title: Effects of Aromatic Fluorine Substitution on Protonated Neurotransmitters: The Case of 2-Phenylethylamine.
abstract: Fluorination of pharmaceutical compounds is a common tool to modulate their physiochemical properties. We determine the effects of site-specific aromatic fluorine substitution on the geometric, energetic, vibrational, and electronic properties of the protonated neurotransmitter 2-phenylethylamine (xF-H(+) PEA, x=ortho, meta, para) by infrared multiphoton photodissociation (IRMPD) in the fingerprint range (600-1750 cm(-1) ) and quantum chemical calculations at the B3LYP-D3/aug-cc-pVTZ level. The IRMPD spectra of all ions are assigned to their folded gauche conformers stabilized by intramolecular NH(+) ⋅⋅⋅π hydrogen bonds (H-bonds) between the protonated amino group and the aromatic ring. H→F substitution reduces the symmetry and allows for additional NH(+) ⋅⋅⋅F interactions in oF-H(+) PEA, leading to three distinct gauche conformers. In comparison to oF-H(+) PEA, the fluorination effects on the energy landscape (energy ordering and isomerization barriers) in pF-H(+) PEA and mF-H(+) PEA with one and two gauche conformers are less pronounced. The strengths of the intramolecular NH(+) ⋅⋅⋅F and NH(+) ⋅⋅⋅π bonds are analyzed by the noncovalent interaction (NCI) method.
authors.affiliation: Institut für Optik und Atomare Physik, Technische Universität Berlin, Hardenbergstr. 36, 10623, Berlin, Germany.
authors.forename: Markus
authors.identifier: 0000-0002-3773-6009
authors.initials: M
authors.lastname: Schütz
authors.affiliation: Institut für Optik und Atomare Physik, Technische Universität Berlin, Hardenbergstr. 36, 10623, Berlin, Germany.
authors.forename: Aude
authors.initials: A
authors.lastname: Bouchet
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma "La Sapienza", P. le A. Moro 5, 00185, Roma, Italy.
authors.forename: Barbara
authors.identifier: 0000-0002-1585-7061
authors.initials: B
authors.lastname: Chiavarino
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma "La Sapienza", P. le A. Moro 5, 00185, Roma, Italy.
authors.forename: Maria Elisa
authors.identifier: 0000-0002-0991-5034
authors.initials: ME
authors.lastname: Crestoni
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma "La Sapienza", P. le A. Moro 5, 00185, Roma, Italy.
authors.forename: Simonetta
authors.identifier: 0000-0002-6312-5738
authors.initials: S
authors.lastname: Fornarini
authors.affiliation: Institut für Optik und Atomare Physik, Technische Universität Berlin, Hardenbergstr. 36, 10623, Berlin, Germany. dopfer@physik.tu-berlin.de.
authors.forename: Otto
authors.identifier: 0000-0002-9834-4404
authors.initials: O
authors.lastname: Dopfer
mesh_terms: D005461:Fluorine / Q000737:chemistry*; D006860:Hydrogen Bonding; D007536:Isomerism; D013058:Mass Spectrometry; D008968:Molecular Conformation; D018377:Neurotransmitter Agents / Q000737:chemistry*; D010627:Phenethylamines / Q000737:chemistry*; D011522:Protons; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D018377:Neurotransmitter Agents; D010627:Phenethylamines; D011522:Protons; D005461:Fluorine; C029261:phenethylamine
keywords: fluorination; hydrogen bonds; neurotransmitters; protonation; structure elucidation