Influence of temperature for the azide displacement in benzodiazepine derivatives: Experimental and DFT study of competing SN1, SN2 and double SN2 reaction pathways

Molecules carrying the azido functionality are widely used as intermediates in medicinal chemistry. Pyrrolobenzodiazepines are molecules with a broad range of interesting pharmacological properties. Due to the wide importance of azido-PBD as a key intermediate in many synthetic pathways, in this work we have investigated the effect of a variety of experimental parameters on the mechanism of nucleophilic substitution reaction for introducing an azide group into the PBD scaffold. This study was carried out by combined experimental and DFT approaches, showing that S(N)2 and double S(N)2 pathways are possible and highly dependent on the reaction temperature. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

This study investigates the importance of azido-PBD as an intermediate in medicinal chemistry and examines the mechanism of nucleophilic substitution reaction for introducing an azide group into the PBD scaffold. Experimental and DFT approaches reveal the possibility of S(N)2 and double S(N)2 pathways, with a high dependence on reaction temperature.