ELSEP - Elucidate and Separate - Palladium Catalysts in C-C and C-N Coupling Reactions

钯催化是合成化学中形成C-C和C-N键的最有力的工具之一。然而，即使在使用非常高的底物与催化剂比或固定化催化剂时，金属浸出和催化剂分解仍然是重大的未解决问题。随着钯催化在精细化工和制药过程中越来越受欢迎，寻找方法将钯降低到可接受的水平成为一项重要的优先任务，特别是在制药应用中。虽然人们普遍认为，在许多情况下，催化活性是由于某种形式的可溶性钯(可从均相和非均相催化剂中获得)，但Pd物种的确切性质仍不清楚。相反，催化剂的失活和分解被认为与钯原子的团聚形成纳米颗粒有关，最终聚集在一起而变得不活跃(钯黑色)。目前还没有可靠的分析技术来现场表征这种可溶的钯物种的结构特征。最近，帝国(化学)的HII小组在这一领域取得了重要进展，研究了导致Pd(OAc)2形成Pd(0)的条件，使用质谱仪和ESRF的光束线ID24相结合进行了研究。有机溶剂纳滤(OSN)膜分离有机液体中的分子是目前膜科学研究的一个新领域。Imperial(化学工程)的利文斯顿小组是该领域的领先研究小组之一，他们开发了新的膜，几乎在所有溶剂中都稳定，具有可调的分子识别性能。这项提议寻求将Hii小组在分析有机反应中的Pd物种方面取得的进展与Livingston小组在OSN膜方面的创新结合起来。这个由化学工程师和化学家组成的强大的跨学科团队将首先试图了解在钯催化的反应中，钯是如何以及以什么形式达到溶液的。然后，我们将利用这些知识开发通过过滤-吸附分离钯的新方法。该项目将使用均相催化的铃木-宫浦(C-C键形成)和Buchwald-Hartwig(C-N键形成)交叉偶联反应，这是工业上最重要的两个钯催化反应。对于每个模型系统，将应用先进的分析技术，如EXAFS和质谱仪，以阐明催化循环中Pd物种的物理和化学结构。利用电喷雾质谱(ESI-MS)和电喷雾离子发射光谱(MALDI-TOF)、电感耦合等离子体发射光谱(ICP)和高效液相色谱(HPLC)等一系列技术，对这些反应进行详细监测，以检测与反应不同阶段相关的钯的种类。反应或反应后的混合物预计会含有钯副产物的混合物，这可能会给分析带来问题。预计这些副产物将具有不同的分子量，并可通过一系列截留分子量逐渐变紧的膜进行分离，从而提供分子分级。将使用上述分析技术对来自膜的渗透和保留流进行分析，以确定反应体系中钯物种的结构和性质的差异。通过这种方式，通过膜进行分子分级将被用来了解这些反应的详细化学。此外，将开发新的OSN膜，其表面官能化的物种捕捉可溶的Pd物种。这一步将利用从基础反应研究中获得的关于钯的形式的知识。总体而言，我们寻求在理解C-C化学工程和C-N偶联反应技术方面取得进展，这是膜科学的一个方面。

Palladium catalysis is one of the most powerful tools in synthetic chemistry for C-C and C-N bond formation. However, even when using very high substrate-to-catalyst ratio or immobilised catalysts, metal leaching and catalyst decomposition remain significant unsolved problems. As Pd catalysis gains greater popularity in fine chemicals and pharmaceutical processes, seeking methods to reduce Pd to acceptable levels becomes a task of major priority especially for pharmaceutical applications. While it is generally accepted that, in many cases, catalytic activity is due to some form of soluble palladium (which can be obtained from both homogeneous and heterogeneous catalysts), the precise nature of the Pd species is still unknown. Conversely, catalyst deactivation and decomposition are thought to be linked to agglomeration of Pd atoms to form nanoparticles, eventually so clustered as to become inactive (Pd black ). There are currently no reliable analytical techniques for the structural characterisation of such soluble palladium species in situ. Recently, the Hii group at Imperial (Chemistry) has made an important advance in this area, by examining the conditions that lead to the formation of Pd(0) from Pd(OAc)2, conducted using a combination of mass spectrometry and beamline ID24 at the ESRF. Molecular scale separation in organic liquids using membranes (Organic Solvent Nanofiltration, OSN) is now emerging as a new area of membrane science. The Livingston group at Imperial (Chemical Engineering) is one the leading research groups in this field, and have developed new membranes, stable in nearly all solvents, with tuneable molecular discrimination properties. This proposal seeks to couple the advances made by the Hii group in the analysis of Pd species in organic reactions with the innovations in OSN membranes coming out of the Livingston group. This powerful, cross-disciplinary team of chemical engineers and chemists will seek first to understand how, and in what form, Pd reaches solution during Pd catalysed reactions. Then, we will use this knowledge to develop new approaches to separation of Pd through filtration-adsorption with a new family of functionalised OSN membranes.The project will advance using homogeneous catalysis for the Suzuki-Miyaura (C-C bond forming) and Buchwald-Hartwig (C-N bond forming) cross-coupling reactions, two of the most important Pd-catalysed reactions of industrial interest. For each of the model systems, advanced analytical techniques such as EXAFS and mass spectrometry will be applied to elucidate physical and chemical structure of Pd species in the catalytic cycles. The reactions will be monitored by mass spectrometry in close detail using a battery of techniques including ESI-MS and MALDI-TOF, ICP and HPLC to detect the species of Pd associated with various stages of the reaction. Reacting or post-reaction mixtures are expected to contain a mixture of palladium by-products which may present problems for the analysis. It is expected that these by-products will be of different molecular weight and could be separated via a series of membranes with progressively tighter molecular weight cut-offs thus providing molecular fractionation. Permeate and retentate streams from the membranes will be analysed using the above analytical techniques to determine the differences in the structure and nature of Pd species in the reacting system. In this way, molecular fractionation by membranes will be used to understand the detailed chemistry of these reactions. Further, new OSN membranes which are surface functionalised with species which capture soluble Pd species will be developed. This step will utilise the knowledge of the form of Pd that is gained from the fundamental reaction studies. Overall we seek to make advances in both understanding anc chemical engineering of C-C and C-N coupling reaction technology, an in membrane science.