Study On The Gas Phase Fragmentation Reaction Of C-S Bond In Three Kinds Of Sulfur-containing Indoles

The indole is an important nitrogen-containing heterocyclic compound.The indole derivatives are widely distributed in nature.Many natural compounds contain indole structures,and some of them are closely related to life activities.At present,many mass spectrometry researchers are interested in the reaction mechanism of indoles in the gas phase.The gas phase reactions of indoles including phenylsulfonylindoles and 3-sulfenylated indoles have been examined in electrospray ionization source?ESI?using a combination of collision induced dissociation?CID?technology,hydrogen-deuterium exchange,regiospecific deuterium labeling and density functional theory calculation.The gas phase reactions mechanism about C-S bond cleavage of above compounds were studied and discussed.The main content include three parts:The 3-phenylsulfonylindoles can produce protonated ions in ESI positive ion mode.These protonated ions mainly produce six kinds of fragment ions by CID-MS/MS.The density functional theory calculations demonstrated that the C³atom and O⁹ atom are the thermodynamically most favorable sites of protonation for this class of compounds.When the proton is added to C³atom,the C³-S bond dissociates spontaneously.Homolytic cleavage and heterolytic cleavage of C³-S bond lead to the formations of product ion a?indole cation radical?and product ion b?benzsulfonyl cation?,respectively.While when the proton is added to the O⁹ of sulfone group,the O⁹ atom could attacks the C³ atom.Then heterolytic cleavage of C³-S bond results in the intramolecular sulfone-sulfinate rearrangement?SSR?reaction,and the protonated 3-phenylsulfonylindoles is transformed to indolyl benzenesulfinates.Subsequently,heterolytic cleavage of C³-S results in ion/neutral complex?INC1?of[phenylsulfinyl cation/3-hydroxyindole],and the dissociation of this complex INC1 generates product ion d?phenylsulfinyl cation?.The ion/neutral complex?INC2?of[3-hydroxyindole cation radical/phenylsulfinyl radical]could be formed through an electron transfer reaction between the ionic and neutral portions of INC1.And direct dissociation of the compelx INC2 obtains the product ion c?3-hydroxyindole derivative cationic radical?.In addition,when the proton on the O⁹atom shifts to the C⁴ atom by the 1,5-proton transfer?1,5-PT?,followed a 1,5-proton transfer from the C⁴ atom to C¹11 atom,the heterolytic cleavage of C¹¹-S bond is triggered,which results in the formation product ion e?3-sulfonylindole cation?by neutral loss of benzene.The neutral loss of SO from the product ion e via an intramolecular SSR leads to the formation of product ion f?3-indolone cation?Moreover,hydrogen-deuterium exchange and regiospecific deuterium labeling experiments confirmed that the“H/D scrambling”phenomenon of product ion e and ion f is caused by multi-step proton migration within the molecule.In the electrospray negative ion mode,both the 3-phenylsulfonylindoles and the 2-phenylsulfonylindoles can lose active hydrogen on the N¹ atom to form deprotonated ions.Moreover,the density functional theory?DFT?was used to compare the optimized ionic structures in the fragmentation processes of3-phenylsulfonylindoles and 2-phenylsulfonylindoles,and to evaluate the possible fragmentation mechanism.Eliminating a SO₂ from the deprotonated ions of3-phenylsulfonylindoles and 2-phenylsulfonylindoles through different rearrangement paths form corresponding phenylindole anion isomers,while the neutral loss of phenyl radical by homolytic cleavage of C-S bond resulted in the corresponding anion radical isomers.According to DFT calculation,the neutral loss of SO₂ from deprotonated 3-phenylsulfonylindoles is initiated by an intramolecular nucleophilic aromatic attack of indole anion to the C⁸atom of aryl ring through a three-membered ring transition accompanied with heterolytic cleavage of C⁸-S bond and C³-S bond.In the case of deprotonated 2-phenylsulfonylindoles,the elimination of SO₂ is gained through a two-step nucleophilic aromatic substitution of indole anion companied with heterolytic cleavage of C-S bonds:the N¹ atom of indole anion nucleophilically attacks the C⁸atom of aryl ring by a four-membered ring transition,then the C² atom of indole anion nucleophilically attacks the C⁸ atom of aryl ring through a three-membered ring transition.The results indicated that the above-mentioned two positional isomers can be distinguished quickly,easily and accurately by ESI-MS/MS in negative ion mode based on the difference in the ratio of the fragment ions and stability of deprotonated ions.The study could provide a theoretical basis for the structural identification and quantitative analysis of phenylsulfonylindoles.The 3-phenylthioindoles could also lose active hydrogen on the N¹ atom to form deprotonated ions in electrospray negative ion mode.According to DFT calculation,a stable ion/neutral complex[3-thioindole anion radical/phenyl radical]is generated by homolytic cleavage of C-S bond on the benzene ring,and the phenyl radical can be rotated into a suitable space due to its instability.The product ion 2?3-phenylindole anion?can be formed through electrophilic attack of phenyl radicals to the C³ atom,leading to heterolytic cleavage of C³-S bond and the neutral elimination of S atom.And the dissociation of this complex INC generates product ion 3?3-thioindole anion radical?.In addition,the intensities of product ions are influenced by the substituents at phenyl ring or indole ring.Electron-withdrawing groups at phenyl ring facilitate the formation of product ion 2,whereas the electron-donating groups are strongly favored the formation of ion 3.When the substituent is at phenyl ring ortho or indole C² position,it is easier to lose the phenyl radical to form ion 3.The mechanism of ion/neutral complex-mediated phenyl radical migration reaction was preliminarily summarized,which provided experimental evidence and theoretical basis for related scientific research in the future.