Adduct formation in electrospray ionization. Part 1: Common acidic pharmaceuticals

Electrospray ionization mass spectrometry is a critically important technique for the determination of small molecules, but its application for this purpose is complicated by its selectivity. For positive ion ESI-MS analysis of basic analytes, several investigators have pointed to the importance of analyte basicity as a source of selectivity. Currently, however, it is not known whether basicity in the gas phase or in solution is ultimately most important in determining responsiveness. The objective of these studies was to investigate the relative importance of basicity in solution and in the gas phase as factors that predict selectivity in positive ion ESI-MS analysis. ESI-MS response was compared for a diverse series of protonatable analytes in two different solvents, neat methanol and methanol with 0.5% acetic acid. A correlation was observed between analyte pK b and electrospray response. However, the response for the analytes with very high pK b values was significantly higher than would be expected based on concentration of the protonated form or the analyte in solution, and this higher response did not appear to result from gas-phase proton transfer reactions. Although all of the analytes investigated had higher gas-phase basicities than the solvent, their relative responses were not dictated by gas-phase basicity. Higher response was observed for all of the analytes studied in acidified methanol compared with neat methanol, and this higher response was most pronounced for weakly basic analytes. These findings support the use of analyte pK b for rational method development in ESI-MS analysis of small molecules.

Section: Surface Activity and Electrospray Responsementioning

confidence: 99%

Relative importance of basicity in the gas phase and in solution for determining selectivity in electrospray ionization mass spectrometry

Ehrmann

Henriksen

Cech

2008

“…Unfortunately, many common oxygen-containing compounds, including carboxylic acids, do not produce stable protonated molecules when ionized by the commonly employed positive-mode ESI. Hence, such compounds have been generally analyzed using negative-mode ESI due to their acidic nature [33][34][35]. Regrettably, the majority of this past work provides no structural information that would allow, for example, the differentiation of isomers.…”

Section: Introductionmentioning

confidence: 99%

Differentiation of Regioisomeric Aromatic Ketocarboxylic Acids by Positive Mode Atmospheric Pressure Chemical Ionization Collision-Activated Dissociation Tandem Mass Spectrometry in a Linear Quadrupole Ion Trap Mass Spectrometer

Amundson

Owen

Gallardo

et al. 2011

Positive-mode atmospheric pressure chemical ionization tandem mass spectrometry (APCI-MS n ) was tested for the differentiation of regioisomeric aromatic ketocarboxylic acids. Each analyte forms exclusively an abundant protonated molecule upon ionization via positive-mode APCI in a commercial linear quadrupole ion trap (LQIT) mass spectrometer. Energy-resolved collision-activated dissociation (CAD) experiments carried out on the protonated analytes revealed fragmentation patterns that varied based on the location of the functional groups. Unambiguous differentiation between the regioisomers was achieved in each case by observing different fragmentation patterns, different relative abundances of ion-molecule reaction products, or different relative abundances of fragment ions formed at different collision energies. The mechanisms of some of the reactions were examined by H/D exchange reactions and molecular orbital calculations.

“…However, the general order of the ion intensities from the deprotonated amides was found to be in good agreement with expected acidity based on resonance effects in aromatic substitution. Schug and McNair compared the negative ionization response of six ibuprofen analogs of similar acidity (pKa values of 4.14 to 4.41) under various solvent conditions [12]. The preference to form cluster ions was found to be related to the structure and properties (such as polarity and nature of substituents) of the individual compounds.…”

mentioning

confidence: 99%

The relative influences of acidity and polarity on responsiveness of small organic molecules to analysis with negative ion electrospray ionization mass spectrometry (ESI-MS)

Henriksen

Juhler

Svensmark

et al. 2005

149

123

The purpose of the work presented here was to evaluate the influence of solution composition and analyte characteristics on responsiveness to analysis with negative ion electrospray ionization mass spectrometry. The responses of a series of structurally diverse acidic molecules were compared in various solvents. Response was generally observed to be higher in methanol than acetonitrile and response for all analytes was poorer when water was mixed with the organic solvent. A positive correlation between negative ion ESI-MS response and log P was observed when either acetonitrile or methanol was used as the electrospray solvent. This result was expected because analytes with significant nonpolar character should be particularly responsive to ESI-MS analysis due to their higher affinity for electrospray droplet surfaces. It was also predicted that highly acidic analytes would be most responsive to analysis with negative ion ESI-MS due to their tendency to form negative ions. However, for the analytes studied here, acidity was found not to have a consistent influence on ESI-MS response. Many of the highly acidic molecules were quite polar and, consequently, were poorly responsive. Furthermore, the deprotonated molecular ion was detected for a number of molecules with very high pKa values, which would not be expected to form negative ions in the bulk solution. Ultimately, these results indicate that acidity is not a conclusive parameter for prediction of the relative magnitudes of negative ion ESI-MS response among a diverse series of analytes. Analyte polarity does; however, appear to be useful for this purpose. (J Am Soc Mass Spectrom 2005, 16, 446 -455)