Potassium Fluoride as a Green Base for Alkylation Reactions in Flow

Carrying out chemical reactions in a continuously flowing stream of liquid known as Flow Chemistry, has gained popularity in recent years due to the simpler operation, greater safety, better control and reproducibility it offers compared to traditional batch chemical approaches. The combination of flow chemistry with optimisation principles has great potential to contribute to the field of Green Chemistry, which focuses on the design of chemicals and processes to make them safer and more sustainable. This work focuses on exploring the use of potassium fluoride (KF) as a green base for alkylation reactions in flow namely N-alkylation and C-alkylation processes. Initially, preliminary batch experiments to evaluate previously reported KF-catalysed alkylation reactions were conducted. In this study it was found that the previously reported alkylation of piperidine and acetylacetone were not replicable, but the N-alkylation of aniline and C-alkylation of 1,3-indandione and diethyl malonate were successful albeit lower yield than was reported in the literature. The successful batch reactions were then attempted in flow, ultimately identifying the reaction between diethyl malonate and benzyl bromide as a suitable target for further optimisation. Subsequently, the stability and lifetime of the KF catalyst were investigated before key parameters such as stoichiometry, flow rate, pressure, and temperature were systematically optimised for the target transformation using fractional factorial design and response surface methodology. The optimised flow conditions significantly reduced the reaction time compared to batch conditions, and it was found that lower flow rates and higher temperatures improved conversion. Although it was found that the stationary point used to predict the optimal value of the response surface curve was too close to the boundary of the parameter space, resulting the inaccurate optimal value, the model was still able to provide information on the optimal levels of each parameter and the final optimised reactions demonstrated the ability of this approach to guide towards the direction of maximum conversion. Promising preliminary results were also observed when the optimised conditions were applied to alternative substrates. Despite the challenges encountered, study demonstrates the potential of combining optimisation principles with flow chemistry to rapidly investigate greener and more efficient reactions

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