title: Identifying the proton transfer reaction mechanism via a proton-bound dimeric intermediate for esomeprazoles by a kinetic method combined with density functional theory calculations.
abstract: BACKGROUND
  Esomeprazole analogs are a class of important proton pump inhibitors for the treatment of gastro-esophageal reflux diseases. Understanding the fragmentation reaction mechanism of the protonated esomeprazole analogs will facilitate the characterization of their complex metabolic fate in humans. In this paper, the kinetic method and theoretical calculations were applied to evaluate the fragmentation of protonated esomeprazole analogs.
  
  
  METHODS
  All collision-induced dissociation (CID) mass spectrometry experiments were carried out using electrospray ionization (ESI) ion trap mass spectrometry in positive ion mode. Also the accurate masses of fragments were measured on by ESI quadrupole time-of-flight (QTOF) MS in positive ion mode. Theoretical calculations were carried out by the density functional theory (DFT) method with the 6-31G(d) basis set in the Gaussian 03 program.
  
  
  RESULTS
  In the fragmentation of the protonated esomeprazole analogs, C-S bond breakage is observed, which gives rise to protonated 2-(sulfinylmethylene)pyridines and protonated benzimidazoles. DFT calculations demonstrate that the nitrogen atom of the pyridine part is the thermodynamically most favorable protonation site, and the C-S bond cleavage is triggered by the transfer of this ionizing proton from the nitrogen atom of the pyridine part to the carbon atom of the benzimidazole part to which the sulfinyl is attached. Moreover, with the kinetic plot, the intensity ratios of two protonated product ions yield a linear relationship with the differences in proton affinities of the corresponding neutral molecules, which provides strong experimental evidence that the reaction proceeds via proton-bound 2-(sulfinylmethylene)pyridine/benzimidazole complex intermediates.
  
  
  CONCLUSIONS
  The kinetic method combined with theoretical calculations was successfully applied to probe the proton transfer reaction by proton-bound 2-(sulfinylmethylene)pyridine/benzimidazole complexes in the fragmentation of protonated esomeprazole analogs by ESI CID MS, which is a strong evidence that the kinetic method can be applied in identifying a proton-bound dimeric intermediate in the fragmentation of protonated ions.
authors.affiliation: Research Center of Analysis and Measurement, Zhejiang University of Technology, 18 Chaowang Rd, Hangzhou, Zhejiang, 310014, P.R. China.
authors.forename: Xiaoji
authors.initials: X
authors.lastname: Cao
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhang
authors.forename: Kundan
authors.initials: K
authors.lastname: Zhu
authors.forename: Xuemin
authors.initials: X
authors.lastname: Ye
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Shen
authors.forename: Jiaoyu
authors.initials: J
authors.lastname: Chen
authors.forename: Weimin
authors.initials: W
authors.lastname: Mo
mesh_terms: D064098:Esomeprazole / Q000737:chemistry*; D008958:Models, Molecular; D011522:Protons; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
chemical_list: D011522:Protons; D064098:Esomeprazole