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Updated: Oct 21, 2025

A Scalable Balz-Schiemann Reaction Protocol in a Continuous Flow Reactor
Published on: February 10, 2023
Gram-Scale Domino Synthesis in Batch and Flow Mode of Azetidinium Salts
Alessandra Sivo1, Vincenzo Ruta1, Gianvito Vilé1
1Department of Chemistry, Materials, and Chemical Engineering "Giulio Natta", Politecnico di Milano, Piazza Leonardo da Vinci 32, IT-20133 Milano, Italy.
Abstract:
Azetidinium salts are important motifs in organic synthesis but are difficult to obtain due to extremely long synthetic protocols. Herein, a rapid continuous-flow process for the on-demand synthesis of azetidinium salts is described. In particular, the nucleophilic addition of secondary amines and the subsequent intramolecular N-cyclization have been investigated in batch and continuous-flow modes, exploring the effects of solvent type, temperature, reaction time, and amine substituent on the synthesis of azetidinium salts. This has enabled us to quickly identify optimal reaction conditions and obtain microkinetic parameters, verifying that the use of a flow reactor leads to a reduction of the activation energy for the epichlorohydrin aminolysis due to the better control of mass and heat transfer during reaction. This confirms the key role of continuous-flow technologies to affect the kinetics of a reaction and make synthetic protocols ultrarapid and more efficient.
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