Use of flow techniques to investigate organic reactions

Abstract

Flow chemistry, the basis of petrochemical and bulk chemicals industry, has recently found various applications in fine chemicals production and discovery chemistry with the development of commercially available laboratory equipment. Due to the precise control of the reaction parameters, the potential for automation and sequencing of reactions, the in situ analysis and for safety reasons the development of this novel technology has proven to make significant impact within organic chemistry.

By taking advantage of the potential of flow chemistry, the optimisation of difficult batch reactions involved in the total synthesis of epicocconone analogues, and the in situ generation of isocyanides were attempted. However, some limitations such as solubility issues and formation of insoluble species made the optimisations complicated.

Then, activation energies and reaction rate constants were determined from the thermolysis of 1,3-dioxin-4-ones by means of in situ analysis (UV and IR) and by using conventional and novel kinetic study methods. Good consistency was observed between both procedures. The significant gain in time and the lower consumption of material were the main advantages of this novel methodology which can be used as a reliable tool to accelerate reaction study and process development.

Finally, the flow platform was employed to develop optimisation of reaction methodologies by using the dispersion effect and the “turn off” light concept. Thermolysis of 1,3-dioxin-4-one, Diels-Alder reaction, [2+2] photocycloaddition, photocyclisation and SRN1 reactions were used as models for the development of these two methodologies.
The determination of the rate constant of both 1st and 2nd order reactions, the determination of the optimum amount of reagent and the determination of the optimum concentration of starting material were achieved with the dispersion effect methodology. Then, the “turn off” light procedure was developed to rapidly determine the optimum reaction time. Consistent results were obtained for both new methodologies.

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Identifiers

ORCID for Richard J. Whitby: orcid.org/0000-0002-9891-5502

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