Latest Developments in Direct and Non-Direct LC-MS Methods Based on Liquid Electron Ionization (LEI)

Mass spectrometry (MS) enables precise identification and quantification of molecules, particularly when combined with chromatography. The advent of atmospheric pressure ionization (API) techniques allowed the efficient coupling of liquid chromatography with MS (LC-MS), extending analyses to nonvolatile and thermolabile compounds. API techniques present limitations such as low informative capacity and reproducibility of mass spectra, increasing instrument complexity and costs. Other challenges include analyzing poorly polar molecules and matrix effects (ME), which negatively impact quantitative analyses, necessitating extensive sample purification or using expensive labeled standards. These limitations prompted the exploration of alternative solutions, leading to the development of the Liquid Electron Ionization (LEI) interface. The system has demonstrated excellent robustness and reproducibility. LEI has been employed to analyze various compounds, including pesticides, drugs of abuse, phenols, polycyclic aromatic hydrocarbons (PAHs), phthalates, and many others. Its versatility has been validated with single quadrupole, triple quadrupole, and QToF detectors, operating in electron ionization (EI) or chemical ionization (CI) modes and with both reverse phase liquid chromatography (RPLC) and normal phase liquid chromatography (NPLC). LEI has also been successfully integrated with the Microfluidic Open Interface (MOI), Membrane Introduction Mass Spectrometry (MIMS), and Microfluidic Water-Assisted Trap Focusing (M-WATF), broadening its application scope and consistently demonstrating promising results in terms of sensitivity and identification power. The most recent advancement is the development of Extractive-Liquid Sampling Electron Ionization-Mass Spectrometry (E-LEI-MS), a surface sampling and real-time analysis technique based on the LEI concept. This review article offers a comprehensive and up-to-date picture of the potential of LEI.