A New Paradigm for Selective Bromination in Flow

溴化是合成用作农用化学品或药物中的活性物质的复杂有机分子的常见起点。然而，它带来了两个关键挑战：（i）处理元素溴是困难的，因为它是有毒的、腐蚀性的和危险的，并且难以处理和储存;（ii）控制反应的选择性是困难的，但对于生产所需产物是至关重要的。克服这些挑战的方法是使用流动化学来“按需”产生溴化试剂，并将它们直接用于与底物的反应中，以产生具有良好选择性的所需产物，例如控制芳环的化学选择性和区域选择性溴化。流动化学的好处有三个方面：（i）不稳定的中间体可以在原位产生并立即部署在反应中;从而最大限度地减少危险库存;（ii）更大的量（在工艺中）易于放大;（iii）通过控制停留时间和更好的热管理可以有利于动力学产物。该项目将在以下方面开展工作：-从无害前体就地生成溴化物质。这可以通过化学方法、电化学或光化学活化来实现。设计和设置合适的流动化学方法，考虑与反应动力学，质量和热量传递，所选反应器类型和其他单元操作，其顺序，安全性，腐蚀和过程控制相关的方面。生产研究量材料的装置的操作及其关于选择性和产率的表征。- 在较长时间内扩大反应器/操作规模，以提供数kg所需组分。该项目的数字方面涉及反应器的建模和设计，以及通过机器学习或实验设计方法优化成分和工艺参数。

Bromination is a common starting point in the synthesis of complex organic molecules to be used as actives in agrochemicals or pharmaceuticals. However, it entails two key challenges: (i) handling elemental bromine is difficult, as it is toxic, corrosive and hazardous and is difficult to handle and store; (ii) controlling selectivity of the reaction is difficult and yet crucial for producing the desired product. The approach to overcome these challenges is to use flow chemistry to generate bromination reagents 'on-demand' and utilise them directly in a reaction with the substrate to yield the desired product with good selectivity, e.g. controlling chemoselective and regioselective bromination of an aromatic ring. The benefits of flow chemistry are threefold: (i) unstableintermediates can be generated in-situ and deployed immediately in the reaction; thus minimizing hazardous inventory, (ii) larger amounts (in the process is easy to scale up, and (iii) the kinetic product can be favoured by controlling residence time and better heat management. In the project the following aspects will be developed: - In-situ generation of the brominating species from non-hazardous precursor. This can be achieved by chemical means, electrochemical, or photochemical activation.- Design and setup of a suitable flow chemistry methodology taking into consideration aspects relating to the reaction kinetics, mass and heat transfer, the selected reactor type and other unit operations, their sequence, safety, corrosion, and process control.- Operation of the setup to produce research amounts of material and its characterization regarding selectivity and yield. - Scale up of the reactor/operation over longer periods to deliver several kg of desired component.- Digital aspects of the project involve modelling and design of the reactor, and optimization of compositional and processing parameters, through machine learning or design-of-experiment approaches, for example.