Unveiling Readily Ionized and Robust Anionic Species: A Gateway to Enhanced Ionization Efficiency in ESI-MS Analysis

Electrospray ionization mass spectrometry has long been a prevalent ionization method in the analysis of low volatility molecules with biological, environmental, and industrial relevance. To address analytical challenges associated with molecules suffering from low ionization efficiencies (IEs), chemical derivatization (CD) strategies have been developed and are frequently adopted into workflows. However, only a minute number of CD techniques have been developed for negative polarity. To address this disparity, we evaluated 27 anions based on three criteria: (1) IE relative to a sodium dodecyl sulfate (<b>11</b> + Na⁺) internal standard; (2) stability to collision induced dissociation; (3) diagnostic tandem mass spectrometry behavior. Highly fluorous ions exhibiting weakly coordinating and hydrophobic properties displayed enhanced IE. Trifluoromethanesulfonyl-containing ions proved to be unexpectedly labile, while tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (<b>23</b>) and bis(nonafluoro-1-butane)sulfonimidate (<b>25</b>) were determined to be of optimal IE of 332% ± 25% and 939% ± 92%, respectively, and in tandem MS exhibited survival yields of 100% ± 0% and 72.6% ± 0.8% at -50 eV. <b>23</b> and <b>25</b> were also comparable in IE across several solvents, and combinations thereof, that are ubiquitous in liquid chromatography. Various salts of <b>25</b> were evaluated for cation effects, where the IE of <b>25</b> ranged from 939% ± 92% to 3195% ± 145% across K⁺, NH₄⁺, Na⁺, and H⁺. Compared to tetra-<i>n</i>-butylammonium, tetra-<i>n</i>-butylphosphonium, and (4-methylphenyl)diphenylsulfonium cations, <b>25</b> displayed signal enhancements ranging from 136% ± 6% to 181% ± 14%, thereby making it an optimal candidate for CD development.