制血液胆固醇水平）、舒利肽（治疗哮喘）和克雷斯特（治疗胆固醇和心血管疾病），都是选择性氟化的芳香有机分子。总体而言，目前市场上高达20%的药品和40%的农用化学品至少含有一种氟取代基。这些产品对现代社会的福祉至关重要，从经济上来说，它们也是巨大的参与者，氟化芳烃每年仅给制药行业带来的收入就超过250亿美元。在健康/福祉和经济繁荣方面的巨大价值意味着，非常需要能够提高生产手段效率的新方法。然而，目前制备这些物质的方法在范围和选择性上是有限的。在这个提议中，我们的目标是开发一种新的方法来合成这些重要的化合物使用过渡金属催化。我们的想法是基于最近的实验工作，我们中的一个人（Whittlesey）为含有几个氟取代基的芳香氟碳化合物的加氢脱氟（HDF）制备了新的钌基催化剂。这使得氟基团被另一个基团（在这种情况下是氢）选择性地取代，使剩余的氟保持特定的模式（邻选择性）。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）已经能够使用计算模型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给氟化底物。使这种氢化物亲核攻击成为可能的一个关键设计特征是使用n -杂环碳（NHC）配体，这不仅提高了催化剂的活性，而且还负责控制过程的选择性。我们现在的目标是结合我们在实验和计算化学方面的专业知识，以支持我们的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。我们将通过以下方式实现这一目标：(i)使用计算模型来阐明支撑Ru-NHC HDF催化剂的因素（立体/电子学），以显示如何使它们更有效；（ii）通过实验建立加氢脱氟系统的全部底物范围（化学选择性，低氟底物等）；（iii）使用计算方法来探测XDF与M-OR， -OH, -NR2， SH和-烃基催化剂的机理。（iv）对XDF催化剂进行全面的实验研究，以确定区域选择性、化学选择性和底物范围；(v)结合计算和实验研究来改进和改进我们的XDF催化剂。我们的工作成果将是一系列新的XDF催化剂，这将使新的氟化芳烃的合成成为可能。这类化合物的全部潜力尚未得到充分发挥，一种成功的XDF催化剂将为广泛的新型氟化物种开辟途径，为健康和福祉带来无限的可能性。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unexpected migratory insertion reactions of M(alkyl)2 (M=Zn, Cd) and diamidocarbenes.

DOI：
10.1002/chem.201406406
发表时间：
2015-02
期刊：
Chemistry
影响因子：
0
作者：
L. R. Collins;Gabriele Hierlmeier;M. Mahon;Ian M. Riddlestone;M. Whittlesey
通讯作者：
L. R. Collins;Gabriele Hierlmeier;M. Mahon;Ian M. Riddlestone;M. Whittlesey

Stoichiometric and catalytic C-F bond activation by the trans-dihydride NHC complex [Ru(IEt2Me2)2(PPh3)2H2] (IEt2Me2 = 1,3-diethyl-4,5-dimethylimidazol-2-ylidene).

DOI：
10.1039/c5dt01996f
发表时间：
2015-11
期刊：
Dalton transactions
影响因子：
4
作者：
Mateusz K. Cybulski;Ian M. Riddlestone;M. Mahon;Timothy J. Woodman;M. Whittlesey
通讯作者：
Mateusz K. Cybulski;Ian M. Riddlestone;M. Mahon;Timothy J. Woodman;M. Whittlesey

Room Temperature Regioselective Catalytic Hydrodefluorination of Fluoroarenes with trans -[Ru(NHC) 4 H 2 ] through a Concerted Nucleophilic Ru-H Attack Pathway

通过协同亲核 Ru-H 攻击途径，用反式 -[Ru(NHC) 4 H 2 ] 进行氟芳烃的室温区域选择性催化加氢脱氟反应