Reagent-Free Flow Chemistry: The Generation and Trapping of Reactive Intermediates
Lead Research Organisation:
University of Southampton
Department Name: Sch of Chemistry
Abstract
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.
Publications
Durand T
(2016)
Thermolysis of 1,3-dioxin-4-ones: fast generation of kinetic data using in-line analysis under flow
in Reaction Chemistry & Engineering
Hamon M
(2014)
Intra- and intermolecular alkylation of N,O-acetals and p-activated alcohols catalyzed by in situ generated acid.
in The Journal of organic chemistry
Harrowven DC
(2012)
An efficient flow-photochemical synthesis of 5H-furanones leads to an understanding of torquoselectivity in cyclobutenone rearrangements.
in Angewandte Chemie (International ed. in English)
Henry C
(2015)
Generation and Trapping of Ketenes in Flow.
in European journal of organic chemistry
Mohamed M
(2011)
New insights into cyclobutenone rearrangements: a total synthesis of the natural ROS-generating anti-cancer agent cribrostatin 6.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Pagnoux-Ozherelyeva A
(2014)
Microwave irradiation and flow chemistry for a straightforward synthesis of piano-stool iron complexes
in Journal of Organometallic Chemistry
Description | An important achievement of the award was the development of a low cost photochemical flow reactor. The original aim was to use LED light sources, but the price of these at the wavelengths needed did not fall as expected so systems using commercial compact fluorescent lamps emitting selectively at particulary frequencies were developed. The flow design, and the ability to select frequencies lead to dramatic improvements in several photochemical processes, particularly involving rearrangements of cyclobutenones. A second aspect of the project was thermal generation of reactive intermediates which was successful synthetically, but also lead to what ended up being an important part of the project - the use of flow techniques with in-line IR and UV analysis to rapidly obtain kinetic data on reactions. |
Exploitation Route | The photochemical reactor was designed to allow an easy entry to flow photochemistry and should find wide use in academia (commercial alternatives cost several thousand pounds). The techniques for rapid acquisition of process data using flow is expected to be particularity useful in industrial process development. Several follow-on grants have demonstrated some ways the technology developed may be taken forward. |
Sectors | Chemicals Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | The grant lead directly to two KTN fellowships to transfer some of the knowledge generated in the project to industrial partners (Astra-Zeneca and Syngenta). It also lead directly to two substantial grants in the 'Manufacturing the Future' area which will produce equipment and techniques for commercial use. The employment of all three students from the project in industry where they are directly applying the skills acquired during the work, is also a significant impact. |
First Year Of Impact | 2011 |
Sector | Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | CASE conversion awards |
Amount | £56,000 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2015 |
End | 09/2018 |
Description | Closed Loop Optimisation for Sustainable Chemical Manufacture |
Amount | £1,271,409 (GBP) |
Funding ID | EP/L003309/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2013 |
End | 10/2015 |
Description | EPSRC Impact Acceleration Account KT Secondment. Bolien |
Amount | £34,438 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2013 |
End | 09/2014 |
Description | EPSRC Impact acceleration Account KT Secondment. Mohamed |
Amount | £49,547 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2014 |
End | 10/2014 |
Description | Factory in a Fumehood: Reagentless Flow Reactors as Enabling Techniques for Manufacture |
Amount | £940,746 (GBP) |
Funding ID | EP/L003325/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2013 |
End | 10/2016 |
Description | Rapid acquisition of process data using gradients in flow |
Amount | £80,000 (GBP) |
Organisation | Syngenta International AG |
Sector | Private |
Country | Switzerland |
Start | 09/2019 |
End | 03/2023 |