Electrospray ionization is one of the most broadly useful and successful approaches for coupling high performance liquid chromatography to mass spectrometry. Most of the research in electrospray ionization mass spectrometry (ESI-MS) has been limited to the positive ion mode, where lower detection limits are generally achieved, due several advantages over the more problematic negative ion mode. However, if one wishes to study anionic species, the negative ion mode traditionally had to be employed, and the problems associated with the negative ion mode had to be tolerated or ameliorated as much as possible.

Recently, novel work has been done to take advantage of the positive ion mode when studying anionic species. This is done by placing small amounts of a multiply-charged cationic reagent in the carrier stream. When an anion of lesser charge is injected into the carrier stream, a complex will form that contains a net positive charge that can be detected in ESI-MS in the positive ion mode. This method has been shown to be significantly more sensitive than detecting the anion in the negative ion mode.

The first two studies in this work have been done by using large, chaotropic dications to study singly-charged anions. A third study was done using trications to analyze dianions by ESI-MS. This method shows great promise for the analysis of anionic species by ESI-MS and should lead to lower detection limits for a wide variety of anionic species.