Effects of Aromatic Fluorine Substitution on Protonated Neurotransmitters: The Case of 2‐Phenylethylamine

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 ( x F‐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 o F‐H + PEA, leading to three distinct gauche conformers. In comparison to o F‐H + PEA, the fluorination effects on the energy landscape (energy ordering and isomerization barriers) in p F‐H + PEA and m F‐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.