Experimental/Computational Study on the Impact of Fluorine on the Structure and Noncovalent Interactions in the Monohydrated Cluster of ortho-Fluorinated 2‑Phenylethylamine

• Published in: Journal of the American Chemical Society 2022-05, Vol.144 (18), p.8337-8346
• Main Authors: Rahimi, Rami, Shachar, Afik, Bar, Ilana
• Format: Article
• Language: English
• Subjects: Fluorine; Hydrogen Bonding; Molecular Conformation; Phenethylamines
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.2c02480

Fluorine-containing medicinal compounds frequently allow modulation of physical–chemical properties. Here, we address the effect of fluorine, near the ethylamino side chain, on conformational flexibility and noncovalent interactions (NCIs) of the selected jet-cooled monohydrated cluster of 2-(2-fluoro-phenyl)-ethylamine (2-FPEA) by mass-selected resonance-enhanced two-photon ionization and ionization-loss stimulated Raman spectroscopies. Our results show that Raman spectral signatures of the 2-FPEA–H2O cluster match the scaled harmonic vibrational Raman frequencies, resulting from density functional theory calculations of the most stable 2-FPEA gauche conformer hydrogen-bonded (HB) to water, confirming the three-dimensional cluster structure. This predicted electronic structure, together with NCI analysis, allows visualization and assessment of the attractive and repulsive interactions. The comparison of the NCIs and revealed red (O–H and N–H stretches) and blue shifts (C–H stretches and CH2 out-of-plane bends) of the cluster to other class members confirm O–H···N, N–H···π, C–H···O, and C–H···F HB formation and their contribution to structure stabilization, uncovering the potential of the approach.