Mechanistic Study of the Gas-Phase In-Source Hofmann Elimination of Doubly Quaternized Cinchona-Alkaloid Based Phase-Transfer Catalysts by (+)-Electrospray Ionization/Tandem Mass Spectrometry

Abstract

An unusual in-source fragmentation pattern observed for 14 doubly quaternized cinchona alkaloid-based phase-transfer catalysts (PTC) was studied using (+)-ESI high resolution mass spectrometry. Loss of the substituted benzyl cation (R1 or R2) was found to be the major product ion [M²⁺ - R₁⁺ or R₂⁺]⁺ in MS spectra of all PTC compounds. A Hofmann elimination product ion [M - H]⁺ was also observed. Only a small amount of the doubly charged M²⁺ ions were observed in the MS spectra, likely due to strong Columbic repulsion between the two quaternary ammonium cations in the gas phase. The positive voltage in the MS inlet but not the ESI probe was found to induce this extensive fragmentation for all PTC diboromo-salts. Compound 1 was used as an example to illustrate the proposed in-source fragmentation mechanism. The mechanism of formation of the Hofmann elimination product ion [M - H]⁺ was further investigated using HRMS/MS, H/D exchange, and DFT calculations. The proposed formation of 2b as the major Hofmann elimination product ion was supported both by HRMS/MS and DFT calculations. Formation of product ion 2b through a concerted unimolecular E_i elimination pathway is proposed rather than a bimolecular E2 elimination pathway for common solution Hofmann eliminations. Graphical Abstract ᅟ.

Keywords: (+)-ESI; DFT; Hofmann elimination; In-source fragmentation; Mechanistic study; Phase-transfer catalysts.