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Flow Chemistry for C-H Activation

Periodic Reporting for period 1 - FlowAct (Flow Chemistry for C-H Activation)

Reporting period: 2018-06-01 to 2020-05-31

The general objectives of this project revolved around the recent research field of C-H bond functionalization. Research in this field aims to demonstrate and improve the modification of organic molecules via the activation and subsequent functionalization of C-H bonds, very common in most organic molecules. The abundance of such bonds make them a versatile handle to increase the complexity of organic compounds; moreover, as such modifications do not require pre-functionalized starting materials, they have the advantage, compared to other methods, to considerably reduce the waste generated during the chemical reaction. The reduction of chemical waste has obvious advantages for society, environment, and industry.
As C-H bonds are relatively unreactive, specific conditions need to be applied for the process to occur in an effective manner, such as transition metal catalysis, photochemistry, and use of oxidants.
Continuous flow chemistry is an alternative methods to perform chemical reactions. In comparison to the classical mixing-and-stirring method typically used, flow chemistry involves pushing the reactants and reagents into a (micro)channel, where the reaction conditions (temperature, pressure, etc) are applied. The advantages of this methods are multiple, including: better heat transfer, better mixing, better irradiation (for photochemical processes), higher safety, and the possibility to continuously monitor the process. In many cases, this results in faster and safer reactions, and better yields and selectivity. Furthermore, it is a continuous method, which makes it suitable for large scale processes.
Due to the low reactivity of C-H bonds, and the often low selectivity of their functionalization (due to the many C-H bonds present in a typical molecule), flow chemistry offer the potential to improve the efficiency and applicability of these transformations. The objectives of this project were to demonstrate the efficiency and applicability of continuous flow chemistry techniques to this field.
The work undertaken during the action demonstrates that indeed flow chemistry can be effective to improve the outcome of C-H functionalization reactions, with particular effects in reducing the reaction time required, and/or increase the productivity in a continuous process. Good part of this work for carried out for light promoted transformations, which offer even more waste-reducing alternatives than metal-catalysed reactions, and for which flow chemistry shows even better performances.
"Several new photochemical transformations were investigated and/or developed during the action. These concern C-H functionalization methods and cross coupling reactions, also part of the initial objectives of the action. A two-step continuous flow process for the synthesis of an important class of reagents used in C-H functionalization methods has also been designed and optimized.
The results of the action were published in several peer-reviewed publications. One novel Iron-catalysed cross coupling was developed under flow photochemical conditions (published in Angewandte Chemie, 2019), as well as a new photocatalyzed C-N cleavage/C-H functionalization reaction for the modification of tetrahydroisoquinolines, important moieties found in several bioactive compounds (published in Beilstein Journal or Organic Chemistry, 2020). A method for the photochemical trifluoromethoxylation of aromatic compounds was transferred into flow conditions, which reduced significantly the reaction time in comparison with the traditional batch process (published in Beilstein Journal of Organic Chemistry, 2020), and another C-H alkylation method was studied in flow employing a recently developed photochemical reactor (published in Organic Process Research and Development, 2020). The multistep process mentioned above will be published in due course.
Other research lines were initiated, under photochemical or electrochemical conditions, and will be continued by the research group later on.
The research work was also presented at different conferences, such as the ""Conference on Frontiers in Organic Synthesis Technology"" (Budapest Oct. 2019), the ""Flow Chemistry Europe 2020"" (Cambridge Mar. 2020), and the virtual #RSCPoster Twitter Conference (Mar. 2020).
Apart from the experimental work, two reviews were published during the action, one dealing with the synthesis of heterocyclic compounds under aerobic conditions (published in Arkivoc, 2018), and one discussing recent advancements in the field of photochemistry in flow (published in Trends in Chemistry, 2020). A book chapter was also written on the functionalization of Csp3-H bonds remote from existing functionalities. This chapter will appear in the book ""Remote C-H Bond Functionalizations: Methods and Strategies in Organic Synthesis"", published by WILEY-VCH (expected: end of 2020)."
During the action, new chemical transformations were investigated and developed, in the general fields of C-H functionalization and cross-coupling. These fields are of high interest in modern synthetic organic chemistry, and are already of primary importance in the synthesis of new pharmaceutical and agrochemical compounds, and the methods developed will contribute to the achievement of more efficient and less wasteful chemical synthesis. Some of the work performed during the fellowship was in collaboration with pharmaceutical companies (Janssen pharma, AbbVie), which clearly show the interest of such companies in the research undertaken.
Other parts of the work demonstrate instead the advantages of flow chemistry as a method in itself, and its potential in improve reaction rate, increase productivity, and allow multistep syntheses. Apart from the effects that this technology has on chemical synthesis in general (e.g. faster, cleaner chemical manufacturing), reactor technology is of primary importance in this area, with corresponding effects on related companies. For example, some of the work undertaken was in collaboration with technology companies (Creaflow), to investigate new reactor types.