page_title: Electrospray ionization
section_title: Ionization mechanism
hierarchical_section_title: Electrospray ionization / Ionization mechanism
caption_attribution_description: English: The single quadrupole mass spectrometer and ion source used for John Fenn's Nobel Prize winning discovery of electrospray ionization. This instrument is on display at the museum of the Science History Institute (formerly the Chemical Heritage Foundation) in Philadelphia, PA.
context_page_description: Electrospray ionization is a technique used in mass spectrometry to produce ions using an electrospray in which a high voltage is applied to a liquid to create an aerosol. It is especially useful in producing ions from macromolecules because it overcomes the propensity of these molecules to fragment when ionized. ESI is different from other ionization processes since it may produce multiple-charged ions, effectively extending the mass range of the analyser to accommodate the kDa-MDa orders of magnitude observed in proteins and their associated polypeptide fragments.
  Mass spectrometry using ESI is called electrospray ionization mass spectrometry or, less commonly, electrospray mass spectrometry. ESI is a so-called 'soft ionization' technique, since there is very little fragmentation. This can be advantageous in the sense that the molecular ion is always observed, however very little structural information can be gained from the simple mass spectrum obtained. This disadvantage can be overcome by coupling ESI with tandem mass spectrometry. Another important advantage of ESI is that solution-phase information can be retained into the gas-phase.
context_section_description: The liquid containing the analyte(s) of interest is dispersed by electrospray, into a fine aerosol. Because the ion formation involves extensive solvent evaporation (also termed desolvation), the typical solvents for electrospray ionization are prepared by mixing water with volatile organic compounds (e.g. methanol acetonitrile). To decrease the initial droplet size, compounds that increase the conductivity (e.g. acetic acid) are customarily added to the solution. These species also act to provide a source of protons to facilitate the ionization process. Large-flow electrosprays can benefit from nebulization of a heated inert gas such as nitrogen or carbon dioxide in addition to the high temperature of the ESI source. The aerosol is sampled into the first vacuum stage of a mass spectrometer through a capillary carrying a potential difference of approximately 3000 V, which can be heated to aid further solvent evaporation from the charged droplets. The solvent evaporates from a charged droplet until it becomes unstable upon reaching its Rayleigh limit. At this point, the droplet deforms as the electrostatic repulsion of like charges, in an ever-decreasing droplet size, becomes more powerful than the surface tension holding the droplet together. At this point the droplet undergoes Coulomb fission, whereby the original droplet 'explodes' creating many smaller, more stable droplets. The new droplets undergo desolvation and subsequently further Coulomb fissions. During the fission, the droplet loses a small percentage of its mass (1.0–2.3%) along with a relatively large percentage of its charge (10–18%).
  There are two major theories that explain the final production of gas-phase ions: the ion evaporation model (IEM) and the charge residue model (CRM). The IEM suggests that as the droplet reaches a certain radius the field strength at the surface of the droplet becomes large enough to assist the field desorption of solvated ions. The CRM suggests that electrospray droplets undergo evaporation and fission cycles, eventually leading progeny droplets that contain on average one analyte ion or less. The gas-phase ions form after the remaining solvent molecules evaporate, leaving the analyte with the charges that the droplet carried.
  A large body of evidence shows either directly or indirectly that small ions (from small molecules) are liberated into the gas phase through the ion evaporation mechanism, while larger ions (from folded proteins for instance) form by charged residue mechanism.
  A third model invoking combined charged residue-field emission has been proposed. Another model called chain ejection model (CEM) is proposed for disordered polymers (unfolded proteins).
  The ions observed by mass spectrometry may be quasimolecular ions created by the addition of a hydrogen cation and denoted [M + H]⁺, or of another cation such as sodium ion, [M + Na]⁺, or the removal of a hydrogen nucleus, [M − H]⁻. Multiply charged ions such as [M + nH]ⁿ⁺ are often observed. For large macromolecules, there can be many charge states, resulting in a characteristic charge state envelope. All these are even-electron ion species: electrons (alone) are not added or removed, unlike in some other ionization sources. The analytes are sometimes involved in electrochemical processes, leading to shifts of the corresponding peaks in the mass spectrum. This effect is demonstrated in the direct ionization of noble metals such as copper, silver and gold using electrospray.
  The efficiency of generating the gas phase ions for small molecules in ESI varies depending on the compound structure, the solvent used and instrumental parameters. The differences in ionization efficiency reach more than 1 million times.
caption: Fenn's first electrospray ionization source coupled to a single quadrupole mass spectrometer
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