Where’s the Charge? Protonation Sites in Gaseous Ions Change with Hydration

Abstract

The role of water in stabilizing sites of protonation in small gaseous ions is investigated using electrospray ionization (ESI) coupled with infrared photodissociation spectroscopy and computational chemistry. Protonation of p-aminobenzoic acid (PABA) and p-aminobenzoic acid methyl ester (PABAOMe) occurs at the carbonyl oxygen atom both in isolation and when one water molecule is attached. However, protonation occurs at the amine nitrogen atom, which is the most favorable site in aqueous solution, for PABAOMeH(+)·(H(2)O)(3) and for a significant fraction of PABAH(+)·(H(2)O)(6). Fewer water molecules are necessary to stabilize the solution-phase isomer of PABAOMeH(+) (3) than for PABAH(+) (≥6), indicating that the favorable hydrogen bonding in PABAH(+) is a more important factor than the higher gas-phase basicity of PABAOMeH(+) in stabilizing protonation at the carbonyl oxygen atom. Relative Gibbs free energies (133 K) calculated using B3LYP and MP2 with the 6-311++G** basis set were significantly different from each other, and both are in poor agreement with results from the experiments. ωB97X-D/6-311++G**, which includes empirical dispersion corrections, gave results that were most consistent with the experimental data. The relative stabilities of protonating at the carbonyl oxygen atom for PABAH(+)·(H(2)O)(0-6) and PABAOMeH(+)·(H(2)O)(0-2) can be rationalized by resonance delocalization. These findings provide valuable insights into the solvent interactions that stabilize the location of a charge site and the structural transitions that can occur during the ESI desolvation process.

Studying Gas-Phase Interconversion of Tautomers Using Differential Mobility Spectrometry

“…This marks the onset of solution phase properties with respect to basicity. This finding is supported by an earlier IR photodissociation spectroscopy/computational study [64] that demonstrated that when fewer than 6 H 2 O molecules were bound to 4-ABA•H + , the O-protonated tautomer was more stable and abundant. However, with 6 and more H 2 O molecules, the Nprotonated tautomer (i.e., the more stable tautomer in protic liquid) was more stable and abundant.…”

Analyzing complex mixtures of drug-like molecules: Ion mobility as an adjunct to existing liquid chromatography-(tandem) mass spectrometry methods

“…Based on IM and MS/MS data, they conclude that these ions only differ in the site of protonation, and are thus referred to as "protomers". Other studies have reported on the observation of protomers for different analytes using both MS as well as other techniques such as gas-phase infrared photodissociation (IRPD) spectroscopy [56][57][58]. We also explain the observation here of two drift times for melphalan by the presence of charge isomers (protomers) in the gas phase [26].…”

Competing Insertion and External Binding Motifs in Hydrated Neurotransmitters: Infrared Spectra of Protonated Phenylethylamine Monohydrate

“…In particular,t he competition between the possible water-binding sites (NH 3 + , COOH)h as thoroughly been exploredt hrough the examples of protonated phenylalanine, [29] valine, [30] glycine, [31] tryptophan, [32,33] and tyrosine. [33] Hydration can also influence the protonation site [34][35][36] and, similar to the neutrals pecies, also the conformation of protonated biomolecules. [37][38][39][40] In contrast to amino acids, no spectrali nformation is availablef or H + PEA-(H 2 O) n clusters and related microhydrated protonated aromatic ethylamino neurotransmitters.…”