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

  • William D. Blincoe
  • Agustina Rodriguez-Granillo
  • Josep Saurí
  • Nicholas A. Pierson
  • Leo A. Joyce
  • Ian Mangion
  • Huaming Sheng
Research Article

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-subtituted triazole was oriented in close proximity to the center. Abundance of NGP product was determined to be a product of three factors: (1) proton affinity of the nucleophilic group; (2) steric impact of the nucleophile; and (3) proximity of the nucleophile to carboxylic acid/ester functional groups.

Graphical Abstract

Keywords

Benzoic acid/ester derivatives Gas phase neighboring group participation effect HRMS (+)-ESI DFT IMS NMR Structural elucidation 

Notes

Acknowledgments

The authors thank the MSD Summer Internship Program for funding, Dr. Gary Martin for helpful discussions, and Dr. R. Thomas Williamson and Dr. Caroline McGregor for their managerial support.

Supplementary material

13361_2017_1884_MOESM1_ESM.docx (2.3 mb)
ESM 1 (DOCX 2345 kb)

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Copyright information

© American Society for Mass Spectrometry 2018

Authors and Affiliations

  • William D. Blincoe
    • 1
  • Agustina Rodriguez-Granillo
    • 2
  • Josep Saurí
    • 1
  • Nicholas A. Pierson
    • 1
  • Leo A. Joyce
    • 1
  • Ian Mangion
    • 1
  • Huaming Sheng
    • 1
  1. 1.Analytical Research and DevelopmentMerck and Co., Inc.RahwayUSA
  2. 2.Chemistry Modeling and InformaticsMerck and Co., Inc.RahwayUSA

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