Ambient ionization

Diagram of ambient ionization in mass spectrometry indicating desorption/extraction (spray, heat, laser), optional post-ionization (electrospray, chemical ionization, plasma), ion formation, and entry into the vacuum of the mass spectrometer.

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.

Solid-liquid extraction

Schematic of a DESI solid-liquid extraction ion source: primary charged droplets hit the sample surface and molecules are extracted into the liquid. Secondary charged droplets removed from the surface produce bare ions as the solvent evaporates.

Solid-liquid extraction based ambient ionization is based on the use of a charged spray, for example electrospray to create a liquid film on the sample surface. Molecules on the surface are extracted into the solvent. The action of the primary droplets hitting the surface produces secondary droplets that are the source of ions for the mass spectrometer.

Desorption electrospray ionization (DESI) is one of the original ambient ionization sources and uses an electrospray source to create charged droplets that are directed at a solid sample. The charged droplets pick up the sample through interaction with the surface and then form highly charged ions that can be sampled into a mass spectrometer.

Desorption atmospheric pressure photoionization (DAPPI) is a solid-liquid extraction ambient ionization method that enables the direct analysis of samples deposited on surfaces by means of a jet of hot solvent vapour and ultraviolet light. The hot jet thermally desorbs the sample from a surface and the vaporized sample is ionized by a vacuum ultraviolet light and consequently sampled into a mass spectrometer.

Plasma-based techniques

Plasma-based ambient ionization is based on an electrical discharge in a flowing gas that produces metastable atoms and molecules and reactive ions. Heat is often used to assist in the desorption of volatile species from the sample. Ions are formed by chemical ionization in the gas phase.

One proposed mechanism involves Penning ionization of ambient water clusters in a helium discharge:

$\mathrm{H}\mathrm{e}{\phantom{A}}^{\ast }+[(\mathrm{H}{\phantom{A}}_2\mathrm{O}){\phantom{A}}_{𝑛}\mathrm{H}]⟶[(\mathrm{H}{\phantom{A}}_2\mathrm{O}){\phantom{A}}_{\mathrm{n}-1}\mathrm{H}]{\phantom{A}}^{+}+\mathrm{O}\mathrm{H}{\phantom{A}}^{\bullet }+\mathrm{e}{\phantom{A}}^{-}$.

The protonated water clusters can then protonate the sample molecules via

$[(\mathrm{H}{\phantom{A}}_2\mathrm{O}){\phantom{A}}_{𝑛}\mathrm{H}]{\phantom{A}}^{+}+\mathrm{M}⟶[\mathrm{M}+\mathrm{H}]{\phantom{A}}^{+}+𝑛\mathrm{H}{\phantom{A}}_2\mathrm{O}$.

For this ionization pathway, the gas-phase acidity of the protonated water clusters and the gas-phase basicity of the analyte molecule are of crucial importance. However, since especially smaller protonated water clusters with n = 1,2,3... exhibit very high gas-phase acidities, even compounds with a rather low gas-phase basicity are readily ionized by proton transfer, yielding [M+H]⁺ quasimolecular ions.

Besides protonated water clusters, other positively charged reagent ions, such as NO⁺, O₂⁺, NO₂⁺ and CO₂⁺, may be formed in the afterglow region. These additional reagent ions are capable of ionizing compounds via charge-transfer processes and, thus, offer alternative routes of ionization besides proton transfer, leading to a broader range of suitable analytes. Nevertheless, these ionization mechanisms may also lead to the formation of adducts and oxidation of the original analyte compounds.

Although most applications focus on the detection of positive ions, measurements in the negative mode are for most of the plasma-based ion sources also possible. In this case, reagent ions, such as O₂^–, can deprotonate the analyte molecules to give [M–H]^– quasimolecular ions, or form adducts with species such as NO₃^–, yielding [M+NO₃]^– ions. Measurements in the negative ion mode are especially favorable when the analyte molecules exhibit a high gas-phase acidity, as it is the case e.g. for carboxylic acids.

A direct analysis in real time (DART) metastable ion source for plasma based ambient ionization.

One of the most used plasma-based techniques for ambient ionization is probably Direct analysis in real time (DART), since it is commercially available. DART is an atmospheric pressure ion source that operates by exposing the sample to a gas stream (typically helium or nitrogen) that contains long-lived electronically or excited neutral atoms, vibronically excited molecules (or "metastables"). Excited states are formed in a glow discharge in a chamber through which the gas flows.

Laser assisted

Ion source for ambient mass spectrometry employing a combination of laser desorption and electrospray. The sample target is on the left.

Laser-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 or plasma to create ions. Lasers with ultraviolet and infrared wavelengths and nanosecond to femtosecond pulse widths have been used. Although atmospheric pressure MALDI is performed under ambient conditions, it is not generally considered to be an ambient mass spectrometry technique.

Laser ablation was first coupled with mass spectrometry in the 1980s for the analysis of metals using laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS). The laser ablates the sample material that is introduced into an ICP to create atomic ions.

File:Probe electrospray ionization (schematic).png

Probe electrospray ionization schematic

Infrared laser desorption can be coupled with atmospheric pressure chemical ionization using laser desorption atmospheric pressure chemical ionization (LD-APCI). For ambient ionization with a spray, the sample material is deposited on a target near the spray. The laser desorbs or ablates material from the sample that is ejected from the surface and into the spray, which can be an APCI spray with a corona discharge or an electrospray. Ambient ionization by electrospray-assisted laser desorption/ionization (ELDI) can be accomplished with ultraviolet and infrared lasers to the desorb material into the electrospray plume. Similar approaches to laser desorption/ablation into an electrospray are matrix-assisted laser desorption electrospray ionization (MALDESI), laser ablation electrospray ionization (LAESI), laser assisted desorption electrospray ionization (LADESI), laser desorption electrospray ionization (LDESI), laser ablation mass spectrometry (LAMS), and laser desorption spray post-ionization (LDSPI). The term laser electrospray mass spectrometry has been used to denote the use of a femtosecond laser for ablation. Laser ablation into an electrospray produces highly charged ions that are similar to those observed in direct electrospray.

An alternative ionization approach following laser desorption is a plasma. UV laser ablation can be combined with a flowing afterglow plasma for mass spectrometry imaging of small molecules. and IR desorption has been combined with a metastable ion source.

Two step non-laser

In two-step non-laser methods, the material removal from the sample and the ionization steps are separate.

Probe electrospray ionization (PESI) is a modified version of conventional electrospray ionization in which the capillary for sample solution transferring is replaced by a solid needle with a sharp tip. Compared with conventional electrospray ionization, high salt tolerance, direct sampling, and low sample consumption are found with PESI. PESI is not a continuous process; the needle for sampling and spraying is driven up and down at a frequency of 3–5 Hz.

Vapor-ion, charge transfer reaction

The analytes are in the vapor phase. This includes breath, odors, VOCs, and other molecules with low volatility that, due to the constant improvements in sensitivity, are detectable in the vapor phase despite their low vapor pressure. Analyte ions are produced via gas-phase chemical reactions, where charging agents collide with the analyte molecules and transfer their charge. In secondary electro-spray ionization (SESI), a nano-electrospray operated at high temperature produces nanodroplets that evaporate very rapidly to produce ions and protonated water clusters that ionize the vapors of interest. SESI is commonly used for the analysis of trace concentrations of vapors being able to detect low volatility species in the gas phase with molecular masses of up to 700 Da.

Table of techniques

In the table below, ambient ionization techniques are classified in the categories "extraction" (a solid or liquid extraction processes dynamically followed by spray or chemical ionization), "plasma" (thermal or chemical desorption with chemical ionization), "two step" (desorption or ablation followed by ionization), "laser" (laser desorption or ablation followed by ionization), "acoustic" (acoustic desorption followed by ionization), multimode (involving two of the above modes), other (techniques that do not fit into the other categories).

Acronym	Technique	Classification
AFAI	Air flow-assisted ionization	Extraction
AFADESI	Air flow-assisted desorption electrospray ionization	Extraction
APGDDI	Atmospheric pressure glow discharge desorption ionization	Plasma
APPIS	Ambient pressure pyroelectric ion source
APTDCI	Atmospheric pressure thermal desorption chemical ionization	Two-step
APTDI	Atmospheric pressure thermal desorption/ionization	Plasma
ASAP	Atmospheric pressure solids analysis probe	Plasma
BADCI	Beta electron-assisted direct chemical ionization	Two step
CALDI	Charge assisted laser desorption/ionization	Laser
DAPCI	Desorption atmospheric pressure chemical ionization	Plasma
DAPPI	Desorption atmospheric pressure photoionization	Extraction
DART	Direct analysis in real time	Plasma
DBDI	Dielectric barrier discharge ionization	Plasma
DCBI	Desorption corona beam ionization	Plasma
DCI	Desorption chemical ionization	Plasma
DEFFI	Desorption electro-flow focusing ionization	Extraction
DEMI	Desorption electrospray/metastable-induced ionization	Multimode
DESI	Desorption electrospray ionization	Extraction
DeSSI	Desorption sonic spray ionization	Extraction
DICE	Desorption ionization by charge exchange	Extraction
DIP-APCI	Direct inlet probe–atmospheric-pressure chemical ionization	Two-step
DPESI	Direct probe electrospray ionization
EADESI	Electrode-assisted desorption electrospray ionization	Extraction
EASI	Easy ambient sonic-spray ionization	Extraction
EESI	Extractive electrospray ionization	Two step
ELDI	Electrospray laser desorption ionization	Laser
ESA-Py	Electrospray-assisted pyrolysis ionization	Spray
ESTASI	Electrostatic spray ionization	Extraction
FAPA	Flowing atmospheric pressure afterglow	Plasma
FIDI	Field-induced droplet ionization
HALDI	High-voltage-assisted laser desorption ionization	Laser
HAPGDI	Helium atmospheric pressure glow discharge ionization	Plasma
IR-LAMICI	Infrared laser ablation metastable-induced chemical ionization	Laser
JeDI	Jet desorption electrospray ionization	Extraction
LADESI	Laser assisted desorption electrospray ionization	Laser
LAESI	Laser ablation electrospray ionization	Laser
LA-FAPA	Laser ablation flowing atmospheric pressure afterglow	Laser
LA-ICP	Laser ablation inductively coupled plasma	Laser
LD-APCI	Laser desorption atmospheric pressure chemical ionization	Laser
LDTD	Laser diode thermal desorption	Laser
LDESI	Laser desorption electrospray ionization	Laser
LDSPI	Laser desorption spray post-ionization	Laser
LEMS	Laser electrospray mass spectrometry	Laser
LESA	Liquid extraction surface analysis	Extraction
LIAD-ESI	Laser-induced acoustic desorption-electrospray ionization	Acoustic
LMJ-SSP	Liquid microjunction-surface sampling probe	Extraction
LPTD	Leidenfrost phenomenon-assisted thermal desorption	Two-step
LS-APGD	Liquid sampling-atmospheric pressure glow discharge	Plasma
LSI	Laser spray ionization	Other
LTP	Low temperature plasma	Plasma
MAII	Matrix-assisted inlet ionization	Other
MALDESI	Matrix-assisted laser desorption electrospray ionization	Laser
MFGDP	Microfabricated glow discharge plasma	Plasma
MIPDI	microwave induced plasma desorption ionization	Plasma
nano-DESI	Nanospray desorption electrospray ionization	Extraction
ND-EESI	Neutral desorption extractive electrospray ionization	Two step
PADI	Plasma-assisted desorption ionization	Plasma
Paint Spray*	Paint spray	Extraction
PALDI	Plasma-assisted laser desorption ionization	Laser
PAMLDI	Plasma-assisted multiwavelength laser desorption ionization	Laser
PASIT	Plasma-based ambient sampling/ionization/transmission	Extraction
PAUSI	Paper assisted ultrasonic spray ionization
PESI	Probe electrospray ionization	Two step
PS	Paper spray
PTC-ESI	Pipette tip column electrospray ionization	Extraction
RADIO	Radiofrequency acoustic desorption and ionization	Acoustic
RASTIR	Remote analyte sampling transport and ionization relay
REIMS	Rapid evaporative ionization mass spectrometry	Other
RoPPI	Robotic plasma probe ionization	Two-step
SACI	Surface activated chemical ionization
SAII	Solvent-assisted inlet ionization	Other
SAWN	Surface acoustic wave nebulization	Acoustic
SESI	Secondary electrospray ionization	Vapor-ion, charge transfer
SPA-nanoESI	Solid probe assisted nanoelectrospray ionization	Two-step
SPAMS	Single-particle aerosol mass spectrometry	Other
SSI	Sponge-Spray Ionization
SSP	Surface sampling probe	Extraction
SwiFerr	Switched ferroelectric plasma ionizer	Other
TDAMS	Thermal desorption-based ambient mass spectrometry	Spray
TM-DESI	Transmission mode desorption electrospray ionization	Extraction
TS	Touch spray	Two-step
UASI	Ultrasonication-assisted spray ionization	Acoustic
V-EASI	Venturi easy ambient sonic-spray ionization	Extraction
BS	Brush-Spray Ionization	Two-step
FS	Fiber-Spray Ionization	Extraction

(*) Not an acronym.

Table of commercially available ambient ionization sources

Technique	Commercial Brand	Company	Website
Ambient Pressure Photo Ionization (APPI)	MasCom GC-(APPI)	MasCom Technologies GmbH	https://www.mascom-bremen.de/
Atmospheric pressure solids analysis probe (ASAP)	RADIAN	Waters, USA	https://www.waters.com/
Desorption Electrospray Ionization (DESI)	DESI2D	Prosolia Inc, Indianapolis, IN	https://prosolia.com/
Direct Analysis in Real Time (DART)	DART	IonSense Inc, Saugus, MA	https://www.ionsense.com/
Liquid Extraction Surface Analysis (LESA)	TriVersaNanoMate	Advion, Ithaca, NY	https://advion.com/
Probe Electrospray Ionization (PESI)	DPiMS-8060	Shimadzu, Japan	https://www.shimadzu.com/
Rapid evaporative Ionization Mass Spectrometry (REIMS)	REIMS	Waters, USA	https://www.waters.com/
Secondary Electrospray Ionization (SESI)	SUPER SESI	Fossil Ion Technology, Spain	https://www.fossiliontech.com/
Soft Ionization by Chemical Reaction In Transfer (SICRIT)	SICRIT	Plasmion GmbH, Germany	https://plasmion.com/