Cover Picture: Aqueous Instability of δ‐Fluorobutylpiperidines (ChemMedChem 6/2017)

Abstract

The front cover picture shows the fate of a δ‐fluorobutylpiperidine in a mixture of organic solvent and water. Fluorinated alkyl groups are chemically quite robust in general. However, when carrying a single fluorine atom (green sphere) four carbon atoms away from an amine nitrogen center (large blue sphere), a fluoroalkyl group may become labile under very mild assay conditions, such as for the determination of lipophilicity. Such δ‐fluoroalkyl amines suffer fluorine expulsion through intramolecular attack by the amine nitrogen to form cyclic products, represented here by the karate kick. The reactivity is extraordinary as such fluorinated N‐alkylamine derivatives are otherwise fully stable in various organic solvents during synthesis, isolation, and purification. These findings constitute an important caveat to molecular design in drug discovery. More information can be found in the Full Paper by Klaus Müller et al. on page 431 in Issue 6, 2017 (DOI: 10.1002/cmdc.201700027).