Rapid study of organic reactions in flow systems

Abstract

Continuous flow processing has become a frequent and invaluable tool in chemistry laboratories, thanks to unique control over reaction parameters, confinement of the reaction space allowing for the execution of hazardous chemistry and increasing the process safety, incorporation of modern analytical techniques for reaction monitoring, and ability to fully automate studied processes. All these aspects allowed for flow chemistry to make a significant impact within the domain of organic chemistry, especially in the field of process investigation and optimisation where various methodologies utilising unique aspects of continuous processing have been developed. The first presented methodology is for the investigation of solvent mixtures effects in organic reactions. A gradient of solvent composition is generated with time during a working flow experiment and in situ reaction monitoring affords information on reaction outcome against a full range of studied solvent mixture composition. The methodology was developed utilising model nucleophilic substitution reaction and then applied to imine formation reaction, where binary and ternary solvent mixtures have been investigated showing interesting non-linear results. The second technique developed allows for rapid investigation of process functional group compatibility and additive effects, presented in the example of solid phase catalysed click reaction. In such, the molecule containing investigated functional group or the additive is injected as a plug into a working stream of organic reaction, with simultaneous monitoring of the reaction mixture. The developed methodology allows for the determination of process compatibility with various organic moieties, and the nature of additive effect as well its reversibleness in a single flow experiment. A robust and versatile protocol for the synthesis of 1-monosubstituted and 1,4-disubstituted 1,2,3-triazoles in flow using copper-on-charcoal as a heterogeneous catalyst is presented. The methodology delivered a diverse set of substituted 1,2,3-triazoles with good functional group tolerance and high yields. Moreover, 2-ynoic acids were used as small-chain alkyne donors in a decarboxylation/cycloaddition cascade, allowing highly hazardous gaseous reagents to be bypassed. Finally, the flow platform was used for validation of the Switch-Off method and analysis of the optimisation experiments. The methodology relies on switching off the light source during the working photochemical flow transformation and monitoring the reaction composition as it leaves the photoreactor. Thus, the effect of all irradiation times up to a maximum can be analysed in a single flow experiment.

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Identifiers

ORCID for Dawid Drelinkiewicz: orcid.org/0000-0002-7181-8366

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

ORCID for David Harrowven: orcid.org/0000-0001-6730-3573

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