title: Aqueous Instability of δ-Fluorobutylpiperidines.
abstract: In a series of partially fluorinated N-propyl- and N-butylpiperidine derivatives, three compounds were found to exhibit unexpected instability under mild biophysical assay conditions. These compounds carry a single terminal fluorine in the δ-position of an N-butyl group as a common structural feature. An adjacent fluorine substituent at the γ-position significantly slows down the reactivity. All other compounds, having either no or more than one fluorine substituent at the δ-position are chemically inert under all assay conditions. The reactivity of the labile compounds is traced to an intramolecular ring-closing fluorine substitution reaction by the moderately basic piperidine unit, leading to a spiro-pyrrolidinium salt. The chemical lability of δ-monofluorinated or γ,δ-difluorinated N-butylpiperidine derivatives even under very mild biophysical assay conditions constitutes a caveat to the molecular design of partially fluorinated alkylamines.
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Raffael
authors.initials: R
authors.lastname: Vorberg
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Erick M
authors.identifier: 0000-0003-1472-490X
authors.initials: EM
authors.lastname: Carreira
authors.affiliation: ETH Zürich, Laboratorium für Organische Chemie, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Klaus
authors.identifier: 0000-0003-3184-476X
authors.initials: K
authors.lastname: Müller
mesh_terms: D004355:Drug Stability; D005461:Fluorine / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010880:Piperidines / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D014867:Water / Q000737:chemistry*
chemical_list: D010880:Piperidines; D014867:Water; D005461:Fluorine; C032727:piperidine
keywords: 5-azaspiro[4.5]decan-5-ium salts; fluorinated n-alkylpiperidines; fluorine displacement; instability; reaction rates; δ-fluorobutylamine