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

传统上，有机化合物的小规模合成是通过间歇过程(无处不在的“圆底烧瓶”)进行的。相比之下，大多数大规模的工业合成是连续的过程，底物通过不同的反应条件和纯化流动。最近，已经开发出一种设备，可以实现通常在研究实验室进行的规模的“流动合成”。工业界热情地采用了这项新技术，但缺乏熟悉这种方法的人进入就业市场，这在很大程度上是由于设备的成本，没有太多地利用流动化学。流动合成有一个优点，我们认为这使它成为合成有机化学的未来--输出是对所用条件的持续反映。为了优化传统的间歇过程，必须在不同的条件下进行许多单独的反应，并对每个反应的产物进行分析，以便在最佳条件下逐渐收敛。使用流动反应器动态改变条件并观察输出，可以在非常短的时间内在高度可控的条件下进行相当于数千个实验的操作，从而实现快速优化。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；开发充分利用流动技术的新化学工艺；通过提供设备和专家帮助，在学术界推广流动化学的使用；并提供三名训练有素的研究生，他们可以推动该领域的发展。从事这项工作的学生有一半的时间与我们的工业合作伙伴在一起，确保了工业界和学术界之间快速的知识交流。我们致力于开发的新流程技术和化学工艺是由重叠的概念统一的，这两个概念是“无试剂合成”和“活性中间体捕集”。前一个概念是由于希望能够通过对多个流动反应进行排序来实现多步骤合成的愿望，其中在一个步骤中使用的试剂的任何副产物可能会干扰后续步骤。第二个概念是由流动系统产生和捕集活性中间体的独特优势所驱动的。间歇过程要求附加成分和反应产物都要稳定到生成活性中间体所用的条件。通过允许在温和条件下快速结合“活性中间”流和第二“组分”流，流量系统克服了这一限制。流动化学很少用于合成发现新药物所需的大量不同的化合物-它的优势传统上是由于开发每条流动合成路线所涉及的努力而合成大量单一化合物。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，以产生一种活性中间体，然后该中间体可能会被广泛的反应伙伴有效地捕获，从而产生所需的化合物。我们计划在很短的时间内使用非常高的温度，或者暴露在高能的紫外光下来产生活性中间体。

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.