Reagent-Free Flow Chemistry: The Generation and Trapping of Reactive Intermediates

无试剂流动化学：反应中间体的生成和捕获

• 批准号: EP/G027986/1
• 负责人: Richard Whitby
• 金额: $ 50.02万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FG027986%2F1
• 关键词: Reagent; Free; Flow; Chemistry; Generation

Traditionally the small-scale synthesis of organic compounds has been carried out using batch processes (the ubiquitous 'round bottom flask'). In comparison most large-scale industrial synthesis are continuous processes where the substrates are flowed through various reaction conditions and purifications. Recently equipment has been developed to allow 'flow synthesis' on the scale typically carried out in a research laboratory. Industry has enthusiastically adopted the new technology but there is a lack of people familiar with the method entering the job market as academia has, largely due to the cost of the equipment, not made much use of flow chemistry. Flow synthesis has one advantage which we believe makes it the future of synthetic organic chemistry - the output is a constant reflection of the conditions being used. To optimise a traditional batch process many separate reactions have to be carried out under various conditions and the product of each analysed in order to gradually converge on the best conditions. Using flow reactors dynamically varying the conditions and observing the output allows the equivalent of thousands of experiments to be carried out in a very short time under highly controlled conditions allowing fast optimisation. It should be possible to automate this optimisation process - an objective that this project takes the first steps towards.Our project is a collaboration between synthetic organic chemists and engineers which aims to: develop new flow technologies; develop new chemical processes which make the best use of flow techniques; promote the use of flow chemistry in the academic community by providing access to equipment and expert help; and provide three highly trained postgraduates who can take the field forward. The students carrying out the work spend half their time with our industrial partner ensuring rapid exchange of knowledge between industry and academia.The new flow technologies and chemical processes we aim to develop are unified by the overlapping concepts of 'Synthesis without Reagents' and 'Reactive Intermediate Trapping'. The former concept is driven by the desire to be able to achieve multi-step synthesis by sequencing a number of flow reactions where any by-products from the reagents used in a step might interfere with subsequent stages. The second concept is driven by the particular advantages of flow systems for the generation and trapping of reactive intermediates. Batch processes require both additional components, and the products of reaction, to be stable to the conditions used to generate the reactive intermediate. By allowing rapid combination of the 'reactive intermediate' stream with second 'component' stream under mild conditions flow systems overcome this limitation. Flow chemistry is little used for synthesis of the large number of diverse compounds needed for the discovery of new pharmaceuticals - its strength is traditionally the synthesis of large amounts of single compounds due to the effort involved in developing each flow synthesis route. We believe that we can achieve the synthesis of many different compounds by optimising a flow process to produce a reactive intermediate which may then be efficiently trapped by a wide range of reaction partners to produce the desired compounds. We plan to use either very high temperatures for a short time, or exposure to high energy Ultra-Violet light to generate the reactive intermediates.

传统上，有机化合物的小规模合成是使用分批工艺（普遍存在的“圆底烧瓶”）进行的。相比之下，大多数大规模工业合成是连续过程，其中底物流过各种反应条件和纯化。最近，已经开发了设备，以允许在通常在研究实验室中进行的规模上的“流动合成”。工业界热情地采用了新技术，但缺乏熟悉该方法的人进入就业市场，因为学术界在很大程度上由于设备的成本而没有充分利用流动化学。流动合成有一个优势，我们相信这使它成为合成有机化学的未来-输出是所使用的条件的恒定反映。为了优化传统的间歇工艺，必须在各种条件下进行许多单独的反应，并分析每个反应的产物，以便逐渐收敛到最佳条件。使用流动反应器动态改变条件并观察输出，允许在高度受控的条件下在非常短的时间内进行相当于数千次实验的实验，从而允许快速优化。我们的项目是合成有机化学家和工程师之间的合作，旨在：开发新的流动技术;开发新的化学工艺，充分利用流动技术;通过提供设备和专家帮助，促进流动化学在学术界的使用;开发新的化学工艺，以提高流动化学的效率。并提供三名训练有素的研究生，他们可以把这个领域向前推进。学生们将一半的时间花在我们的工业合作伙伴身上，以确保工业界和学术界之间的快速知识交流。我们旨在开发的新流程技术和化学工艺通过“无试剂合成”和“反应中间体捕获”的重叠概念统一起来。前一个概念是由能够通过对许多流动反应进行测序来实现多步合成的期望驱动的，其中来自步骤中使用的试剂的任何副产物可能干扰后续阶段。第二个概念是由流动系统产生和捕获活性中间体的特殊优势驱动的。间歇工艺需要额外的组分和反应产物，以在用于产生反应性中间体的条件下保持稳定。通过允许“反应性中间体”流与第二“组分”流在温和条件下快速组合，流动系统克服了这种限制。流动化学很少用于合成新药发现所需的大量不同化合物-其优势传统上是合成大量单一化合物，这是由于开发每个流动合成路线所涉及的努力。我们相信，我们可以通过优化流程来合成许多不同的化合物，以产生反应性中间体，然后该反应性中间体可以被广泛的反应伙伴有效地捕获，以产生所需的化合物。我们计划使用非常高的温度短时间，或暴露于高能量紫外线光来产生活性中间体。

项目成果

Thermolysis of 1,3-dioxin-4-ones: fast generation of kinetic data using in-line analysis under flow

1,3-二恶英-4-酮的热解：使用流动下在线分析快速生成动力学数据

• DOI: 10.1039/c5re00007f
• 发表时间: 2016
• 期刊: Reaction Chemistry & Engineering
• 影响因子: 3.9
• 作者: Durand T

Generation and Trapping of Ketenes in Flow.

• DOI: 10.1002/ejoc.201403603
• 发表时间: 2015-03
• 期刊: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
• 影响因子: 2.8
• 作者: Henry, Cyril;Bolien, David;Ibanescu, Bogdan;Bloodworth, Sally;Harrowven, David C.;Zhang, Xunli;Craven, Andy;Sneddon, Helen F.;Whitby, Richard J.
• 通讯作者: Whitby, Richard J.