https://doi.org/10.15255/KUI.2021.070
Published: Kem. Ind. 71 (5-6) (2022) 359–373
Paper reference number: KUI-70/2021
Paper type: Review
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Renaissance of the Hofmann-Löffler-Freytag Reaction – Development of C–H Functionalisation Strategies Based on Green Chemistry Principles

G. Zubčić, S. Shkunnikova, D. Šakić and M. Marijan

Abstract

Increased demand for drugs has promoted the pharmaceutical and chemical industries as the most dynamic industries of the 21^st century. By using the Hofmann-Löffler-Freytag (HLF) reaction, the modification of pharmacologically active substances and biologically important compounds can be achieved in an environmentally friendly manner by highly efficient syntheses. This reaction enables the formation of new compounds according to the principles of green chemistry, without expensive metal catalysts. Numerous computational and experimental studies have shown exceptional flexibility and the possibility of optimising this method in order to increase the economy and reduce the amount of waste generated as by-products of synthetic processes. However, the mechanism of this reaction is yet to be elucidated sufficiently, and further experiments are necessary in order to determine the thermodynamic and kinetic parameters that control and guide the HLF reaction. It is necessary to determine the influence of substituents and solvents on 1,5-HAT or 1,6-HAT regioselectivity, and to recognise the mechanism responsible for switching between the radical and ionic mechanism of the reaction.

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Keywords

Hofmann-Löffler-Freytag reaction, green chemistry, 1,5-HAT, 1,6-HAT, regioselectivity, mechanistic switch