Unraveling the protonation site of oxazole and solvation with hydrophobic ligands by infrared photodissociation spectroscopy

Abstract

Protonation and solvation of heterocyclic aromatic building blocks control the structure and function of many biological macromolecules. Herein the infrared photodissociation (IRPD) spectra of protonated oxazole (H⁺Ox) microsolvated by nonpolar and quadrupolar ligands, H⁺Ox-L_n with L = Ar (n = 1–2) and L = N₂ (n = 1–4), are analyzed by density functional theory calculations at the dispersion-corrected B3LYP-D3/aug-cc-pVTZ level to determine the preferred protonation and ligand binding sites. Cold H⁺Ox-L_n clusters are generated in an electron impact cluster ion source. Protonation of Ox occurs exclusively at the N atom of the heterocyclic ring, in agreement with the thermochemical predictions. The analysis of the systematic shifts of the NH stretch frequency in the IRPD spectra of H⁺Ox-L_n provides a clear picture of the sequential cluster growth and the type and strength of various competing ligand binding motifs. The most stable structures observed for the H⁺Ox-L dimers (n = 1) exhibit a linear NH⋯L hydrogen bond (H-bond), while π-bonded isomers with L attached to the aromatic ring are local minima on the potential and thus occur at a lower abundance. From the spectra of the H⁺Ox-L(π) isomers, the free NH frequency of bare H⁺Ox is extrapolated as ν_NH = 3444 ± 3 cm⁻¹. The observed H⁺Ox-L₂ clusters with L = N₂ feature both bifurcated NH⋯L₂ (2H isomer) and linear NH⋯L H-bonding motifs (H/π isomer), while for L = Ar only the linear H-bond is observed. No H⁺Ox-L₂(2π) isomers are detected, confirming that H-bonding to the NH group is more stable than π-bonding to the ring. The most stable H⁺Ox-(N₂)_n clusters with n = 3–4 have 2H/(n − 2)π structures, in which the stable 2H core ion is further solvated by (n − 2) π-bonded ligands. Upon N-protonation, the aromatic C–H bonds of the Ox ring get slightly stronger, as revealed by higher CH stretch frequencies and strongly increased IR intensities.