Electrospray ionization

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Electrospray (nanoSpray) ionization source NanoESIFT.jpg
Electrospray (nanoSpray) ionization source

Electrospray ionization (ESI) 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 (e.g. matrix-assisted laser desorption/ionization (MALDI)) 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. [1] [2]


Mass spectrometry using ESI is called electrospray ionization mass spectrometry (ESI-MS) or, less commonly, electrospray mass spectrometry (ES-MS). 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 (or more accurately a pseudo molecular ion) is almost 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 (ESI-MS/MS). Another important advantage of ESI is that solution-phase information can be retained into the gas-phase.

The electrospray ionization technique was first reported by Masamichi Yamashita and John Fenn in 1984. [3] The development of electrospray ionization for the analysis of biological macromolecules [4] was rewarded with the attribution of the Nobel Prize in Chemistry to John Bennett Fenn in 2002. [5] One of the original instruments used by Dr. Fenn is on display at the Science History Institute in Philadelphia, Pennsylvania.


Diagram of electrospray ionization in positive mode: under high voltage, the Taylor cone emits a jet of liquid drops. The solvent from the droplets progressively evaporates, leaving them more and more charged. When the charge exceeds the Rayleigh limit the droplet explosively dissociates, leaving a stream of charged (positive) ions ESI positive mode (21589986840).jpg
Diagram of electrospray ionization in positive mode: under high voltage, the Taylor cone emits a jet of liquid drops. The solvent from the droplets progressively evaporates, leaving them more and more charged. When the charge exceeds the Rayleigh limit the droplet explosively dissociates, leaving a stream of charged (positive) ions

In 1882, Lord Rayleigh theoretically estimated the maximum amount of charge a liquid droplet could carry before throwing out fine jets of liquid. [6] This is now known as the Rayleigh limit.

In 1914, John Zeleny published work on the behaviour of fluid droplets at the end of glass capillaries and presented evidence for different electrospray modes. [7] Wilson and Taylor [8] and Nolan investigated electrospray in the 1920s [9] and Macky in 1931. [10] The electrospray cone (now known as the Taylor cone) was described by Sir Geoffrey Ingram Taylor. [11]

The first use of electrospray ionization with mass spectrometry was reported by Malcolm Dole in 1968. [12] [13] John Bennett Fenn was awarded the 2002 Nobel Prize in Chemistry for the development of electrospray ionization mass spectrometry in the late 1980s. [14]

Ionization mechanism

Fenn's first electrospray ionization source coupled to a single quadrupole mass spectrometer Fenn ESI Instrument.jpg
Fenn's first electrospray ionization source coupled to a single quadrupole mass spectrometer

The liquid containing the analytes of interest is dispersed by electrospray, [15] 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 [16] 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. [17] 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. [18] 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%). [19] [20]

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. [21] [22] The CRM suggests that electrospray droplets undergo evaporation and fission cycles, eventually leading progeny droplets that contain on average one analyte ion or less. [12] The gas-phase ions form after the remaining solvent molecules evaporate, leaving the analyte with the charges that the droplet carried.

IEM, CRM and CEM schematic. IEM, CRM and CEM.png
IEM, CRM and CEM schematic.

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, [22] [23] [ citation needed ] [24] while larger ions (from folded proteins for instance) form by charged residue mechanism. [25] [26] [27]

A third model invoking combined charged residue-field emission has been proposed. [28] Another model called chain ejection model (CEM) is proposed for disordered polymers (unfolded proteins). [29]

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. [30]

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. [31] The differences in ionization efficiency reach more than 1 million times.


The electrosprays operated at low flow rates generate much smaller initial droplets, which ensure improved ionization efficiency. In 1993 Gale and Richard D. Smith reported significant sensitivity increases could be achieved using lower flow rates, and down to 200 nL/min. [32] In 1994, two research groups coined the name micro-electrospray (microspray) for electrosprays working at low flow rates. Emmett and Caprioli demonstrated improved performance for HPLC-MS analyses when the electrospray was operated at 300–800 nL/min. [33] Wilm and Mann demonstrated that a capillary flow of ~ 25 nL/min can sustain an electrospray at the tip of emitters fabricated by pulling glass capillaries to a few micrometers. [34] The latter was renamed nano-electrospray (nanospray) in 1996. [35] [36] Currently the name nanospray is also in use for electrosprays fed by pumps at low flow rates, [37] not only for self-fed electrosprays. Although there may not be a well-defined flow rate range for electrospray, microspray, and nano-electrospray, [38] studied "changes in analyte partition during droplet fission prior to ion release". [38] In this paper, they compare results obtained by three other groups. [39] [40] [41] and then measure the signal intensity ratio [Ba2+ + Ba+]/[BaBr+] at different flow rates.

Cold spray ionization is a form of electrospray in which the solution containing the sample is forced through a small cold capillary (10–80 °C) into an electric field to create a fine mist of cold charged droplets. [42] Applications of this method include the analysis of fragile molecules and guest-host interactions that cannot be studied using regular electrospray ionization.

Electrospray ionization has also been achieved at pressures as low as 25 torr and termed subambient pressure ionization with nanoelectrospray (SPIN) based upon a two-stage ion funnel interface developed by Richard D. Smith and coworkers. [43] The SPIN implementation provided increased sensitivity due to the use of ion funnels that helped confine and transfer ions to the lower pressure region of the mass spectrometer. Nanoelectrospray emitter is made out of a fine capillary with a small aperture about 1–3 micrometer. For sufficient conductivity this capillary is usually sputter-coated with conductive material, e.g. gold. Nanoelectrospray ionization consumes only a few microliters of a sample and forms smaller droplets. [44] Operation at low pressure was particularly effective for low flow rates where the smaller electrospray droplet size allowed effective desolvation and ion formation to be achieved. As a result, the researchers were later able to demonstrate achieving an excess of 50% overall ionization utilization efficiency for transfer of ions from the liquid phase, into the gas phase as ions, and through the dual ion funnel interface to the mass spectrometer. [45]

Ambient ionization

Diagram of a DESI ambient ionization source DESI ion source.jpg
Diagram of a DESI ambient ionization source

In ambient ionization, the formation of ions occurs outside the mass spectrometer without sample preparation. [46] [47] [48] Electrospray is used for ion formation in a number of ambient ion sources.

Desorption electrospray ionization (DESI) is an ambient ionization technique in which a solvent electrospray is directed at a sample. [49] [50] The electrospray is attracted to the surface by applying a voltage to the sample. Sample compounds are extracted into the solvent which is again aerosolized as highly charged droplets that evaporate to form highly charged ions. After ionization, the ions enter the atmospheric pressure interface of the mass spectrometer. DESI allows for ambient ionization of samples at atmospheric pressure, with little sample preparation.

Diagram of a SESI ambient ionization source Diagram of a SESI ambient ionization source.png
Diagram of a SESI ambient ionization source

Extractive electrospray ionization is an spray-type, ambient ionization method that uses two merged sprays, one of which is generated by electrospray. [47]

Laser-based electrospray-based ambient ionization is a two-step process in which a pulsed laser is used to desorb or ablate material from a sample and the plume of material interacts with an electrospray to create ions. [47] For ambient ionization, the sample material is deposited on a target near the electrospray. The laser desorbs or ablates material from the sample which is ejected from the surface and into the electrospray which produces highly charged ions. Examples are electrospray laser desorption ionization, matrix-assisted laser desorption electrospray ionization, and laser ablation electrospray ionization.

SESI-MS SUPER SESI coupled with Thermo Fisher Scientific-Orbitrap SESI-MS.png
SESI-MS SUPER SESI coupled with Thermo Fisher Scientific-Orbitrap

Electrostatic spray ionization (ESTASI) involved the analysis of samples located on a flat or porous surface, or inside a microchannel. A droplet containing analytes is deposited on a sample area, to which a pulsed high voltage to is applied. When the electrostatic pressure is larger than the surface tension, droplets and ions are sprayed.

Secondary electrospray ionization (SESI) is an spray type, ambient ionization method where charging ions are produced by means of an electrospray. These ions then charge vapor molecules in the gas phase when colliding with them. [51] [52]

In paper spray ionization, the sample is applied to a piece of paper, solvent is added, and a high voltage is applied to the paper, creating ions.


The outside of the electrospray interface on an LTQ mass spectrometer. Electrospray interface on the LTQ.jpg
The outside of the electrospray interface on an LTQ mass spectrometer.

Electrospray is used to study protein folding. [53] [54] [55]

Liquid chromatography–mass spectrometry

Electrospray ionization is the ion source of choice to couple liquid chromatography with mass spectrometry (LC-MS). The analysis can be performed online, by feeding the liquid eluting from the LC column directly to an electrospray, or offline, by collecting fractions to be later analyzed in a classical nanoelectrospray-mass spectrometry setup. Among the numerous operating parameters in ESI-MS,for proteins, [56] the electrospray voltage has been identified as an important parameter to consider in ESI LC/MS gradient elution. [57] The effect of various solvent compositions [58] (such as TFA [59] or ammonium acetate, [20] or supercharging reagents, [60] [61] [62] [63] or derivitizing groups [64] ) or spraying conditions [65] on electrospray-LCMS spectra and/or nanoESI-MS spectra. [66] have been studied.

Capillary electrophoresis-mass spectrometry (CE-MS)

Capillary electrophoresis-mass spectrometry was enabled by an ESI interface that was developed and patented by Richard D. Smith and coworkers at Pacific Northwest National Laboratory, and shown to have broad utility for the analysis of very small biological and chemical compound mixtures, and even extending to a single biological cell.

Noncovalent gas phase interactions

Electrospray ionization is also utilized in studying noncovalent gas phase interactions. The electrospray process is thought to be capable of transferring liquid-phase noncovalent complexes into the gas phase without disrupting the noncovalent interaction. Problems [20] [67] such as non specific interactions [68] have been identified when studying ligand substrate complexes by ESI-MS or nanoESI-MS. An interesting example of this is studying the interactions between enzymes and drugs which are inhibitors of the enzyme. [69] [70] [71] Competition studies between STAT6 and inhibitors [71] [72] [73] have used ESI as a way to screen for potential new drug candidates.

See also

Related Research Articles

Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are typically presented as a mass spectrum, a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used in many different fields and is applied to pure samples as well as complex mixtures.

Ion source Device that creates charged atoms and molecules (ions)

An ion source is a device that creates atomic and molecular ions. Ion sources are used to form ions for mass spectrometers, optical emission spectrometers, particle accelerators, ion implanters and ion engines.

Matrix-assisted laser desorption/ionization

In mass spectrometry, matrix-assisted laser desorption/ionization (MALDI) is an ionization technique that uses a laser energy absorbing matrix to create ions from large molecules with minimal fragmentation. It has been applied to the analysis of biomolecules and various organic molecules, which tend to be fragile and fragment when ionized by more conventional ionization methods. It is similar in character to electrospray ionization (ESI) in that both techniques are relatively soft ways of obtaining ions of large molecules in the gas phase, though MALDI typically produces far fewer multi-charged ions.

Electron-capture dissociation

Electron-capture dissociation (ECD) is a method of fragmenting gas-phase ions for structure elucidation of peptides and proteins in tandem mass spectrometry. It is one of the most widely used techniques for activation and dissociation of mass selected precursor ion in MS/MS. It involves the direct introduction of low-energy electrons to trapped gas-phase ions.

Liquid chromatography–mass spectrometry Analytical chemistry technique

Liquid chromatography–mass spectrometry (LC–MS) is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry (MS). Coupled chromatography - MS systems are popular in chemical analysis because the individual capabilities of each technique are enhanced synergistically. While liquid chromatography separates mixtures with multiple components, mass spectrometry provides structural identity of the individual components with high molecular specificity and detection sensitivity. This tandem technique can be used to analyze biochemical, organic, and inorganic compounds commonly found in complex samples of environmental and biological origin. Therefore, LC-MS may be applied in a wide range of sectors including biotechnology, environment monitoring, food processing, and pharmaceutical, agrochemical, and cosmetic industries.

Atmospheric-pressure chemical ionization

Atmospheric pressure chemical ionization (APCI) is an ionization method used in mass spectrometry which utilizes gas-phase ion-molecule reactions at atmospheric pressure (105 Pa), commonly coupled with high-performance liquid chromatography (HPLC). APCI is a soft ionization method similar to chemical ionization where primary ions are produced on a solvent spray. The main usage of APCI is for polar and relatively less polar thermally stable compounds with molecular weight less than 1500 Da. The application of APCI with HPLC has gained a large popularity in trace analysis detection such as steroids, pesticides and also in pharmacology for drug metabolites.


Thermospray is a soft ionization source by which a solvent flow of liquid sample passes through a very thin heated column to become a spray of fine liquid droplets. As a form of atmospheric pressure ionization in mass spectrometry these droplets are then ionized via a low-current discharge electrode to create a solvent ion plasma. A repeller then directs these charged particles through the skimmer and acceleration region to introduce the aerosolized sample to a mass spectrometer. It is particularly useful in liquid chromatography-mass spectrometry (LC-MS).

3-Nitrobenzyl alcohol Chemical compound

The compound 3-nitrobenzyl alcohol is an organic compound with the formula C7H7NO3.

Protein mass spectrometry

Protein mass spectrometry refers to the application of mass spectrometry to the study of proteins. Mass spectrometry is an important method for the accurate mass determination and characterization of proteins, and a variety of methods and instrumentations have been developed for its many uses. Its applications include the identification of proteins and their post-translational modifications, the elucidation of protein complexes, their subunits and functional interactions, as well as the global measurement of proteins in proteomics. It can also be used to localize proteins to the various organelles, and determine the interactions between different proteins as well as with membrane lipids.

Desorption electrospray ionization

Desorption electrospray ionization (DESI) is an ambient ionization technique that can be coupled to mass spectrometry for chemical analysis of samples at atmospheric conditions. Coupled Ionization sources-MS systems are popular in chemical analysis because the individual capabilities of various sources combined with different MS systems allow for chemical determinations of samples. DESI employs a fast-moving charged solvent stream, at an angle relative to the sample surface, to extract analytes from the surfaces and propel the secondary ions toward the mass analyzer. This tandem technique can be used to analyze forensics analyses, pharmaceuticals, plant tissues, fruits, intact biological tissues, enzyme-substrate complexes, metabolites and polymers. Therefore, DESI-MS may be applied in a wide variety of sectors including food and drug administration, pharmaceuticals, environmental monitoring, and biotechnology.

Sample preparation for mass spectrometry is used for the optimization of a sample for analysis in a mass spectrometer (MS). Each ionization method has certain factors that must be considered for that method to be successful, such as volume, concentration, sample phase, and composition of the analyte solution. Quite possibly the most important consideration in sample preparation is knowing what phase the sample must be in for analysis to be successful. In some cases the analyte itself must be purified before entering the ion source. In other situations, the matrix, or everything in the solution surrounding the analyte, is the most important factor to consider and adjust. Often, sample preparation itself for mass spectrometry can be avoided by coupling mass spectrometry to a chromatography method, or some other form of separation before entering the mass spectrometer. In some cases, the analyte itself must be adjusted so that analysis is possible, such as in protein mass spectrometry, where usually the protein of interest is cleaved into peptides before analysis, either by in-gel digestion or by proteolysis in solution.

Laser spray ionization

Laser spray ionization refers to one of several methods for creating ions using a laser interacting with a spray of neutral particles or ablating material to create a plume of charged particles. The ions thus formed can be separated by m/z with mass spectrometry. Laser spray is one of several ion sources that can be coupled with liquid chromatography-mass spectrometry for the detection of larger molecules.

Matrix-assisted laser desorption electrospray ionization

Matrix-assisted laser desorption electrospray ionization (MALDESI) was first introduced in 2006 as a novel ambient ionization technique which combines the benefits of electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). An infrared (IR) or ultraviolet (UV) laser can be utilized in MALDESI to resonantly excite an endogenous or exogenous matrix. The term ‘matrix’ refers to any molecule that is present in large excess and absorbs the energy of the laser, thus facilitating desorption of analyte molecules. The original MALDESI design was implemented using common organic matrices, similar to those used in MALDI, along with a UV laser. The current MALDESI source employs endogenous water or a thin layer of exogenously deposited ice as the energy-absorbing matrix where O-H symmetric and asymmetric stretching bonds are resonantly excited by a mid-IR laser.

Capillary electrophoresis–mass spectrometry

Capillary electrophoresis–mass spectrometry (CE-MS) is an analytical chemistry technique formed by the combination of the liquid separation process of capillary electrophoresis with mass spectrometry. CE-MS combines advantages of both CE and MS to provide high separation efficiency and molecular mass information in a single analysis. It has high resolving power and sensitivity, requires minimal volume and can analyze at high speed. Ions are typically formed by electrospray ionization, but they can also be formed by matrix-assisted laser desorption/ionization or other ionization techniques. It has applications in basic research in proteomics and quantitative analysis of biomolecules as well as in clinical medicine. Since its introduction in 1987, new developments and application has made CE-MS powerful separation and identification technique. Use of CE-MS has increased for protein and peptides analysis and other biomolecules. However, the development of online CE-MS is not without challenges. Understanding of CE, the interface setup, ionization technique and mass detection system is important to tackle problems while coupling capillary electrophoresis to mass spectrometry.

Ambient ionization

Ambient ionization is a form of ionization in which ions are formed in an ion source outside the mass spectrometer without sample preparation or separation. Ions can be formed by extraction into charged electrospray droplets, thermally desorbed and ionized by chemical ionization, or laser desorbed or ablated and post-ionized before they enter the mass spectrometer.

Laser ablation electrospray ionization

Laser ablation electrospray ionization (LAESI) is an ambient ionization method for mass spectrometry that combines laser ablation from a mid-infrared (mid-IR) laser with a secondary electrospray ionization (ESI) process. The mid-IR laser is used to generate gas phase particles which are then ionized through interactions with charged droplets from the ESI source. LAESI was developed in Professor Akos Vertes lab by Dr. Peter Nemes in 2007 and is was marketed commercially by Protea Biosciences, Inc until 2017. Fiber-LAESI for single-cell analysis approach was developed by Dr. Bindesh Shrestha in Professor Vertes lab in 2009. LAESI is a novel ionization source for mass spectrometry (MS) that has been used to perform MS imaging of plants, tissues, cell pellets, and even single cells. In addition, LAESI has been used to analyze historic documents and untreated biofluids such as urine and blood. The technique of LAESI is performed at atmospheric pressure and therefore overcomes many of the obstacles of traditional MS techniques, including extensive and invasive sample preparation steps and the use of high vacuum. Because molecules and aerosols are ionized by interacting with an electrospray plume, LAESI's ionization mechanism is similar to SESI and EESI techniques.

Extractive electrospray ionization

Extractive electrospray ionization (EESI) is a spray-type, ambient ionization source in mass spectrometry that uses two colliding aerosols, one of which is generated by electrospray. In standard EESI, syringe pumps provide the liquids for both an electrospray and a sample spray. In neutral desorption EESI (ND-EESI), the liquid for the sample aerosol is provided by a flow of nitrogen.

Peter Nemes, Ph.D., is a Hungarian-American chemist, who is active in the fields of bioanalytical chemistry, mass spectrometry, cell/developmental biology, neuroscience, and biochemistry.

Secondary electrospray ionization

Secondary electro-spray ionization (SESI) is an ambient ionization technique for the analysis of trace concentrations of vapors, where a nano-electrospray produces charging agents that collide with the analyte molecules directly in gas-phase. In the subsequent reaction, the charge is transferred and vapors get ionized, most molecules get protonated and deprotonated. SESI works in combination with mass spectrometry or ion-mobility spectrometry.

Probe electrospray ionization (PESI) is an electrospray-based ambient ionization technique which is coupled with mass spectrometry for sample analysis. Unlike traditional mass spectrometry ion sources which must be maintained in a vacuum, ambient ionization techniques permit sample ionization under ambient conditions, allowing for the high-throughput analysis of samples in their native state, often with minimal or no sample pre-treatment. The PESI ion source simply consists of a needle to which a high voltage is applied following sample pick-up, initiating electrospray directly from the solid needle.


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