The Case for Radical Cations: Bringing EI-Style Spectra to LC–MS

For most liquid chromatography–mass spectrometry (LC–MS) work, electrospray ionization is the default: it produces protonated species whose collision-induced fragmentation builds the spectral libraries used for compound identification, but the structural information those fragments provide can be rich or frustratingly thin depending on the compound. Gérard Hopfgartner of the University of Geneva, trained originally on gas chromatography (GC)–MS methods for steroids and hydrocarbons, where electron ionization (EI) produces the kind of information-dense spectra electrospray often cannot match. His research asks whether LC–MS can recover that EI-style richness without leaving the LC–MS platform behind. The answer, Hopfgartner and his team found, is atmospheric pressure photoionization (APPI), introduced independently in 2000 by two parallel groups: Jack Syage's team at Syagen Technology, who commercialized the first standalone APPI source,¹ and D. B. Robb, T. R. Covey, and Andries Bruins, who developed a separate dopant-assisted approach²—both aimed at ionizing highly apolar compounds, like squalene, that electrospray struggles with. Revisiting APPI, the group found that dopants such as chlorobenzene or toluene can tune the ion source toward forming either protonated species or radical cations.³ Pairing microLC with a constant post-column methanol flow keeps source conditions controlled and reproducible even as gradient LC conditions change, allowing the radical cations to undergo collision-induced dissociation across a 10 to 70 electron volt range. The result is a spectrum structurally similar to classic EI, but, unlike true EI fragmentation, one that retains the precursor ion, adding confidence to the match. That opens access to NIST's EI library of more than 300,000 high-quality spectra as a second identification pathway alongside conventional electrospray MS/MS, all from the same LC–MS run. It's an approach that treats radical cation formation not as a side effect to work around, but as a tunable feature of the ion source itself.

Hopfgartner answered the following question:

• What’s driving research into generating radical cations for LC–MS using atmospheric pressure photoionisation?

References

1. Syage, J.A.; Evans, M.D.; Hanold, K.A. Photoionization Mass Spectrometry. Am Lab 2000, 32, 24–29.
2. Robb, D.B.; Covey, T.R.; Bruins, A.P. Atmospheric Pressure Photoionization: An Ionization Method for Liquid Chromatography–Mass Spectrometry. Anal Chem 2000, 72 (15), 3653–3659. DOI: 10.1021/ac0001636.
3. Hopfgartner, G. Multidimensional Mass Spectrometric and Liquid Separation Approaches for the General Screening of Low Molecular Weight Compounds and Lipids. Presented at ISC 2026, in Prague, Czech Republic. https://www.czech-in.org/cmPortalv15/Searchable/isc26/config/normal#!sessionschedule (accessed 2026-09-18).