Connected nucleophilic substitution-Claisen rearrangement in flow : analysis for kilo-lab process solutions with orthogonality


Shahbazali, E., Spapens, M.R.P., Kobayashi, H., Ookawara, S., Noel, T. & Hessel, V. (2015). Connected nucleophilic substitution-Claisen rearrangement in flow : analysis for kilo-lab process solutions with orthogonality. Chemical Engineering Journal, 281, 144-154. In Scopus Cited 2 times.

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The two-step synthesis of phenol to 2-allylphenol in micro flow is investigated. This synthesis involves a nucleophilic substitution (SN2) reaction of phenol with allyl bromide towards allyl phenyl ether and the thermal Claisen rearrangement of allyl phenyl ether to 2-allylphenol. This carbon–carbon bond forming reaction route would provide a valuable path towards complex molecules. Flow cascades have turned into a powerful approach to provide chemical diversity (process-design intensification). This is enabled by chemical intensification of the Claisen rearrangement in micro flow, by reducing the reaction time to minutes without the need of a catalyst. While both individual reaction steps have been optimized separately in earlier research, an initial directly connected two-step synthesis gave low selectivity.

Accordingly, the main topic investigated is how to achieve orthogonality in case of reagent mismatch between the two reactions. First, four flow process protocols using three different kinds of in-flow separation and one kinetic approach, are developed at laboratory scale. From there, process design sheets for kilolab processing set-ups of the suited approaches are developed which shed first light on their industrial practicality. In particular, it has been found that the main causes for the drop in selectivity are the presence of the base DBU and the reactant allyl bromide during the Claisen rearrangement. Three of the four investigated separation approaches demonstrated the ability to improve the overall yield – acid–base extraction, acid absorption by using ion exchange resin, using heterogeneous base, and dilution as kinetic approach. Finally, for every option, the proposed respective production set-up, anticipated advantages and drawbacks are given to facilitate a decision.


Flow chemistry;


Claisen rearrangement;

Continuous process design