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Journal of Chromatography A, 1216 (2009) 685–699
Contents lists available at ScienceDirect
Journal of Chromatography A
journa l homepage: www.e lsev ier .com/ locate /chroma
Review
Effect of eluent on the ionization process in liquid
chromatography–mass spectrometry
Risto Kostiainen ∗, Tiina J. Kauppila
Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, P.O. Box 56, FIN-00014, Helsinki, Finland
a r t i c l e i n f o
Article history:
Available online 2 September 2008
Keywords:
Electrospray ionization
Atmospheric pressure chemical ionization
Atmospheric pressure photoionization
Liquid chromatography–mass spectrometry
Solvent effect
a b s t r a c t
The most widely used ionization techniques in liquid chromatography–mass spectrometry (LC–MS) are
electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) and atmospheric pressure
photoionization (APPI). All three provide user friendly coupling of LC to MS. Achieving optimal LC–MS
conditions is not always easy, however, owing to the complexity of ionization processes and the many
parameters affecting mass spectrometric sensitivity and chromatographic performance. The selection of
eluent composition requires particular attention since a solvent that is optimal for analyte ionization often
does not provide acceptable retention and resolution in LC. Compromises must then be made between
ionization and chromatographic separation efficiencies. The review presents an overview of studies con-
cerning the effect of eluent composition on the ionization efficiency of ESI, APCI and APPI in LC–MS. Solvent
characteristics are discussed in the light of ionization theories, and selected analytical applications are
described. The aim is to provide practical background information for the development and optimization
may result in the formation of ammonium adducts, [M+NH4]+,
instead of the protonated molecule. Ammonium adduct formation
is common for compounds having a proton affinity close to that
of ammonia (853.6 kJ/mol), for example for steroids [86,87], tetra-
cyclines [71], saccharides [88], certain wax esters [89] and lipids
[90,91]. Sodium adducts [M+Na]+ are often formed in addition to
[M+H]+ ions since sodium is always present in the mobile phase at
concentrations of 0.01–0.1 mM due to impurities derived from sam-
ple vials, LC-lines or solvents (even from HPLC grade solvents). The
concentration of sodium depends on experimental conditions and
the origin of the sample, and the relative abundance of [M+Na]+
may vary, decreasing the repeatability of the analysis. The for-
mation of sodium clusters may be deleterious in the analysis of
polyprotic organic acids such as oligonucleotides [92] and bispho-
sphonates [93]. The formation of sodium adducts and clusters can
be decreased by adding formic acid to the eluent after the column,
for example as sheath liquid.
The addition of a controlled amount of sodium or lithium salts
has been used to enhance ionization and improve repeatabil-
ity in the analysis of trichothecenes [94], carbohydrates [95–98],
and lipids [99,100]. In negative ion mode, chloride, formate
and acetate anions are effective in promoting the formation of
adducts ([M+Cl]−, [M+HCOO]−, [M+CH3COO]−) for analytes that
do not readily undergo deprotonation [101]. Chlorinated solvents
(dichloromethane, chloroform, carbon tetrachloride) and chlorine
salts have been used as a source of chloride anions for example
in the analysis of carbohydrates [102,103], lipids [104] and explo-
sives [105]. Formate and acetate adducts have been utilized in the
analysis of glycosides [106] and explosives [105]. In practice, only
low concentrations of salts (likely below 0.1 mM) can be added to
facilitate ionization in ESI via adduct ion formation since higher
concentrations may lead to strong background interference and
rapid contamination of the ion source.
Salts may also have effect on the charge distribution of multi-
ply charged peptides and proteins. Mirza and Chait [107] showed
that the charge states of peptides and proteins were shifted
to lower values due to neutralization of the positive charge by
a counterion present in solution. The nature of the counterion
influenced the magnitude of the shift in the order CCl3COO− >
CF3COO− > CH3COO− = Cl−. The influence of counterions on the ESI
spectra of peptides and proteins has been summarized by Wang
and Cole [108].
2.4. Ion-pairing and ion exchange
Ion-pairing can be used in reversed-phase LC–ESI/MS to improve
the retention and resolution of polar ionic compounds. Volatile ion-
690 R. Kostiainen, T.J. Kauppila / J. Chromatogr. A 1216 (2009) 685–699
Fig. 3. Effect of “TFA-fix” on signal intensity (A) 100% water + 0.2% TFA (B) 100% water + 0.2% TFA + “TFA-fix” (IPA 25 �L/min and 75 �L/min propanoic acid) (reproduced with
permission from ref. [62]).
pairing agents, such as TFA, pentafluoropropanoic acid (PFPA) and
heptafluorobutanoic acid (HFBA), have commonly been used in the
analysis of polar basic compounds [62,109–113]. These ion-pairing
agents form relatively stable ion-pairs with basic compounds,
decreasing the secondary interactions between free silanol groups
of the stationary phase, and resulting in decreased peak tailing,
improved resolution and better retention. However, acidic ion-
pairing agents may suppress ionization. For example, Gustavsson
et al. [109] showed that the use of fluorinated carboxylic acids as
ion-pairing agents at useful concentrations (a few mM) decreased
the ESI signal of certain amines by about 30–80% relative to the
signal intensity with formic acid–ammonium formate buffer. The
suppression effect of TFA, which is often used as an ion-pairing
agent in the analysis of peptides and proteins in LC, is well known
in LC–ESI/MS. [48,63,107]. The deleterious effect of TFA can be
eliminated by the “TFA-fix” method, i.e., by post-column addi-
tion of propionic acid in 2-propanol (75:25, v/v). Improvement in
the signal-to-noise ratio is 10–100-fold [62]. A weak acid, in this
case propionic acid, added at high concentration, becomes concen-
trated in the charged droplet due to the stronger evaporation of
TFA resulting in decreased suppression (Fig. 3). Although the “TFA-
fix” method is feasible, it complicates the analysis, and formic acid,
which provides adequate chromatographic performance without
suppression, has routinely been preferred in the analysis of pep-
tides by LC–ESI/MS. The effect of ion-pairing agents and buffers in
the analysis of peptides and proteins by LC–ESI/MS is summarized
by Carcia [114].
Alkylamines are commonly used as ion-pairing reagents in
reversed-phase LC-negative ion ESI/MS analysis of acidic com-
pounds, such as nucleoside mono-, di- and triphosphates [115,116]
sulfonates, sulfates, sulfonated dyes, and halogenated acids [117].
For example, 50 mM aqueous triethylammonium bicarbonate
has been used for nucleic acids [118], N,N-dimethylhexylamine
for nucleosides [115], and trialkyl amines (triethylamine, N,N-
dimethyl-n-butylamine, and tri-n-butylamine) for aromatic sul-
fonates [84]. The ion-pairing reagents used in the analysis of acids
may also cause suppression. Storm et al. [84] showed that alky-
lamines at concentrations higher than 2.5 mM resulted in a strongly
reduced signal in the analysis of aromatic sulfonates. As a con-
clusion, although ion-pair reversed-phase LC–ESI/MS may offer a
useful method for strong acids and bases, the ion-pairing agent may
cause signal suppression and increased background disturbance.
Ion-exchange chromatography (IEC)–ESI/MS is an alternative to
the ion-pair reversed-phase LC–ESI/MS for the analysis of ionic
compounds. There are four types of ion exchangers: weak anion,
weak cation, strong anion and strong cation exchangers. The mobile
phase normally consists of water and organic modifier, and the
ionic compounds are eluted by increasing the salt concentration
or changing the pH in the mobile phase. High salt concentrations,
commonly used in the elution of ionic compounds in IEC, suppress
ionization and rapidly contaminate the ion source in IEC–ESI/MS.
Salts must therefore be removed after the column by an on-line
desalting method, such as on-line dialysis [119], use of membrane
suppressor [120] or use of solid-phase chemical suppressor [121].
The use of a pH gradient instead of salt gradient for the elu-
tion of ionic analytes is more compatible with IEC–ESI/MS. For
example, nucleoside triphosphates were successfully analyzed by
IEC–ESI/MS using a pH gradient with ammonium acetate in ace-
tonitrile at pH 6 (mobile phase A) and pH 10.5 (mobile phase B)
as solvents [122]. Multidimensional LC combined to ESI/MS utiliz-
ing IEC and reversed-phase LC has been widely used in proteomics
instead of two-dimensional electrophoresis [123–127]. The pep-
tides are fractionated by IEC, and the fractions are transferred for
desalting and separation by using reversed-phase LC and eluents
compatible with ESI/MS.
3. Atmospheric pressure chemical ionization
Atmospheric pressure chemical ionization provides an alterna-
tive ionization method to ESI. In APCI, analytes eluting from LC are
vaporized at high temperature (300–500 ◦C) and ionized via gas-
phase ion–molecule reactions initiated by corona discharge needle.
APCI was introduced and combined with MS analysis in the early
1970s [9,10]. In the first APCI sources, the ionization was initiated by
a 63Ni source, but this was soon replaced by a corona discharge nee-
dle, which provides significantly higher signal intensity [10,128].
APCI is best suited for relatively stable and small molecules of
molecular weights less than about 1000–2000 Da. Since the com-
pounds are vaporized to the gas phase by thermal energy, the
method is not suitable for labile and large biomolecules such as
R. Kostiainen, T.J. Kauppila / J. Chromatogr. A 1216 (2009) 685–699 691
Table 1Ionization reactions in positive ion APCI [130]
N2 + e− → N2+• + 2e− (1)
N2+• + 2N2 → N4
+• + N2 (2)
H2O+• + H2O → H3O+ + HO• (3)
H3O+ + H2O + N2 → H+(H2O)2 + N2 (4)
H+(H2O)n − 1 + H2O + N2 → H+(H2O)n + N2 (5)
A + B+• → A+• + B (6)
A + BH+ → AH+ + B (7)
proteins, larger peptides or oligonucleotides. The main advantages
of APCI over ESI are that neutral and less polar compounds can
be ionized with good sensitivity, polar and non-polar solvents can
be used, and the system tolerates higher salt and additive concen-
trations than does ESI. The most important gas-phase reactions in
APCI are proton transfer, charge exchange and adduct formation,
the reactions being the same as those in classical chemical ioniza-
tion (CI) [129]. Because the ionization in APCI takes place in gas
phase, the ionization mechanism is less complicated than that in
ESI. However, understanding of the gas-phase reactions that lead to
the formation of reactant and analyte ions in APCI in light of solvent
properties is essential. Because the ionization process for positive
and negative ions in APCI is different, positive ion and negative ion
APCI are discussed separately below.
3.1. Positive ion APCI
In the absence of solvent the primary reacting molecules in APCI
originate from atmospheric species, such as nitrogen, carbon diox-
ide, oxygen and water. The primary reactant ions of the gases are
formed by the corona discharge (Table 1, Reactions (1)–(5)). When
solvent is introduced to the APCI source, further reactions take place
via proton transfer or charge exchange reactions (Table 1, Reactions
(6) and (7)). The formation of reactant and analyte ions in APCI
has previously been reviewed by Carroll et al. [130]. The ionization
reactions in the gas-phase are governed by the ion energetics of the
reacting species, i.e., ionization energies (IEs) and proton affinities
(PAs) in positive ion mode [28]. In proton transfer (Table 1, Reac-
tion (7)) the proton is transferred to the species of highest proton
affinity. The charge exchange reaction (Table 1, Reaction (6)) can
take place with the compounds having low ionization energy.
Table 2 shows the PAs and IEs of some atmospheric gases and
solvents commonly used in LC. Water, methanol and acetonitrile,
the most widely used solvents, have higher PAs and lower IEs than
atmospheric gases, and protonated solvent molecules acting as
reagent ions are efficiently formed in APCI. The analytes are then
Table 2Ionization energies (IE) and proton affinities (PA) of atmospheric gases and selected
LC solvents [28]
IE (eV) PA (kJ/mol)
Nitrogen 15.581 493.8
Oxygen 12.1 421.0
Carbon dioxide 13.777 540.5
Water 12.6 691.0
Methanol 10.84 754.3
Ethanol 10.48 776.4
Acetonitrile 12.2 779.2
Ammonia 10.07 853.6
n-Hexane 10.13 –
Chloroform 11.37 –
2-Propanol 10.17 793
Isooctane 9.89 –
Benzene 9.243 750.4
Toluene 8.83 784.0
Acetone 9.703 812.0
Anisole 8.20 839.6
ionized via proton transfer between protonated solvent molecule
and an analyte, if PA of the analyte is higher than that of the solvent
molecule. Note that the solvents, especially at lower temperatures,
can form solvent clusters, which have higher PAs and IEs than the
individual solvent monomers [131,132]. Solvents that possess low
PAs and IEs (e.g., benzene) can form molecular ions (M+•), which
can react further through charge exchange (Table 1, Reaction (6)).
It is important to note that the reagent ion composition changes
when the concentration of the eluent species changes during LC
gradient runs. Even small changes in eluent composition may
lead to significant changes in reagent ion composition, which
is highly dependent on the differences in PAs between solvent
components. Enke and co-workers [29] showed that the addi-
tion of 6% of methanol to water results in 50% of protonated
methanol molecules and 50% of protonated water molecules. Sim-
ilarly, when the concentration of ethanol in methanol exceeds
10%, protonated ethanol molecules become dominant, and when
the concentration of propanol in ethanol exceeds 15%, protonated
propanol molecules become dominant. The PAs of water, methanol,
ethanol and propanol are 691, 754, 776, and 793 kJ/mol, respectively
(Table 2). The results show that the larger the difference between
the PA of the solvent species, the lower concentration of solvent
with higher PA is needed to produce a reagent ion composition
dominated by protonated molecules of the higher PA solvent.
3.1.1. Solvents
The most popular polar mobile phase in reversed-phase
LC–APCI/MS applications consists of a mixture of methanol or
acetonitrile and water. Several groups have reported signal sup-
pression for low PA analytes when acetonitrile is used in place of
methanol as the organic modifier [45,133,134]. Most likely this is
because PA of acetonitrile is higher than that of methanol. Fig. 4
shows the reversed-phase LC–APCI/MS analysis of steroids by Ma
and Kim [133] with acetonitrile and methanol as organic mobile-
phase modifiers. For all steroids except testosterone, which have the
highest proton affinity, a significantly stronger signal was obtained
when methanol was used as the LC solvent. Hence, methanol may
be a better choice than acetonitrile for LC separations, especially
when, the PAs of the analytes are relatively low.
Both polar and non-polar solvents can be used in APCI, whereas
only polar or medium polar solvents can be used in ESI. In view
of this, several groups have chosen APCI for normal-phase liq-
fluoroacetate) can be ionized by proton transfer, but the ionization
of analytes with lower gas-phase acidity may be suppressed [147].
Furthermore, the response for analytes having higher gas-phase
acidities may be improved by high buffer concentrations. Schae-
R. Kostiainen, T.J. Kauppila / J. Chromatogr. A 1216 (2009) 685–699 693
Table 4Gas-phase acidities and electron affinities of selected gases and solvents [28]
Compound EA (eV) �Gacid (kJ/mol)
Oxygen 0.451 –
HO2• – 1451
Water – 1607
Methanol – 1565
Acetonitrile 0.01 1528
Chloroform 0.622 1464
Acetic acid – 1429
Formic acid – 1415
Trifluoroacetic acid – 1328
fer and Dixon [147] compared the signals of carboxylic acids and
phenols with 10 and 100 mM ammonium acetate added to the
LC solvent. They observed that the signal of weakly acidic com-
pounds was weaker with 100 mM than 10 mM ammonium acetate,
whereas the signal of the strongest acids improved with the
100 mM concentration. The suggested explanation of the stronger
signal at higher buffer concentrations was the increased number
of acetate ions resulting in more efficient proton transfer reac-
tion.
The basic buffers that can accept protons may enhance the
deprotonation reaction and thus the ionization efficiency. This
was shown by Schaefer and Dixon [147], who studied the effect
of different buffers to the ionization efficiency of carboxylic
acids and phenols in negative ion APCI. The basic buffer, N-
methylmorpholine, gave better ionization efficiency for all analytes
than the acidic buffers or solvent without buffer (Fig. 5).
Compounds that do not possess high gas-phase acidities or
positive electron affinities and cannot be ionized by deproto-
nation, charge exchange or electron capture can sometimes be
ionized by adduct ion formation through the addition, for exam-
ple, of chloroform or chloride salts ([M+Cl]−) or certain acids
([M+HCOO]−, [M+CH3COO]−) directly to the LC mobile phase or
post column [70,142,147,149,150]. Optimal adduct ion formation
usually requires low vaporizer temperatures [150]. Kato and Numa-
jiri [149] achieved efficient ionization of carbohydrates by APCI
when 0.5% of chloroform was introduced to the LC mobile phase
solvent flow. Chloroform was found to provide better sensitivity
than either dichloromethane or carbon tetrachloride. According to
Kato and Numajiri [149], formation of the chloride adduct ion is
efficient for compounds such as carbohydrates that possess adja-
cent OH-groups. Carbon tetrachloride has been added to achieve
ionization of nitroglycerin via chloride adduct ion formation [150].
The addition of chlorinated solvents can also prevent in-source
fragmentation in APCI, as was reported by Zencak and Oehme for
polychlorinated n-alkanes [142].
In addition to charge exchange and proton transfer reactions,
substitution reactions between a neutral analyte and superoxide
ion (Table 3, Reaction (6)) or between the negative molecular ion
of an analyte and oxygen (Table 3, Reaction (7)) may produce ions
of the form [M−X+O]−. These types of ion are commonly formed
with aromatic compounds containing a halogen or a nitro-group
[151–154]. For certain chlorine-substituted aromatic compounds,
the formation of phenoxide ions has been reported to compete with
the formation of negative molecular ions, so that in low pressure
conditions, where it is possible to remove oxygen from the ion-
Fig. 5. Reconstructed ion traces for the [M−H]− at m/z 153 for Z-norbomaneacetic acid obtained using HPLC mobile phases composed of a 1:1 mixture of acetonitrile with
the following aqueous buffers: (A) 10 mM N-methylmorpholine, (B) 10 mM ammonium acetate, (C) 100 mM ammonium acetate, or (D) 10 mM formic acid. The value in the
upper right corner of each trace represents signal height (reproduced with permission from ref. [147]).
694 R. Kostiainen, T.J. Kauppila / J. Chromatogr. A 1216 (2009) 685–699
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