Infrared spectrum of the cold ortho-fluorinated protonated neurotransmitter 2-phenylethylamine: competition between NH+⋯π and NH+⋯F interactions

Abstract

Halogenation of pharmaceutical molecules is a common tool to modify their physiological properties. The geometric, vibrational, and electronic properties of the ortho-fluorinated protonated neurotransmitter 2-phenylethylamine (oF-H⁺PEA) are characterized by infrared photodissociation (IRPD) spectroscopy in the NH stretch range using the messenger technique and dispersion-corrected density functional theory calculations at the B3LYP-D3/aug-cc-pVTZ level to elucidate the drastic effect of site-specific ortho-fluorination. The IRPD spectra of cold oF-H⁺PEA–Rg dimers (Rg = Ne, Ar) are assigned to the most stable gauche conformer (Gf1) of oF-H⁺PEA, which benefits from both NH⁺⋯π and NH⁺⋯F interactions. A minor contribution (∼5%) of the slightly less stable Gf2 gauche conformer (E₀ = +1.1 kJ mol⁻¹) is also identified. Comparison of oF-H⁺PEA with unsubstituted H⁺PEA reveals a much stronger NH⁺⋯π interaction in H⁺PEA resulting in a large red shift of the bonded NH stretch frequency. This behavior is confirmed by natural bond orbital (NBO) analysis and noncovalent interaction (NCI) calculations. The Rg ligand prefers a binding site at which it can maximize the interaction with the aromatic π electron system and the ammonium group. Although the intermolecular interactions with the Rg atoms can compete with the noncovalent intramolecular bonds, they induce only minor spectral shifts in the NH stretch range.