Mass Spectrometry Based Approach for Organic Synthesis Monitoring

Article abstract of DOI:10.1021/acs.analchem.9b02681

Current mass spectrometry-based methodologies for synthetic organic reaction monitoring largely use electrospray ionization (ESI), or other related atmospheric pressure ionization-based approaches. Monitoring of complex, heterogeneous systems may be problematic because of sampling hardware limitations, and many relevant analytes (neutrals) exhibit poor ESI performance. An alternative monitoring strategy addressing this significant impasse is condensed phase membrane introduction mass spectrometry using liquid electron ionization (CP-MIMS-LEI). In CP-MIMS, a semipermeable silicone membrane selects hydrophobic neutral analytes, rejecting particulates and charged chemical components. Analytes partition through the membrane, and are then transported to the LEI interface for sequential nebulization, vaporization, and ionization. CP-MIMS and LEI are both ideal for continuous monitoring applications of hydrophobic neutral molecules. We demonstrate quantitative reaction monitoring of harsh, complex reaction mixtures (alkaline, acidic, heterogeneous) in protic and aprotic organic solvents. Also presented are solvent-membrane compatibility investigations and, in situ quantitative monitoring of catalytic oxidation and alkylation reactions.

Full text of DOI:10.1021/acs.analchem.9b02681

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Article
A New Mass Spectrometry Based Approach for Organic Synthesis Monitoring
Veronica Termopoli, Elena Torrisi, Giorgio Famiglini, Pierangela Palma, Giovanni Zappia,
Achille Cappiello, Gregory W. Vandergrift, Misha Zvekic, Erik T. Krogh, and Chris G. Gill
Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b02681 • Publication Date (Web): 12 Aug 2019
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Analytical Chemistry
A New Mass Spectrometry Based Approach for Organic Synthesis
Monitoring
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Veronica Termopoli1‡, Elena Torrisi4, Giorgio Famiglini1, Pierangela Palma1,2, Giovanni Zappia4,
Achille Cappiello1,2*
and
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Gregory W. Vandergrift2,3‡, Misha Zvekic2, Erik T. Krogh2,3, Chris G. Gill2,3,5,6
*
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1 LC-MS Laboratory, Department of Pure and Applied Sciences, University of Urbino Carlo Bo, Urbino, Italy, 61029
2 Applied Environmental Research Laboratories (AERL), Chemistry Department, Vancouver Island University, Nanaimo,
BC, Canada, V9R 5S5
3 Chemistry Department, University of Victoria, Victoria, BC, Canada, V8P 5C2
4 Biomolecular Sciences Department, University of Urbino Carlo Bo, Urbino, Italy, 61029
5 Chemistry Department, Simon Fraser University, Burnaby, BC, Canada, V5A 1S6
6 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA, 98195
ABSTRACT: Current mass spectrometry-based methodologies for synthetic organic reaction monitoring largely use
electrospray ionization (ESI), or other related atmospheric pressure ionization-based approaches. Monitoring of complex,
heterogeneous systems may be problematic because of sampling hardware limitations, and many relevant analytes (neutrals)
exhibit poor ESI performance. An alternative monitoring strategy addressing this significant impasse is condensed phase
membrane introduction mass spectrometry using liquid electron ionization (CP-MIMS-LEI). In CP-MIMS, a semi-permeable
silicone membrane selects hydrophobic neutral analytes, rejecting particulates and charged chemical components. Analytes
partition through the membrane, and are then transported to the LEI interface for sequential nebulization, vaporization, and
ionization. CP-MIMS and LEI are both ideal for continuous monitoring applications of hydrophobic neutral molecules. We
demonstrate quantitative reaction monitoring of harsh, complex reaction mixtures (alkaline, acidic, heterogeneous) in protic
and aprotic organic solvents. Also presented are solvent-membrane compatibility investigations, and in situ, quantitative
monitoring of catalytic oxidation and alkylation reactions.
The synthesis of organic compounds on an industrial scale is
of enormous economic importance. Understanding optimum
reaction conditions is key to maximizing the yields of desired
products, as well as simultaneously reducing the production of
inadvertent side products, which lower yields, may be harmful,
and require additional separation steps. Synthetic chemists
have a wide variety of analytical methodologies at their
disposal to investigate and optimize reaction conditions for
industrial applications. These include spectroscopic methods
(e.g. FT-IR, UV-vis, fluorescence, NMR, etc.)1-3 as well as
mass spectrometry (MS)4. However, many of these techniques
are carried out off-line, requiring subsample collection and
rapid analysis, frequently with some form of quenching. This
is because the reaction will continue in the subsamples until
the time of measurement, potentially compromising any
information obtained. Online dilutions of subsampled reaction
mixtures are also frequently employed to make satisfactory
measurements, reducing sensitivity for trace analytes. Kinetic
data obtained in this manner is laborious and often
intermittent. A number of spectroscopic techniques have been
adapted for continuous online monitoring5-6, but these tend to
lack specificity for target analytes and/or the sensitivity for
quantitation of trace components.
analysis strategies (i.e., monitoring chromophores).
Atmospheric pressure ionization sources, particularly
electrospray ionization (ESI), have been used extensively for
coupling reactions to MS. As a recent example, the Cooks
group has demonstrated online, multiplexed MS reaction
monitoring system based upon direct sampling ESI-MS,
simultaneously monitoring up to six reactions types without
sample carryover7. The McIndoe group has also been
exploring the use of online ESI-MS monitoring to investigate
catalytic reactions8-10. Many other variants of ESI-MS have
been used for reaction monitoring, including desorption ESI
(DESI), extractive ESI (EESI), ESI assisted laser desorption
ionization (ELDI) and paper spray (PS-MS)4. However, for
many ESI-based techniques, care must be taken to ensure that
clogging of fine sampling capillaries does not occur. This may
preclude their use in complicated, heterogeneous reaction
slurries or for small reaction volumes, as the monitoring itself
consumes a portion of the reacting mixture.
While the Cooks group has bypassed many practical
challenges of this strategy by using inductive ESI11-12, perhaps
the most significant obstacle associated with ESI related
monitoring techniques is the requirement that the chemical
species being monitored must be satisfactorily ionized by ESI
(e.g. easily charged species). ESI sensitivity is further
confounded by high salt concentrations and varying solvent
compositions13-14, excluding the use of these techniques from
many reaction monitoring applications because of analyte and
To increase both sensitivity and selectivity for quantitative
online reaction monitoring, chemists have largely turned to
MS based approaches, as resolution by m/z ratios is more
selective and reliable when compared to other chemical
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aqueous chlorination reactions,24,
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reaction mixture incompatibility. Other ambient ionization
techniques, such as direct analysis in real-time (DART)15, have
been used to bypass ESI ionization complications encountered
in reaction monitoring in principle. In a particularly intriguing
application of DART-MS/MS, the Volmer group monitored
micro-reactions in acoustically levitated droplets16. However,
DART based MS methods often lack reliable quantitative
information, and are predominantly restricted to offline,
snapshot measurements4.
as well as the photo-
oxidative degradation28 and adsorption of naphthenic acids in
aqueous solutions18 by CP-MIMS using ESI. The coupling of
LEI with CP-MIMS is of particular interest for reaction
monitoring, as it is a more universal ion source and overcomes
a limitation with ESI, which typically requires polar functional
group to carry a charge. Thus, CP-MIMS paired with LEI
represents an ideal monitoring strategy for synthetic organic
reactions, especially for measuring neutral hydrophobic
analytes that exhibit poor performance with ESI.
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As an alternative sample introduction strategy for online
reaction monitoring, the method of membrane introduction
mass spectrometry (MIMS) may offer a suitable solution to the
identified deficiencies. There are several reviews of MIMS
that explain the methodology, as well as its suitability for
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The LEI concept has been discussed in several recent
publications30-31. It represents a new approach for efficiently
addressing the difficult conversion of a liquid-phase into a gas-
phase for EI, using a nano-scale flowrate, generating library
searchable spectra. Since ionization occurs in the gas phase,
LEI strongly mitigates suppression effects from co-eluting
reaction components permeating through the membrane,
offering reliable quantitative reaction data.
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direct, online monitoring in complex sample mixtures17-18
Simply described, MIMS utilizes semi-permeable
.
a
membrane, often polydimethylsiloxane (PDMS, aka silicone),
to non-exhaustively extract and directly transfer analytes (as a
mixture) to a mass spectrometer, where they are resolved by
their m/z ratios, by selective ionization, and/or by tandem mass
spectrometry (MS/MS). The membrane rejects particulate
materials and is hydrophobic, with perm-selectivity
characteristics favoring mass transfer of non-polar analytes,
rejecting highly polar and charged components, making MIMS
ideally suited for the online extraction of neutral compounds
We present the newer variant of LEI33 paired with CP-MIMS,
as a strategy for direct, quantitative online monitoring directly
in organic solvent reaction mixtures. Permeating neutral
analytes are effectively vaporized and ionized directly by LEI,
where the vaporization and ionization steps are spatially
decoupled. As previously mentioned, LEI is effective for
ionizing analytes with poor ESI performance, and as presented
with CP-MIMS, addresses a significant gap in currently
available online quantitative reaction monitoring approaches,
providing complementary results to those obtained using ESI
based strategies. This manuscript presents the first use of CP-
MIMS coupled with LEI for quantitative online monitoring of
non-aqueous synthetic organic reactions. The resulting system
is robust, and facilitates direct, quantitative measurements of
neutral reactant and product species in complex, highly acidic
and heterogeneous organic solvent reaction mixtures.
from a complex reaction mixture17-18
.
There is some precedent in the literature for the use of MIMS
for reaction monitoring utilizing electron ionization (EI). As a
few examples, in early work, the Cooks group used a silicone
membrane interface to transfer permeating analytes directly
into a high vacuum EI triple quadrupole MS. While effective,
the membrane interface design was also prone to memory
effects and slow signal response times19. The Cooks group also
demonstrated MIMS use for the online monitoring of the
reactions of epichlorohydrin in water using a polyphenyl ether
liquid membrane and a quadrupole ion trap20. Our group has
used a flow cell interface MIMS system to follow the
oxidative degradation kinetics for trace gasoline contaminants
in aqueous samples21 and also the reductive dehalogenation
kinetics of organic contaminants in natural waters22. A
commonality with these early MIMS reaction-monitoring
studies was the use of a gaseous acceptor (or high vacuum) to
desorb permeating analytes from the membrane, and
frequently from aqueous reaction systems. While effective for
smaller analytes of higher volatility, these strategies were
ineffective for larger, less volatile analytes. Alternatively,
permeating analytes in a MIMS measurement can be
transferred from the membrane by a continuously flowed
liquid (condensed) phase, and then coupled with a variety of
atmospheric pressure ionization strategies. This approach has
been termed condensed phase MIMS (CP-MIMS), and has
Experimental section
Standards and Solvents
Details regarding solvent and standard sources and their
preparation and the characterization of the alkyl glycinate
standards is reported in the supporting information. All
standard and reaction measurements were made in
magnetically stirred 20 or 40 mL glass vials with Teflon faced
septum seals (EPA/VOA Type, Scientific Specialties Inc.,
Hanover, MD, USA) at ambient conditions (ca 25 °C, 101
kPa) unless otherwise noted.
Instrumentation
been described in several reviews17-18
.
Two EI-MS systems were employed for these studies,
including a single quadrupole system (Model 5975, Agilent
Technologies, Santa Clara, CA, USA) operated in selected ion
monitoring mode (SIM), and a triple quadrupole tandem mass
spectrometry (MS/MS) system (Model 7010, Agilent
Technologies, Santa Clara, CA, USA) operated in multiple
reaction monitoring mode (MRM). Both MS systems were
equipped with identical CP-MIMS, hollow fiber
polydimethylsiloxane membranes (5.0 mm long, 0.30 mm i.d.,
0.64 mm o.d., 170 m thick and LEI configurations (Figure 1).
Details of the SIM and MRM conditions used for all analytes
are given in the supporting information (Table S-1). In
The use of CP-MIMS has allowed researchers to utilize a
variety of MS ionization strategies, including ESI, atmospheric
pressure chemical ionization (APCI)23-28 and liquid electron
ionization (LEI),29-31 to extend the application of MIMS to
larger, significantly less volatile analytes. In early work,
Creaser and co-workers demonstrated the use of a CP-MIMS
type interface system with a hydrophobic polyvinylidene
fluoride microporous sheet membrane coupled with APCI to
follow the course of a synthetic reaction, implemented by
sampling reaction aliquots as
a
function of time32.
Additionally, we have presented the real-time monitoring of
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addition, for the MS/MS system, concomitant changes in the
tunable, and may be adjusted according to the requirements of
a given online reaction monitoring application.
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UV/Vis absorbance of post membrane permeant was also
continuously monitored by diverting the splitter waste flow
through a capillary UV-Vis detector (Spectra 100, Spectra
Physics Inc., Santa Clara, CA). MS tuning parameters were
checked periodically, and remained constant for the studies
shown here, demonstrating robustness and ease of use.
Solvent-Membrane Compatibility Investigations
To date, the majority of CP-MIMS type measurements have
25,
been made in aqueous samples23,
29-30. It is known that
solvent-membrane solubility can significantly influence
membrane permeability35-37. We have begun to exploit
acceptor phase co-solvents with CP-MIMS by forming in situ
polymer inclusion membranes, which improve both the
sensitivity and measurement duty cycle30, 36. In addition, recent
developments utilizing modified donor phases (e.g. mixed
organic samplesolvents) with CP-MIMS have shown promise
for making direct measurements of fatty acids38. However,
because synthetic reactions are most often conducted in non-
aqueous solvents, the analytical performance of PDMS
membranes in a variety of non-aqueous sample solvents was
investigated.
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Oxidation of Phenylacetylene Reaction
Phenylacetylene undergoes acid-catalyzed hydrolysis, and the
reaction rate is greatly increased in the presence of a
chloroauric acid (HAuCl4) catalyst. 90 mM phenylacetylene
was added to the 20 mL reaction mixture (95:4:1 methanol:de-
ionized water:sulfuric acid v/v, 4 mM HAuCl4) with gentle
heating (~50°C) and magnetic stirring. This procedure is
described elsewhere34.
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Alkyl Glycinate Reaction
A series of individual standards containing biphenyl or
chlorobenzene in the 10 to 50 mM range were prepared in a
wide range of common protic and aprotic solvents that could
potentially be used for organic syntheses (acetonitrile,
To initiate the reaction, 1.0 mL of ethylbromoacetate (yielding
an initial concentration of 330 mM) was added to a
magnetically stirred mixture containing 330 mM
triethylamine, and 300 mM α-methyl benzylamine in 24 mL of
dry acetonitrile.
dichloromethane,
N,N-dimethylformamide,
ethanol,
methanol). Analyte signals for CP-MIMS-LEI measurements
for each standard were allowed to reach steady state, and were
background-subtracted using the signal from the appropriate
solvent blank (Table S-2 and S-3). In all cases, calibrations
showed satisfactory linearity (R2≥0.98), suggesting broad
applicability of CP-MIMS-LEI quantitative reaction
monitoring in different solvent/reaction systems. The order of
the relative sensitivities for both analytes (i.e. calibration
slopes) in the different solvents was conserved., and faster t10-
Alkyl Glycinate Standard Synthesis
To a mixture of (R)-α-methyl benzylamine (0.92 mL, 7.27
mmol) and triethylamine (1.11 mL, 7.99 mmol) in dry
acetonitrile (20 ml), 0.89 mL of ethyl bromoacetate (7.99
mmol) was added in one portion. The solution was maintained
under stirring at room temperature until the disappearance of
(R)-α-methyl benzylamine, concentrating the reaction mixture
under reduced pressure. The residue was dissolved in ethyl
acetate (50 ml) and washed with H2O (15 ml), saturated NaCl
brine (15 ml), dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel, eluting with cyclohexane/ethyl
acetate (20:80%, v/v) to give first the dialkyl product: diethyl
(R)-2,2’-((1-phenylethyl)-azanediyl)-diacetate [Minor product]
(0.176 g, 0.6 mmol, 8%) as an oil, followed by the monoalkyl
product: ethyl (R)-(1-phenylethyl)glycinate [Major product]
(1.18 g, 5.7 mmol, 78%) as an oil.
signal response times also correlated with greater
90%
sensitivities. These trends may be understood by considering
the intrinsic factors governing membrane transport. For a
given analyte, the steady-state signal intensity for a CP-MIMS
measurement is related to membrane permeability (P), which
can be expressed as the product of analyte diffusivity through
the membrane (Dm) and the partitioning constant of the analyte
between the membrane
and the sample (Km-s, Eq.1)39:
(1) P = Km-s Dm
The time required for an analyte signal to reach steady-state
can be expressed as the t10-90% response time and is inversely
proportional to Dm (Eq. 2)40.
Results and Discussion
CP-MIMS-LEI Instrumentation
(2) t10-90% ∝ l2 / Dm
The CP-MIMS-LEI experimental system has been described
elsewhere30. A schematic diagram of the specific configuration
used for synthetic reaction monitoring is given in Figure 1.
Several modifications were necessary to reduce the analyte
flux transferred to the MS ion source, allowing successful
monitoring of high concentrations present in synthetic reaction
mixtures. These included a shorter membrane, an increased
methanol acceptor phase flowrate through the membrane
lumen (100 µL/min), and drastically reducing acceptor phase
flowrate to the LEI interface (ca 50 nL/min, split ratio 1:
2000); all of which act to reduce the mass transfer of analyte to
the MS. The sensitivity of the presented system is highly
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based upon changes in their optical properties, they are
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inherently less selective than MS, and may therefore be
challenging in complex reaction mixtures with overlapping
chromophores. This highlights the advantages of MS based
reaction monitoring strategies.
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Online Synthetic Reaction Monitoring Examples
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As a first demonstration of CP-MIMS-LEI for in situ,
continuous reaction monitoring, the catalytic oxidation of
phenylacetylene to acetophenone in highly acidic methanol
solvent was examined (Figure 3) using a single quadrupole
MS system (SIM mode). As shown in Figure 3,
phenylacetylene (m/z 102) undergoes rapid catalytic
conversion to the Markovnikov-favoured addition product,
acetophenone (m/z 105, 100% yield). Concentrations were
determined using direct calibrations made with methanol
standards, and the t10-90% signal rise times were ≤0.4 minutes
(Table S-4), whereas the reaction occurred over ca 30 minutes.
The presence of acetophenone was monitored by m/z 105 ([M-
CH3]+), chosen since it is free of isobaric interference from
phenylacetaldehyde, a possible non-Markovnikov product. No
substantial amount of phenylacetaldehyde was formed under
the given reaction conditions, indicated by the stoichiometric
mass balance illustrated in Figure 3.
The online reaction monitoring of phenylacetylene oxidation
to acetophenone illustrates the significance of MIMS-LEI
pairing, as both the reactant and product are incompatible with
ESI based monitoring systems. As shown by the photo insets
in Figure 3, the reaction is occurring in a heterogeneous
(cloudy) system, which would pose serious problems if direct
capillary sampling strategies (e.g. ESI) were employed.
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Figure 1. Schematic diagram of the modified CP-MIMS-LEI
system.
The differing analyte response times in different solvents
indicate changes in the corresponding diffusivities (Dm), as
these solvents swell membrane to varying extents and change
their permeation characteristics. However, it is clear that the
permeability is also affected by concomitant changes in the
partitioning behavior (Km-s) in different solvent systems.
Simultaneous Time Resolved MS and UV-Vis Detection
Because a large fraction of the (post-membrane) acceptor
phase is diverted from the CP-MIMS-LEI combination via the
passive flow splitter (Figure 1), this stream can also be
analyzed by other continuous analyzers to provide orthogonal
datasets. To demonstrate this, the diverted acceptor phase
waste was passed through a capillary UV-Vis detector. Figure
2 illustrates an example of an orthogonal time series dataset
obtained from MS and UV-Vis detection of a 25 mM
chlorobenzene standard prepared in methanol (Original MS
and UV-Vis recorded traces are given in the supporting
information Figure S-1). As expected, the data illustrates
identical time resolved signals, with superior signal-to-noise
for the MS trace (due to the lower sensitivity of UV-Vis
absorbance measurements). The time constant associated with
the rise to steady-state signal is correlated with membrane
transport kinetics and depends on a variety of factors including
the membrane thickness, the size of the permeant and the
presence of solvent co-permeants. The t10-90% signal risetime
for chlorobenzene under these conditions is 0.33 minutes,
typical for the compounds studied here. The technique is
therefore well suited for monitoring reactions that take place
on the time scale of minutes to hours, applicable for a wide
range of synthetic organic reactions. While spectroscopic
methods can be utilized to characterize a number of reactions
Figure 2. Comparison of simultaneous online monitoring data
measured by CP-MIMS-LEI (m/z 112) and parallel UV-Vis
spectrophotometry detection (=260 nm) for 25 mM
chlorobenzene in methanol (spiked at t = 0.2 minutes).
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sampling pH adjustments to protonate the analytes, as well as
dilution steps. Figure also illustrates that the
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ethylbromoacetate alkylation reagent is consumed at a faster
rate than α-methyl benzylamine. This is likely due to
formation of the dialkylated product and the presence of trace
moisture in the reaction system, possibly present in the
triethylamine catalyst used. Information such as that shown in
Figure 4 may be used for rapid, online reaction optimization,
as the real-time data allows for continuous assessment of
reagent purity, consumption, and production of possible side-
products.
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All reagents and products for this study demonstrated linear
direct calibrations over the concentration ranges presented, and
the t10-90% signal rise times were significantly faster than the
observed reaction rates (Table S-5). Even for reactions where
product crystallization occurred over the course of
a
measurement (Figure 5), free solution concentration changes
for reactants and products were still observable in these
heterogeneous slurries, further demonstrating the robustness of
the CP-MIMS-LEI synthesis monitoring strategy.
Conclusions
We demonstrate the use of an in-situ mass spectrometry based
reaction monitoring technique compatible with complex, non-
aqueous solutions. This approach yields real-time feedback for
the optimization of synthetic reaction conditions and important
mechanistic insight. The coupling of CP-MIMS and LEI
exploits advantages of both methodologies, resulting in a
robust system that allows the direct measurements of neutral
organic analytes in complex, heterogeneous and corrosive
reaction mixtures. CP-MIMS and LEI are ideally paired to suit
the online measurement of a variety of synthetic reactants and
products. Further, CP-MIMS-LEI quantitatively measures
molecules that are not amenable to other online reaction
monitoring strategies, such as direct sampling ESI approaches,
Figure 3. CP-MIMS-LEI online monitoring of the catalytic
oxidation of phenylacetylene (A) to acetophenone (B) under
highly acidic conditions.
The PDMS membrane provides an on-line ‘clean-up’ that
effectively removes particulates, and charged corrosive
components (e.g. sulfuric acid, chloroauric acid catalyst),
while allowing hydrophobic molecules to permeate for
continuous mass spectrometric analysis. While some oxidative
damage was observed for the PDMS membrane near the
completion of the reaction (due to the high concentration of
sulfuric acid, ~1% v/v in methanol, larger images in Figure S-
2), the membrane and/or probe assembly are both inexpensive
and easily replaced within minutes, without the need to vent
the MS. The LEI interface required no maintenance during the
experiments here, but the LEI capillary may also be simply
replaced as needed without venting the MS.
To further demonstrate the utility of CP-MIMS-LEI for online
reaction monitoring, the synthesis of alkyl glycinates in an
aprotic solvent was examined. Alkyl glycinates have been
used as intermediates for the preparation of -amino acids41,
as well as building blocks in the preparation of
peptidomimetics42. A synthesis strategy is presented in the
reaction scheme given in Figure 4. While advantageous
because of the mild reaction conditions, this reaction can be
plagued by over-alkylation products, reducing the yield of a
desired product43. In this context, simultaneous monitoring of
the formation of various alkylation products is of significant
synthetic interest.
providing
a complementary strategy that addresses a
significant gap in current synthetic reaction monitoring
methodology using mass spectrometry. The quality of online
quantitative data is ensured by both membrane selectivity and
LEI’s capacity to operate in the presence of co-permeating
reagents, with concentrations varying in time, and by
employing analytical calibrations obtained in the same
solvents used for a given reaction. Although beyond the scope
of the presented work, in future studies, the membrane may be
replaced with one made from a different material (such as
NafionTM) for more polar compound applications. Future work
includes the use of online CP-MIMS monitoring
simultaneously employing both LEI-MS and ESI-MS to
enable the simultaneous online measurement of both charged
and neutral species in synthetic reactions.
For this demonstration, the MS/MS system was employed. To
initiate the reaction, ethylbromoacetate was added to reaction
mixture at t = 2 min. Production of both monoalkylated (major
product, 70% Yield) and dialkylated (minor product, 0.7%
Yield) species was observed (Figure 4). The synthesis was
conducted in acetonitrile with a basic catalyst, yielding an
alkaline reaction mixture. Under these conditions, both the
reactants and products are neutral, and successfully monitored
by CP-MIMS-LEI. If attempted, direct sampling ESI reaction
monitoring would not be satisfactory, as it would require post-
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* Professor Chris G. Gill, Ph.D., P. Chem.
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Co-Director, Applied Environmental Research Laboratories
(AERL) Chemistry Department
Vancouver Island University
900 Fifth Street, Nanaimo, BC
Canada V9R 5S5
Ph: 250-753-3245
Chris.Gill@viu.ca
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* Professor Achille Cappiello
LC-MS Laboratory, Department of Pure and Applied Sciences
University of Urbino
Piazza Rinascimento, 6
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Urbino, Italy 61029
Ph: +390722303344
achille.cappiello@uniurb.it
ORCID
Achille Cappiello: 0000-0002-6416-304X
Chris G. Gill: 0000-0001-7696-5894
Author Contributions
‡
These authors contributed equally.
Funding Sources
Natural Sciences and Engineering Research Council of Canada
(NSERC), Discovery Grants Program Funding (RGPIN-2016-
05380)
Notes
Figure 4. CP-MIMS-LEI demonstration of the quantitative
online monitoring of an alkyl glycinate synthesis in dry
acetonitrile with triethylamine (TEA) catalyst. A) (R)-α-
methyl benzylamine; B) ethyl bromoacetate; C) ethyl (R)-(1-
phenylethyl)glycinate; D) diethyl (R)-2,2’-((1-phenylethyl)-
azanediyl)-diacetate.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors would like to thank the AERL and LC-MS group
members for their contributions that helped make this work
possible. The authors acknowledge the Natural Sciences and
Engineering Research Council of Canada (NSERC) for research
funding under the Discovery Grants Program (RGPIN-2016-
05380), Urbino University for providing a visiting Professor
Appointment for Prof. Gill during a portion of this work, and also
Vancouver Island University and the University of Victoria for
their on-going support of both faculty and graduate students. We
gratefully acknowledge Agilent Technologies for providing the
instrumentation used for this study.
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Graphical Abstract
84x51mm (300 x 300 DPI)
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