Gas phase retro-Michael reaction resulting from dissociative protonation: fragmentation of protonated warfarin in mass spectrometry

• Published in: Journal of mass spectrometry. Vol. 47; no. 8; pp. 1059 - 1064
• Main Authors: Zhang, Jia, Chai, Yunfeng, Jiang, Kezhi, Yang, Huameng, Pan, Yuanjiang, Sun, Cuirong
• Format: Journal Article
• Language: English
• Published: Chichester Blackwell Publishing Ltd 01.08.2012; Wiley; Wiley Subscription Services, Inc
• Subjects: 4-Hydroxycoumarins - chemistry; Activation; Atomic and molecular physics; Bond strengths, dissociation energies; Butanones - chemistry; Chemistry; Derivatives; dissociative proton transfer; Exact sciences and technology; Gases - chemistry; Hydrogen bonds; ion-neutral complex; Mass spectrometry; Mass Spectrometry - methods; Models, Molecular; Molecular properties and interactions with photons; Organic chemistry; Physics; Properties of molecules and molecular ions; Protonation; Protons; Reactivity and mechanisms; Reproduction; retro-Michael reaction; Tautomers; Warfarin; Warfarin - chemistry; Ion molecule reaction; Tandem mass spectrometry; retro-Michael reaction; Coumarine derivatives; Fragmentation pattern; Anticoagulant; Antivitamin K; dissociative proton transfer; Protonated form; ion-neutral complex; mass spectrometry; Michael addition; Proton affinity; Warfarin; Collisional activation; Pesticides; Reverse reaction; Proton transfer; Theoretical study; Lactone; Energy diagram; Rodenticide; Density functional method; Alkalinity; Gas phase
• ISSN: 1076-5174; 1096-9888
• DOI: 10.1002/jms.3055

A mass spectrometric study of protonated warfarin and its derivatives (compounds 1 to 5) has been performed. Losses of a substituted benzylideneacetone and a 4‐hydroxycoumarin have been observed as a result of retro‐Michael reaction. The added proton is initially localized between the two carbonyl oxygens through hydrogen bonding in the most thermodynamically favorable tautomer. Upon collisional activation, the added proton migrates to the C‐3 of 4‐hydroxycoumarin, which is called the dissociative protonation site, leading to the formation of the intermediate ion‐neutral complex (INC). Within the INC, further proton transfer gives rise to a proton‐bound complex. The cleavage of one hydrogen bond of the proton‐bound complex produces the protonated 4‐hydroxycoumarin, while the separation of the other hydrogen bond gives rise to the protonated benzylideneacetone. Theoretical calculations indicate that the 1, 5‐proton transfer pathway is most thermodynamically favorable and support the existence of the INC. Both substituent effect and the kinetic method were utilized for explaining the relative abundances of protonated 4‐hydroxycoumarin and protonated benzylideneacetone derivative. For monosubstituted warfarins, the electron‐donating substituents favor the generation of protonated substituted benzylideneacetone, whereas the electron‐withdrawing groups favor the formation of protonated 4‐hydroxycoumarin. Copyright © 2012 John Wiley & Sons, Ltd.