Identification of ortho-Substituted Benzoic Acid/Ester Derivatives via the Gas-Phase Neighboring Group Participation Effect in (+)-ESI High Resolution Mass Spectrometry

Journal of the American Society for Mass Spectrometry
William D BlincoeHuaming Sheng

Abstract

Benzoic acid/ester/amide derivatives are common moieties in pharmaceutical compounds and present a challenge in positional isomer identification by traditional tandem mass spectrometric analysis. A method is presented for exploiting the gas-phase neighboring group participation (NGP) effect to differentiate ortho-substituted benzoic acid/ester derivatives with high resolution mass spectrometry (HRMS1). Significant water/alcohol loss (>30% abundance in MS1 spectra) was observed for ortho-substituted nucleophilic groups; these fragment peaks are not observable for the corresponding para and meta-substituted analogs. Experiments were also extended to the analysis of two intermediates in the synthesis of suvorexant (Belsomra) with additional analysis conducted with nuclear magnetic resonance (NMR), density functional theory (DFT), and ion mobility spectrometry-mass spectrometry (IMS-MS) studies. Significant water/alcohol loss was also observed for 1-substituted 1, 2, 3-triazoles but not for the isomeric 2-substituted 1, 2, 3-triazole analogs. IMS-MS, NMR, and DFT studies were conducted to show that the preferred orientation of the 2-substituted triazole rotamer was away from the electrophilic center of the reaction, whereas the 1-s...Continue Reading

References

Dec 16, 2000·Journal of the American Society for Mass Spectrometry·G E ReidR A O'Hair
Nov 13, 2010·Current Opinion in Chemical Biology·Ry R Forseth, Frank C Schroeder
Mar 4, 2011·Journal of Computational Chemistry·Stefan GrimmeLars Goerigk
Jun 26, 2012·Organic Letters·Ian K MangionFred J Fleitz
Dec 18, 2013·Annual Review of Physical Chemistry·Thomas WyttenbachMichael T Bowers
Apr 25, 2014·Rapid Communications in Mass Spectrometry : RCM·D Vijay DarshanS Prabhakar

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