Development of solvent-free ambient mass spectrometry for green chemistry applications

Article abstract of DOI:10.1021/ac500527q

Green chemistry minimizes chemical process hazards in many ways, including eliminating traditional solvents or using alternative recyclable solvents such as ionic liquids. This concept is now adopted in this study for monitoring solvent-free reactions and analysis of ionic liquids, solids, and catalysts by mass spectrometry (MS), without using any solvent. In our approach, probe electrospray ionization (PESI), an ambient ionization method, was employed for this purpose. Neat viscous room-temperature ionic liquids (RTILs) in trace amounts (e.g., 25 nL) could be directly analyzed without sample carryover effect, thereby enabling high-throughput analysis. With the probe being heated, it can also ionize ionic solid compounds such as organometallic complexes as well as a variety of neat neutral solid chemicals (e.g., amines). More importantly, moisture-sensitive samples (e.g., [bmim][AlCl₄]) can be successfully ionized. Furthermore, detection of organometallic catalysts (including air-sensitive [Rh-MeDuPHOS][OTf]) in ionic liquids, a traditionally challenging task due to strong ion suppression effect from ionic liquids, can be enabled using PESI. In addition, PESI can be an ideal approach for monitoring solvent-free reactions. Using PESI-MS, we successfully examined the alkylation of amines by alcohols, the conversion of pyrylium into pyridinium, and the condensation of aldehydes with indoles as well as air- and moisture-sensitive reactions such as the oxidation of ferrocene and the condensation of pyrazoles with borohydride. Interestingly, besides the expected reaction products, the reaction intermediates such as the monopyrazolylborate ion were also observed, providing insightful information for reaction mechanisms. We believe that the presented solvent-free PESI-MS method would impact the green chemistry field.

Full text of DOI:10.1021/ac500527q

Article
pubs.acs.org/ac
Development of Solvent-Free Ambient Mass Spectrometry for Green
Chemistry Applications
Pengyuan Liu,† Amanda Forni,† and Hao Chen*,†,‡
Center for Intelligent Chemical Instrumentation, †Department of Chemistry and Biochemistry, ‡Edison Biotechnology Institute, Ohio
University, Athens, Ohio 45701, United States
S
* Supporting Information
ABSTRACT: Green chemistry minimizes chemical process
hazards in many ways, including eliminating traditional solvents
or using alternative recyclable solvents such as ionic liquids. This
concept is now adopted in this study for monitoring solvent-free
reactions and analysis of ionic liquids, solids, and catalysts by
mass spectrometry (MS), without using any solvent. In our
approach, probe electrospray ionization (PESI), an ambient
ionization method, was employed for this purpose. Neat viscous
room-temperature ionic liquids (RTILs) in trace amounts (e.g.,
25 nL) could be directly analyzed without sample carryover
effect, thereby enabling high-throughput analysis. With the
probe being heated, it can also ionize ionic solid compounds
such as organometallic complexes as well as a variety of neat
neutral solid chemicals (e.g., amines). More importantly, moisture-sensitive samples (e.g., [bmim][AlCl4]) can be successfully
ionized. Furthermore, detection of organometallic catalysts (including air-sensitive [Rh-MeDuPHOS][OTf]) in ionic liquids, a
traditionally challenging task due to strong ion suppression effect from ionic liquids, can be enabled using PESI. In addition, PESI
can be an ideal approach for monitoring solvent-free reactions. Using PESI-MS, we successfully examined the alkylation of
amines by alcohols, the conversion of pyrylium into pyridinium, and the condensation of aldehydes with indoles as well as air-
and moisture-sensitive reactions such as the oxidation of ferrocene and the condensation of pyrazoles with borohydride.
Interestingly, besides the expected reaction products, the reaction intermediates such as the monopyrazolylborate ion were also
observed, providing insightful information for reaction mechanisms. We believe that the presented solvent-free PESI-MS method
would impact the green chemistry field.
droplet evaporation for ion generation during the ESI
ionization process.
reen chemistry is the design of chemical products and
Gprocesses that reduce or eliminate the use or generation
of hazardous substances.1 In order to minimize pollution before
it is produced, green chemistry optimizes every element of
chemical processing, including reagent, atom economy,
molecular design, waste, etc.2 Among these elements, solvent
optimization is currently one of the most active research fields,
which involves several hot topics: using water, alternative
recyclable solvents (e.g., ionic liquids), and alternative nontoxic
reaction media (e.g., supercritical fluids), or no solvent for
chemical reactions.3,4 These nontraditional solvent systems
have been applied to many organic and inorganic syntheses.
Unfortunately, in the field of mass spectrometry (MS), the
“solvent optimization revolution” has not gained popularity yet
and is still in its infancy stage, although efforts were made
toward developing “solvent-free” MS.5−8 The reason for this
might be due to the difficulty of eliminating the solvent use for
analysis. Currently dominant ionization methods, such as
electrospray ionization (ESI)9 and matrix-assisted laser
desorption ionization (MALDI),10 typically need organic
solvents like acetonitrile or methanol to dissolve/dilute samples
or to prepare matrix solutions. The organic solvent also helps
Solvent-free ionization MS analysis has been an attractive
goal for chemical analysis. The reason is obvious. Solvent-free
ionization not only results in easy sample handling but also
leads to the analysis of a wide range of compounds, including
moisture-sensitive samples and traditional MS solvent insoluble
samples. More importantly, solvent-free analysis is environ-
mentally friendly and in accordance with the concept of green
chemistry. When being combined with green chemical
synthesis, it makes the entire synthesis and subsequent analysis
process “green”. Furthermore, solvent-free ionization techni-
ques also have unique applications for working in extreme
environments, such as in volcanoes or in space, using
miniaturized or unmanned mass spectrometers.11 In literature,
several atmospheric pressure solvent-free ionization methods
were reported and demonstrated. Solvent-free MALDI5,12 is
probably the most developed solvent-free ionization technique
Received: February 6, 2014
Accepted: March 26, 2014
Published: March 26, 2014
© 2014 American Chemical Society
4024
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032

Analytical Chemistry
Article
Figure 1. (a) PESI-MS apparatus using a stainless steel as the probe and (b) thermally assisted-PESI-MS apparatus using a soldering iron as the
probe.
so far, in which analyte and matrix are solvent-freely
homogenized by grinding5 or sublimed vapor desorption.13
pounds. The surprising capability of PESI of directly spraying
viscous liquid samples prompted us to use it for additional
green chemistry-related applications such as monitoring
solvent-free organic reactions as well as detecting organo-
metallic catalysts in ionic liquids.
A
major advantage of the method is its capability of ionizing
insoluble/poorly soluble samples, such as polycyclic aromatic
compounds,7 amyloid peptides,14 and fatty acids,15 et al.12
Another solvent-free ionization technique is direct analysis in
real time (DART),16 which desorbs and ionizes samples with
electronic or vibronic excited neutral species. DART can
solvent-freely analyze various samples including ionic liquids
and polycyclic aromatics.8,17 In addition, the solvent-free
analysis has also been achieved by DART-similar ionization
methods, such as plasma-assisted desorption/ionization
(PADI),18 flowing afterglow-atmospheric pressure glow dis-
charge (FA-APGD),19 dielectric barrier discharge ionization
(DBDI),20 low-temperature plasma (LTP) probe ionization,21
and beta electron-assisted direct chemical ionization
(BADCI).22 However, current atmospheric pressure solvent-
free MS methods still require complex sample preparations or
complicated instrumentation. In addition, the direct analysis of
solvent-free reaction intermediates and products, present in
sticky liquid or solid mixtures, is still missing in the literature.
What could be a convenient solvent-free ambient ionization
MS23−25 method for green chemistry applications? We found
the answer to be probe electrospray ionization (PESI).
EXPERIMENTAL SECTION
■
Reagents. 1-Ethyl-3-methylimidazolium tetrafluoroborate
([emim][BF4]), 1-butyl-3-methylpyridinium tetrafluoroborate
([bmpy][BF4]), 1-ethyl-2,3-dimethylimidazolium bis-
(trifluoromethanesulfonyl)imide ([edmim][NTf2]), trihexylte-
tradecylphosphonium bis(2,4,4-trimethylpentyl)phosphinate
([P66614][TMPP]), 1-ethyl-3-methylimidazolium nitrate
([emim][NO3]), 1-butyl-3-methylimidazolium tetrafluorobo-
rate ([bmim][BF4]), 1-butyl-2,3-dimethylimidazolium tetra-
fluoroborate ([bdmim][BF4]), 2,4,6-triphenylpyrylium tetra-
fluoroborate ([TPP][BF4]), perylene, 1-butyl-3-methylimida-
zolium tetrachloroaluminate ([bmim][AlCl4 ]),
cyclopentadienyl(p-cymene)ruthenium(II) hexafluorophos-
phate ([CpRu(p-cymene)][PF6]), ferrocene, silver bis-
( t r i fl u o r o m e t h a n e s u l f o n y l ) i m i d e ( A g N T f 2 ) ,
pentamethylcyclopentadienyliridium(III) chloride dimer
([Cp*IrCl2]2), 1-naphthylamine, benzylamine, 1,5-pentanediol,
phenylhydrazine, cyclohexanone, potassium borohydride
(KBH4), 3,5-dimethylpyrazole, 3-phenyl-5-methylpyrazole, in-
dole, and benzaldehyde were all purchased from Sigma-Aldrich
(St. Louis, MO). Bis(cyclopentadienyl)zirconium dichloride
(Cp2ZrCl2) and 1,2-bis[(2S,5S)-2,5-dimethylphospholano]-
benzene(cyclooctadiene)rhodium(I) trifluoromethanesulfonate
([Rh-MeDuPHOS][OTf]) were purchased from Strem (New-
buryport, MA). All the reagents were used without further
purifications.
The term PESI was introduced by Hiraoka and co-workers.26
In contrast with ESI of using a capillary for sample
introduction, PESI employs a conductive solid probe on
which a microliter droplet of analyte solution is deposited.
When a high voltage is applied to the probe, the droplet
deforms to a Taylor Cone at the tip of the probe to emit a
spray.27 Using PESI-MS, various chemical and biological assays
were performed,28 including imaging biological tissues,29
monitoring chemical reactions in solution,30 and analyzing
living biological samples in real time.31,32 It was shown that
PESI had high tolerance to salt33 and detergent.34 Some earlier
work relevant to PESI was carried out by Shiea and co-
workers,35 in which copper wire,35,36 optical fiber,37 or platinum
rod38 could be used as the probe. However, PESI was
previously only used for ionizing samples in either aqueous
or organic solvents. In our laboratory, we serendipitously found
that highly viscous room temperature ionic liquids (RTILs) can
be directly loaded on a needle probe and sprayed to generate
gas-phase ions, without using solvent for sample dilution. This
phenomenon is also applicable to ionic solid samples, in which
the solvent-free PESI ionization can be achieved simply by
heating the needle probe to convert the loaded solid sample
into liquid followed by application of a high voltage to the
probe for spray ionization. Such a solvent-free MS method
provides opportunity to analyze moisture-/air-sensitive com-
Apparatus. A Thermal Finnigan LCQ DECA ion trap mass
spectrometer (San Jose, CA) and an AB SCIEX Q-trap 2000
triple-quadrupole-linear ion trap mass spectrometer (Concord,
Canada) were used for all experiments. The commercial ion
source was removed for the accommodation of homemade
PESI sources. Two different homemade PESI ionization probes,
a regular PESI, and a thermally assisted-PESI were designed,
which simply consisted of a stainless steel needle (Fisher
Scientific, no. 70005-98033) and a soldering iron (Weller,
WSB25HK), respectively, as the probe. The former probe
(Figure 1a) was used for ionizing liquid samples only by
applying a high voltage of 5 kV to the probe. The latter probe
(Figure 1b) was used for the analysis of higher melting-point
analytes like ionic solids, in which solid samples were loaded
onto the probe and then heated to melting (30 °C ∼ 300 °C),
by plugging the soldering iron in a power socket. The samples
were ionized by PESI as soon as they were melted. The
4025
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032

Analytical Chemistry
Article
Figure 2. PESI-MS spectra of RTIL samples: (a) [emim][BF4], (b) [bmpy][BF4], (c) [edmim][NTf2], and (d) [P66614][TMPP].
Figure 3. Thermally assisted-PESI-MS spectra of (a) [bdmim][BF4] (mp 38−40 °C), (b) [TPP][BF4] (mp 250−251 °C), (c) Cp2ZrCl2 (mp 242−
245 °C), and (d) perylene (mp 276−279 °C). The red lines in the Figure 3c inset show the theoretically calculated isotopic peak distribution of
Cp2ZrCl+ (m/z 255).
distance between the probe tips and MS inlet capillary varied
from 0.5 to 5.0 cm.
(Figure 2), cation peaks were clearly observed. For instance, in
the case of [emim][BF4] (Figure 2a), the intact cation (labeled
as “C” and this denotation is applicable throughout the paper)
was observed at m/z 111 along with the cluster ions C2A, C3A2,
and C4A3 (the denotation of “A” presents the corresponding
anion, which is tetrafluoroborate in this case), appearing at m/z
309, 507, and 705, respectively. The cluster ions provide
information about the counteranions for the analytes. In
addition, in the experiment, the ion signal immediately
disappeared if the high voltage was turned off. By simply
wiping the residue off from the probe, no leftover would be
seen to influence subsequent runs, thus allowing high-
throughput analysis. As a demonstration, three RTIL samples
can be analyzed in less than 2.5 min (Figure 1S of the
Supporting Information) without cross-talking and sample
carryover effect. In contrast, if traditional ESI method was used
for the analysis of the three samples, carryover issue occurred
and both sample preparation and cleaning were time-
consuming (see Figure 2S and discussion of the Supporting
Information). In addition to the advantage of being capable of
high-throughput analysis, the PESI method is also highly
sensitive. Good signal was obtained for RTILs as low as 25 nL
(Figure 3S of the Supporting Information).
RESULTS AND DISCUSSION
■
Direct Ionization of Ionic Liquids and Ionic Solids.
RTILs are popular solvents used for organic reactions due to
their recyclability.39 The most common RTILs are imidazolium,
pyridinium, pyrrolidinium, and phosphonium-based organic
salts.40 In previous ESI-MS studies, RTILs were used to
increase the detection selectivity and sensitivity of analytes such
as neutral polysaccharides or organometallic compounds
because they could serve as good charge carriers.41,42 ESI-MS
was also used to analyze ionic liquids;43,44 however, heated
curtain/desolvation gas was required to reduce the sample
viscosity,43 and the contamination to the mass spectrometer
was often the major problem.44 In our experiment, [emim]-
[BF4], [bmpy][BF4], [edmim][NTf2], and [P66614][TMPP],
were chosen as representative examples for PESI test, using the
regular probe (Figure 1a). The results are shown in Figure 2.
One microliter of each RTIL sample was loaded onto the
needle tip and then ionized by applying a high voltage of 5 kV
to the needle. In all cases, the continuous signal lasted for
several minutes. As shown in the obtained positive ion spectra
4026
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032

Analytical Chemistry
Article
Figure 4. (a) PESI-MS and (b) ESI-MS spectra of [bmim][AlCl4] in the positive ion mode; (c) PESI-MS and (d) ESI-MS spectra of [bmim][AlCl4]
in the negative ion mode. The red lines in the insets of (a and c) show theoretically calculated isotopic peak distributions of m/z 445 and 167,
respectively.
In addition to liquid samples, solid samples can also be
analyzed by PESI-MS with a new design of the ionization
probe. In the new design (Figure 1b), the probe is replaced by a
soldering iron on which solid samples could be thermally
converted (heating the samples by soldering iron) to liquids for
spray ionization. In this thermally assisted-PESI, the soldering
iron tip was polished to a small triangle shape for promoting
spray ionization because of the high electric field on the tip
(analogous to paper tip used in the paper spray ionization
method).45,46 Four different types of solid samples were chosen
for demonstration, including ionic solids, organometallics,
organic salts, and polycyclic aromatics. These compounds
have melting points (MPs) varying from 38 to 279 °C. As soon
as the sample started melting, the high voltage of 5 kV was
applied to the probe to affect ionization. The collected spectra
are shown in Figure 3, in which no fragmentation was observed.
In contrast, directly ionizing the samples in solid state with
PESI received no signal at all, proving that the heating for
sample phase conversion was important to the ionization.
As depicted in Figure 3 (panels a and b), [bdmim][BF4] and
[TPP][BF4] show intact cations as well as cluster ion peaks,
similar to the liquid samples discussed above (Figure 2). This is
reasonable as the solid samples are intrinsically organic salts but
have MPs exceeding room temperature. Interestingly, solid
organometallic compounds could also be ionized by thermally-
assisted-PESI. For example, Cp2ZrCl+ was detected at m/z 255
(Figure 3c) for the organometallic complex Cp2ZrCl2 when the
solid complex was melted around 240 °C on the probe and
then sprayed with 5 kV applied to the probe. The observed
isotopic peak distribution of m/z 255 agreed well with the
theoretical simulation (Figure 3c, inset). In addition, its water
adduct ion was observed at m/z 273. Equally interestingly, solid
polycyclic aromatic compounds with high melting points such
as perylene could also be ionized by thermally assisted-PESI-
MS (Figure 3d). In the spectrum, the observed peak appears at
m/z 252, which corresponds to the perylene radical cation and
might result from ionization via corona discharge of the melted
sample vapor. This result shows the strength of our PESI
method because perylene, like other polycyclic aromatic
compounds, is difficult to be ionized by ESI, as it is insoluble
in traditional ESI solvents. For this reason, methods such as
DART, solvent-free MALDI, and atmospheric pressure photo
ionization (APPI)47,48 were developed to ionize this type of
nonpolar aromatic species. Herein, thermally assisted-PESI
provides an alternative and simple solution.
Strikingly, PESI can be used for direct analysis of moisture-
sensitive compounds as it does not need the use of a solvent.
For demonstration, a moisture-sensitive ionic liquid, [bmim]-
[AlCl4], was analyzed. [Bmim][AlCl4] is one of the earliest
developed RTILs,49 which is known to vigorously react with
−
water (i.e., the hydrolysis of tetrachloroaluminate AlCl4 ). The
moisture sensitive property makes it difficult to be ionized using
traditional ionization methods like ESI, which involve the use of
solvent. Figure 4a shows the spectrum of [bmim][AlCl4]
analyzed by PESI-MS. In the spectrum, both the intact cation
and the cation cluster ion C2A appears at m/z 139 and 445,
respectively. The observation of C2A provides the information
on the anionic component of the sample. The isotopic
distribution of ion C2A at m/z 445 matches well with the
theoretical simulation (Figure 4a, inset), confirming the peak
assignment. By contrast, the m/z 445 was completely missing,
using ESI-MS analysis of the ionic liquid dissolved in MeOH/
H2O with a dilution factor of 2/104 (v/v) (Figure 4b),
indicating depletion of anion AlCl4− in the solvent used for ESI.
Typically, the cluster ions like C2A would be detectable in ESI
of moisture-stable ionic liquid samples (e.g., the example shown
in Figure 2S of the Supporting Information). Indeed, when the
negative ESI spectrum of [bmim][AlCl4] was acquired, ions at
−
m/z 131 and 149, resulting from AlCl4 hydrolysis, were
−
noticed (Figure 4d). In contrast, the intact anion AlCl4 was
observed as the dominant peak at m/z 167 in the negative ion
PESI-MS spectrum, with isotopic peak distribution fitting well
with the theoretical simulation (Figure 4c, inset).
The results shown above demonstrate the strength of
solvent-free PESI, as exemplified by its capability in ionizing
ionic liquids, ionic solids, as well as moisture-sensitive species.
These features of PESI prompted us to apply it to the analysis
of solvent-free reactions and the detection of organometallic
catalysts in RTILs, two applications with significance in green
chemistry.
Direct Monitoring of Solvent-Free Reactions. With
increased attention in the pursuit of green chemistry for
reducing environmental pollution, people have begun utilizing
solvent-free organic reactions for chemical synthesis. Other
4027
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032

Analytical Chemistry
Article
Figure 5. Thermally assisted-PESI-MS spectra of (a) the solid reaction product from the solvent-free reaction of 1 mmol ferrocene and 1 mmol
AgNTf2; (b) the solid reaction product from the solvent-free reaction of 1 mmol KBH4 and 5 mmol 3,5-dimethylpyrazole; and (c) the solid reaction
product from the solvent-free reaction of [TPP][BF4] and 1-naphthylamine. Reaction equations are shown as figure insets.
driving forces for the development of dry media reactions in
chemistry are economics (save money on solvents), ease of
purification (no postsynthesis solvent removal), and high
reaction rate (due to high concentration of reactants).
However, solvents are usually still being used in traditional
postsynthesis analysis. In our view, the monitoring/analysis of
the solvent-free reactions without using any solvent would be
ideal and in accordance with the green chemistry concept. It
turns out that PESI is the method of choice for this purpose.
Several solvent-free reactions were successfully monitored by
PESI in this study.
The first example is the solvent-free synthesis of metal-
containing ionic liquids, in which ferrocene can be milled with
silver salts to provide ferrocenium ionic liquids (see reaction eq
1 shown in Figure 5a).50 The whole preparation was performed
in a N2 gas atmosphere glovebox as the product is air sensitive,
following the reported procedure.50 One mmol ferrocene and 1
mmol AgNTf2 were mixed and grounded in a motor for 5 min.
Dark color solid product was produced after grounding. The
product was directly analyzed by thermally assisted-PESI-MS.
In the collected spectrum (Figure 5a), the ferrocenium ion
from the resulting product ferrocenium bis-
(trifluoromethanesulfonyl)imide was observed at m/z 186 as
the major peak.
Tris(pyrazolyl)borated metal salts are a class of intriguing
catalysts because of their excellent thermal stabilities.51 As a
synthesis precursor of catalysts, potassium tris(pyrazolyl)borate
(KTp) can be prepared by reacting KBH4 with pyrazoles. In
our experiment, the solvent-free reaction was performed by
mixing and grounding 1 mmol KBH4 and 5 mmol 3,5-
dimethylpyrazole followed with heating to 220 °C for 4 h. After
cooling, a white solid product was obtained. The product was
directly analyzed by thermally assisted-PESI-MS. In the
acquired spectrum (Figure 5b), tris(3,5-dimethylpyrazolyl)-
borate anion TpMe2 (m/z 297; structure shown in Figure 5b) of
the expected triply pyrazolylated product, potassium tris(3,5-
dimethylpyrazolyl)borate (KTpMe2), was clearly observed.
Upon collision-induced dissociation (CID), m/z 297 lost
bis(3,5-dimethylpyrazolyl)borane to form the deprotonated
pyrazole of m/z 95, consistent with its structure (Figure 4S-a of
the Supporting Information). In Figure 5b, the deprotonated
starting material pyrazole of m/z 95 was also seen. Interestingly,
4028
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032

Analytical Chemistry
Article
Figure 6. (a) PESI-MS spectrum of an oily reaction mixture from microwave-assisted alkylation reaction of benzylamine and 1,5-pentanediol
catalyzed by [Cp*IrCl2]2. Thermally assisted-PESI-MS spectra of (b) the solid product from solvent-free reaction of phenylhydrazine and
cyclohexanone, and (c) the gel product from solvent-free reaction of indole, benzaldehyde, and [bmim][BF4]. Reaction equations are shown as
figure insets.
the monopyrazolylborate intermediate ion was detected at m/z
109. Upon CID, m/z 109 shows the losses of HN•-BH2 and
CH3CHCH•, confirming the proposed structure (Figure 4S-
b of the Supporting Information). The presence of the
monopyrazolylborate intermediate in the reaction mixture is
in agreement with the previously reported stepwise substitution
mechanism.52 This monopyrazolylborate intermediate is
moisture-sensitive. Indeed, in a comparison experiment, when
the solid reaction product was dissolved in methanol and
ionized by ESI-MS, m/z 109 was not observed (Figure 4S-c of
the Supporting Information). In addition, the same phenomena
were seen in the analysis of solvent-free reaction of KBH4 with
another similar substrate, 3-phenyl-5-methyl pyrazole (Figure
5S of the Supporting Information). The capability of analyzing
the moisture-sensitive species allows one to use PESI for
detecting reaction intermediates, which provides valuable
information for the reaction mechanism.
was chosen as the nucleophile to attack pyrylium. The solvent-
free reaction was performed by mixing [TPP][BF4] with 1-
naphthylamine (eq 3, Figure 5c), and then ionized by thermally
assisted-PESI-MS. In the obtained spectrum (Figure 5c), both
[TPP] cation (m/z 309) and the 1-naphthylamine radical
cation from remaining starting materials (m/z 143, probably
due to corona discharge involved in PESI) were observed.
Meanwhile, the 1-(1-naphthyl)-2,4,6-triphenylpyridinium ion
from the expected condensation reaction product was seen at
m/z 434, which was produced during heating of the mixture on
the PESI probe and instantaneously monitored by PESI-MS.
The solvent-free PESI analysis is also applicable to probe
neutral reaction products generated in solvent-free organic
reactions. The alkylation of amines is an important reaction in
both pharmaceutical and chemical industries. Transition metals,
such as iridium and ruthenium catalysts are known to promote
alkylation using alcohols. For example, [Cp*IrCl2]2 can
efficiently catalyze an atom-economical and solvent-free
amine alkylation reaction using microwave irradiation (eq 4,
In another example of converting pyrylium to the pyridinium
ion with primary amine,53 1-naphthylamine (MP 47−50 °C)
4029
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032

Analytical Chemistry
Article
Figure 7. PESI-MS spectra of (a) 1 mM [CpRu(p-cymene)][PF6] in [emim][BF4] and (b) 1 mM [Rh-MeDuPHOS][OTf] in [bmim][PF6]. The
red lines in the insets show theoretically calculated isotopic peak distributions.
Figure 6a).54 One millimole of benzylamine, 1 mmol of 1,5-
pentanediol, and 1% mmol [Cp*IrCl2]2 were added to a
microwave vial. The vial was purged with N2 gas and then
sealed for microwave irradiation. After 1 h, an oily reaction
mixture was produced and directly analyzed by PESI-MS
without heating. The protonated alkylation product 1-
benzylpiperidine was observed as the dominant peak (m/z
176, Figure 6a), which was confirmed by MS/MS spectrum,
showing losses of piperidine and toluene (Figure 6S-a of the
Supporting Information). In addition, the PESI-MS spectrum
of the reaction mixture in absence of the iridium catalyst
showed only the adduct ion of the protonated benzylamine and
1,5-pentanediol (m/z 212) without product ion (Figure 6S-b of
the Supporting Information), indicating that the catalyst is
essential for the occurrence of amine alkylation by alcohols.
This example also demonstrates that PESI-MS is a good tool
for reaction monitoring. In Figure 6a, another peak at m/z 192
was observed, probably corresponding to the protonated ion of
the condensation product between benzylamine and 5-
hydroxypentanal, an impurity of 1,5-pentanediol.
ion of the product and cyclohexanone appeared at m/z 377 and
m/z 287, respectively.
The condensation reaction of aldehyde with indoles could be
catalyzed by ionic liquid [bmim][BF4] at room temperature
without using any additional organic solvent (eq 6, Figure
6c).57 Five millimoles of indole, 2.5 mmol benzaldehyde, and
0.125 mmol [bmim][BF4] were mixed together for 2 h to yield
a red gel product. The product was directly analyzed by
thermally assisted-PESI-MS. In the obtained spectrum, the
radical cation of the produced bis(indolyl)phenylmethane was
observed at m/z 322 (presumably due to corona discharge
ionization mechanism of PESI), as confirmed by its dissociation
pattern showing losses of benzene and indole radicals upon
CID (Figure 8S of the Supporting Information). In addition,
the observed ion of m/z 206 might be a fragment ion m/z 322
by loss of an indole radical. These results are in line with the
literature report using MALDI as the ionization method.57
Compared to MALDI, our method is faster as no sample
preparation is in need and more environmentally friendly
because no organic solvent is used.
Arylhydrazones are important precursors for synthesizing
various nitrogen-containing compounds, such as nitriles,
nitrones, pyrazoles, triazoles, and others. Phenylhydrazones
can be easily prepared solvent-free by grounding aldehydes and
ketones (eq 5, Figure 6b).55 One millimoles of phenylhydrazine
and 1 mmol cyclohexanone were mixed in a test tube. After
stirring for 10 min, a yellow solid product was formed. The
product was directly tested by thermally assisted-PESI-MS. A
dominant peak was observed at m/z 189, which was confirmed
as the protonated cyclohexanone phenylhydrazone, by
observing the characteristic neutral loss of NH3 via the
Borsche−Drechsel cyclization pathway56 upon CID (Figure
7S of the Supporting Information). Meanwhile, the dimer ion
of the product cyclohexanone phenylhydrazone and the adduct
Detection of Organometallic Catalysts in Ionic
Liquids. Ionic liquids have become more and more popular
reaction media for catalyst immobilization. However, the
analysis of catalysts in ionic liquids remains problematic in
1
part because in situ H and 13C NMR analysis necessitates
deuterated ionic liquids, which are extremely expensive.
Furthermore, extraction of the catalyst after reaction is often
not possible (at least for catalysts that do not easily leach),
which prevents postreaction analysis. ESI was previously used
for analysis of ionic catalysts in RTILs, in which the catalyst in
ionic liquids was diluted with methanol by 103−106 fold to
reduce the ion suppression effect of ionic liquids and catalysts
of interest were detected with low signal intensity.58 In this
study, our results show that direct analysis of catalysts in RTILs
4030
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032

Analytical Chemistry
Article
by solvent-free PESI is possible, even without any dilution or
using any solvent.
CONCLUSIONS
■
In conclusion, the solvent-free PESI-MS is fast, sensitive, and
versatile, with several unique green chemistry applications as
demonstrated in this paper. Using PESI to analyze both intact
ionic liquids and ionic solid samples is straightforward; and
high-throughput analysis is possible. More importantly, it can
be used for monitoring solvent-free reactions and analyzing
moisture-/air-sensitive reaction products and catalysts in
RTILs. We believe the PESI-MS technique would have many
interesting utilities in the green chemistry field.
Ruthenium-based organometallic catalysts are commonly
used in ionic liquid media for catalyzing many hydrogenation
reactions.59,60 In our PESI-MS experiment, organometallic
catalyst [CpRu(p-cymene)][PF6] was chosen as a test sample,
which was dissolved in ionic liquid [emim][BF4], a commonly
used reaction medium, to be 1 mM (a typical catalyst
concentration in ionic liquids which is 10−3−10−4 folds lower
than the ionic liquid concentration). Then the solution was
directly analyzed by PESI without any pretreatment. In the
obtained spectrum (Figure 7a), the cation peak of [emim]-
[BF4] and the cation cluster C2A peak appeared at m/z 111 and
309, respectively. Strikingly, [CpRu(p-cymene)] cation (m/z
301) was observed in the spectrum (Figure 7a), with its
isotopic peak distribution matching the calculated peak
distribution (Figure 7a, inset).
ASSOCIATED CONTENT
■
S
* Supporting Information
The data of high-throughput analysis, trace amount of ionic
liquid analysis, and additional solvent-free reactions are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
[Rh-MeDuPHOS][OTf] is another type of important
catalyst for asymmetric hydrogenation.61 But this catalyst is
air sensitive and it is difficult to be analyzed by traditional MS
methods. However, it has been reported that ionic liquids could
stabilize the catalyst by protecting it from the atmospheric
oxygen attack in the ionic environment of ionic liquids, and the
asymmetric hydrogenations of methyl α-acetamidoacrylate and
methyl α-acetamidocinnamate were catalyzed by [Rh-
MeDuPHOS][OTf] with employment of [bmim][PF6] as the
reaction media.62 For these reasons, it would be necessary and
highly valuable to directly analyze the catalyst in the presence of
ionic liquids. Our PESI-MS would be the method of choice for
this purpose. For demonstration, the catalyst was weighted in a
glovebox, dissolved in [bmim][PF6], and diluted to 1 mM.
Then the solution was directly analyzed by PESI-MS. As shown
in the acquired spectrum (Figure 7b), in addition to the ionic
liquid cation and cation cluster ions (m/z 139 and 423), the
intact catalyst cation [Rh-MeDuPHOS]+ was observed at m/z
517, with isotope peak distribution matching with the
simulation. This result also confirms that the compound can
be stable in ionic liquid and can be directly visualized by PESI-
MS. It also reveals the strength and potential of PESI-MS in
green chemistry (e.g., monitoring catalyst transformation in
ionic liquids).
PESI Ionization Mechanisms. In general, based on our
observation, both ESI-like spray ionization27 and APCI-like
corona discharge ionization are involved in the solvent-free
PESI ionization process. By applying a high voltage, an
electrospray cone could be formed from the liquid droplet on
the probe tip. In the case of solid analytes, samples can be
thermally converted into liquids followed with spray ionization.
The unique feature of the PESI used in this study is that no
solvent is used; therefore, desolvation should not be involved in
the ionization. Since neat ionic liquids already carry charges, the
protonation/deprotonation is not in need either. But the
declustering of ion aggregates into free cation or anion is
required for ion detection. In addition, neutral amine or
aromatic hydrocarbon compounds can also be ionized into
protonated species or radical cations, respectively, which could
be accounted for by the corona discharge mechanism. Due to
the high potential applied to the probe and no solvent is used,
the corona discharge of air occurs to form reagent ions like
hydronium ions H3O+ and N2 radicals, which are responsible
for forming protonated ions or radical cations via proton
transfer or charge transfer.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail:chenh2@ohio.edu. Tel: 1-(740)-593-0719. Fax: 1-
(740)-597-3157.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
Career Award (NSF CHE-1149367). We also thank Dr.
Michael Jensen and his students, Haoshuang Wang and Caitlin
Anderson, for help on handling air-/moisture-sensitive samples
and providing us with potassium tris(pyrazolyl)borates.
REFERENCES
■
(1) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35 (9),
686−694.
(2) Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39 (1), 301−312.
(3) DeSimone, J. M. Science 2002, 297 (5582), 799−803.
(4) Sheldon, R. A. Green Chem. 2005, 7 (5), 267−278.
(5) Trimpin, S.; Rouhanipour, A.; Az, R.; Rader, H. J.; Mullen, K.
̈
̈
Rapid Commun. Mass Spectrom. 2001, 15 (15), 1364−1373.
(6) Trimpin, S.; Deinzer, M. L. Anal. Chem. 2007, 79 (1), 71−78.
(7) Trimpin, S.; Keune, S.; Rader, H. J.; Mullen, K. J. Am. Soc. Mass
̈
̈
Spectrom. 2006, 17 (5), 661−671.
(8) Domin, M. A.; Steinberg, B. D.; Quimby, J. M.; Smith, N. J.;
Greene, A. K.; Scott, L. T. Analyst 2010, 135 (4), 700−704.
(9) Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S. F.; Whitehouse, C.
M. Science 1989, 246 (4926), 64−71.
(10) Karas, M.; Hillenkamp, F. Anal. Chem. 1988, 60 (20), 2299−
2301.
(11) Diaz, J. A.; Pieri, D.; Arkin, C. R.; Gore, E.; Griffin, T. P.;
Fladeland, M.; Bland, G.; Soto, C.; Madrigal, Y.; Castillo, D.; Rojas, E.;
Achí, S. Int. J. Mass Spectrom. 2010, 295 (3), 105−112.
(12) Trimpin, S. J. Mass Spectrom. 2010, 45 (5), 471−485.
(13) Kim, S. H.; Shin, C. M.; Yoo, J. S. Rapid Commun. Mass
Spectrom. 1998, 12 (11), 701−704.
(14) Trimpin, S.; Deinzer, M. J. Am. Soc. Mass Spectrom. 2007, 18
(8), 1533−1543.
(15) Trimpin, S.; Clemmer, D. E.; McEwen, C. N. J. Am. Soc. Mass
Spectrom. 2007, 18 (11), 1967−1972.
́
(16) Cody, R. B.; Laramee, J. A.; Durst, H. D. Anal. Chem. 2005, 77
(8), 2297−2302.
(17) Mazzotta, M.; Pace, R.; Wallgren, B.; Morton, S., III; Miller, K.;
Smith, D. J. Am. Soc. Mass Spectrom. 2013, 24 (10), 1616−1619.
4031
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032

Analytical Chemistry
Article
(18) Ratcliffe, L. V.; Rutten, F. J. M.; Barrett, D. A.; Whitmore, T.;
Seymour, D.; Greenwood, C.; Aranda-Gonzalvo, Y.; Robinson, S.;
McCoustra, M. Anal. Chem. 2007, 79 (16), 6094−6101.
(19) Andrade, F. J.; Shelley, J. T.; Wetzel, W. C.; Webb, M. R.;
Gamez, G.; Ray, S. J.; Hieftje, G. M. Anal. Chem. 2008, 80 (8), 2654−
2663.
(50) Inagaki, T.; Mochida, T.; Takahashi, M.; Kanadani, C.; Saito, T.;
Kuwahara, D. Chem.Eur. J. 2012, 18 (22), 6795−6804.
(51) Trofimenko, S. Chem. Rev. 1993, 93 (3), 943−980.
(52) Trofimenko, S. J. Am. Chem. Soc. 1967, 89 (24), 6288−6294.
(53) Chen, H.; Ouyang, Z.; Cooks, R. G. Angew. Chem., Int. Ed. 2006,
45 (22), 3656−3660.
(54) Zhang, W.; Dong, X.; Zhao, W. Org. Lett. 2011, 13 (19), 5386−
(20) Na, N.; Zhang, C.; Zhao, M.; Zhang, S.; Yang, C.; Fang, X.;
Zhang, X. J. Mass Spectrom. 2007, 42 (8), 1079−1085.
(21) Harper, J. D.; Charipar, N. A.; Mulligan, C. C.; Zhang, X.;
Cooks, R. G.; Ouyang, Z. Anal. Chem. 2008, 80 (23), 9097−9104.
(22) Steeb, J.; Galhena, A. S.; Nyadong, L.; Janata, J.; Fernandez, F.
M. Chem. Commun. 2009, 31, 4699−4701.
5389.
(55) Mokhtari, J.; Naimi-Jamal, M. R.; Hamzeali, H.; Dekamin, M.
G.; Kaupp, G. ChemSusChem 2009, 2 (3), 248−54.
(56) Chen, H.; Eberlin, L. S.; Nefliu, M.; Augusti, R.; Cooks, R. G.
Angew. Chem., Int. Ed. 2008, 47 (18), 3422−3425.
(57) Chakraborti, A. K.; Roy, S. R.; Kumar, D.; Chopra, P. Green
Chem. 2008, 10 (10), 1111−1118.
(23) Cooks, R. G.; Ouyang, Z.; Takats, Z.; Wiseman, J. M. Science
2006, 311 (5767), 1566−1570.
(58) Dyson, P. J.; McIndoe, J. S.; Zhao, D. Chem. Commun. 2003, 4,
508−509.
(24) Shin, Y.-S.; Drolet, B.; Mayer, R.; Dolence, K.; Basile, F. Anal.
Chem. 2007, 79 (9), 3514−3518.
(59) Suarez, P. A. Z.; Dullius, J. E. L.; Einloft, S.; de Souza, R. F.;
Dupont, J. Inorg. Chim. Acta 1997, 255 (1), 207−209.
(60) Brown, R. A.; Pollet, P.; McKoon, E.; Eckert, C. A.; Liotta, C. L.;
Jessop, P. G. J. Am. Chem. Soc. 2001, 123 (6), 1254−1255.
(61) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115 (22), 10125−10138.
(25) Sarver, S.; Chetwani, N.; Dovichi, N.; Go, D.; Gartner, C. J. Am.
Soc. Mass Spectrom. 2014, 25 (4), 524−529.
(26) Hiraoka, K.; Nishidate, K.; Mori, K.; Asakawa, D.; Suzuki, S.
Rapid Commun. Mass Spectrom. 2007, 21 (18), 3139−3144.
(27) Chen, L. C.; Nishidate, K.; Saito, Y.; Mori, K.; Asakawa, D.;
Takeda, S.; Kubota, T.; Hori, H.; Hiraoka, K. J. Phys. Chem. B 2008,
112 (35), 11164−11170.
(62) Guernik, S.; Wolfson, A.; Herskowitz, M.; Greenspoon, N.;
Geresh, S. Chem. Commun. 2001, 22, 2314−2315.
(28) Chen, L. C.; Nishidate, K.; Saito, Y.; Mori, K.; Asakawa, D.;
Takeda, S.; Kubota, T.; Terada, N.; Hashimoto, Y.; Hori, H.; Hiraoka,
K. Rapid Commun. Mass Spectrom. 2008, 22 (15), 2366−2374.
(29) Chen, L. C.; Yoshimura, K.; Yu, Z.; Iwata, R.; Ito, H.; Suzuki, H.;
Mori, K.; Ariyada, O.; Takeda, S.; Kubota, T.; Hiraoka, K. J. Mass
Spectrom. 2009, 44 (10), 1469−1477.
(30) Yu, Z.; Chen, L. C.; Erra-Balsells, R.; Nonami, H.; Hiraoka, K.
Rapid Commun. Mass Spectrom. 2010, 24 (11), 1507−1513.
(31) Yu, Z.; Chen, L. C.; Suzuki, H.; Ariyada, O.; Erra-Balsells, R.;
Nonami, H.; Hiraoka, K. J. Am. Soc. Mass Spectrom. 2009, 20 (12),
2304−2311.
(32) Yoshimura, K.; Chen, L. C.; Yu, Z.; Hiraoka, K.; Takeda, S. Anal.
Biochem. 2011, 417 (2), 195−201.
(33) Mandal, M. K.; Chen, L. C.; Hashimoto, Y.; Yu, Z.; Hiraoka, K.
Anal. Methods 2010, 2 (12), 1905−1912.
(34) Mandal, M. K.; Chen, L. C.; Yu, Z.; Nonami, H.; Erra-Balsells,
R.; Hiraoka, K. J. Mass Spectrom. 2011, 46 (10), 967−975.
(35) Hong, C.-M.; Lee, C.-T.; Lee, Y.-M.; Kuo, C.-P.; Yuan, C.-H.;
Shiea, J. Rapid Commun. Mass Spectrom. 1999, 13 (1), 21−25.
(36) Kuo, C.-P.; Shiea, J. Anal. Chem. 1999, 71 (19), 4413−4417.
(37) Yuan, C.-H.; Shiea, J. Anal. Chem. 2001, 73 (6), 1080−1083.
(38) Kuo, C.-P.; Yuan, C.-H.; Shiea, J. J. Am. Soc. Mass Spectrom.
2000, 11 (5), 464−467.
(39) Earle, M. J.; Seddon, K. R. Pure Appl. Chem. 2000, 72, 1391−
1398.
(40) Hallett, J. P.; Welton, T. Chem. Rev. 2011, 111 (5), 3508−3576.
(41) Chang, Y.-L.; Lee, Y.-C.; Yang, W.-B.; Chen, C.-H. J. Mass
Spectrom. 2011, 46 (4), 367−375.
(42) Walton, B. L.; Joshi, U.; Dzyuba, S. V.; Youngblood, W. J.;
Verbeck, G. F. Rapid Commun. Mass Spectrom. 2013, 27 (17), 1954−
1960.
(43) Jackson, G. P.; Duckworth, D. C. Chem. Commun. 2004, 5,
522−523.
(44) Dyson, P. J.; Khalaila, I.; Luettgen, S.; McIndoe, J. S.; Zhao, D.
Chem. Commun. 2004, 19, 2204−2205.
(45) Liu, J.; Wang, H.; Cooks, R. G.; Ouyang, Z. Anal. Chem. 2011,
83 (20), 7608−7613.
(46) Wang, H.; Liu, J.; Cooks, R. G.; Ouyang, Z. Angew. Chem., Int.
Ed. 2010, 49 (5), 877−880.
(47) Robb, D. B.; Covey, T. R.; Bruins, A. P. Anal. Chem. 2000, 72
(15), 3653−3659.
(48) Cai, S.-S.; Syage, J. A.; Hanold, K. A.; Balogh, M. P. Anal. Chem.
2009, 81 (6), 2123−2128.
(49) Wilkes, J. S.; Levisky, J. A.; Wilson, R. A.; Hussey, C. L. Inorg.
Chem. 1982, 21 (3), 1263−1264.
4032
dx.doi.org/10.1021/ac500527q | Anal. Chem. 2014, 86, 4024−4032