Aqueous Microdroplets Capture Elusive Carbocations

Article abstract of DOI:10.1021/jacs.0c12512

Carbocations are short-lived reactive intermediates in many organic and biological reactions that are difficult to observe. This field sprung to life with the discovery by Olah that a superacidic solution allowed the successful capture and nuclear magnetic resonance characterization of transient carbocations. We report here that water microdroplets can directly capture the fleeting carbocation from a reaction aliquot followed by its desorption to the gas phase for mass spectrometric detection. This was accomplished by employing desorption electrospray ionization mass spectrometry to detect a variety of short-lived carbocations (average lifetime ranges from nanoseconds to picoseconds) obtained from different reactions (e.g., elimination, substitution, and oxidation). Solvent-dependent studies revealed that aqueous microdroplets outperform organic microdroplets in the capture of carbocations. We provide a mechanistic insight demonstrating the survival of the reactive carbocation in a positively charged aqueous microdroplet and its subsequent ejection to the gas phase for mass spectrometric analysis.

Full text of DOI:10.1021/jacs.0c12512

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Aqueous Microdroplets Capture Elusive Carbocations
Anubhav Kumar, Supratim Mondal, and Shibdas Banerjee*
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ABSTRACT: Carbocations are short-lived reactive intermediates in many organic and biological reactions that are difficult to
observe. This field sprung to life with the discovery by Olah that a superacidic solution allowed the successful capture and nuclear
magnetic resonance characterization of transient carbocations. We report here that water microdroplets can directly capture the
fleeting carbocation from a reaction aliquot followed by its desorption to the gas phase for mass spectrometric detection. This was
accomplished by employing desorption electrospray ionization mass spectrometry to detect a variety of short-lived carbocations
(average lifetime ranges from nanoseconds to picoseconds) obtained from different reactions (e.g., elimination, substitution, and
oxidation). Solvent-dependent studies revealed that aqueous microdroplets outperform organic microdroplets in the capture of
carbocations. We provide a mechanistic insight demonstrating the survival of the reactive carbocation in a positively charged aqueous
microdroplet and its subsequent ejection to the gas phase for mass spectrometric analysis.
he long-standing search for the existence of alkyl
Tcarbocations in the twentieth century evolved through
indirect evidence from kinetic, stereochemical, and product
studies, conductivity measurements, gas-phase ion chemistry,
and spectroscopic studies.1 Because of its high reactivity
toward nucleophiles present in the system, capture and
characterization of the transient carbocation species became
a major challenge until a breakthrough development in
superacid chemistry. The pioneering work of Olah using
superacid resulted in the first direct observation of alkyl
carbocations by ionizing the corresponding alkyl fluoride in the
excess superacid medium.1,2 Despite the remarkable progress
of carbocation chemistry,1−8 direct capture and isolation of the
intermediate carbocation from a reaction mixture appears like a
hunt for elusive species, as they are transient and exist in low
Figure 1. DESI-MS experimental setup for capturing short-lived
carbocations using microdroplets. A 10 μL amount of a reaction
aliquot was bombarded with charged microdroplets. This resulted in
the immediate extraction of reactive species in the splashed
concentrations (Supplementary Note 1).
Inspired by the recent findings of the mysterious nature of
water microdroplets,9−13 which differ sharply from the
corresponding bulk phase, we attempted to directly capture
and isolate elusive carbocation intermediates from the reaction
aliquot using aqueous microdroplets followed by mass
spectrometric detection. We find that positively charged
water microdroplets can behave as a magic acid for the
capture and stabilization of carbocations.
Figure 1 shows the experimental setup involving desorption
electrospray ionization mass spectrometry (DESI-MS), a form
of ambient ionization technique, which was employed in this
study (Supplementary Note 2). We followed three different
types of model reactions, such as elimination,14 substitution,15
and oxidation16 to examine the formation of a wide variety of
short-lived carbocation species (e.g., tertiary, secondary,
nonclassical, bridgehead, benzylic, and allylic) (Figure 2).
Literature precedents show that the lifetime of these
carbocation intermediates ranges from nanoseconds to pico-
seconds depending upon the reaction, which were estimated by
laser flash photolysis, azide clocks, and theoretical calculations
microdroplets, from where the species were transferred to a high-
resolution mass spectrometer for their detection on a time scale of
milliseconds.
(Supplementary Note 3).17−23 These reactions were con-
ducted following the reported protocol (details in Supporting
Information), which were proposed earlier to involve the
intermediacy of carbocations.14−16
We began our investigation by impacting the positively
charged water microdroplets (Figure 1) with the reaction
Received: December 1, 2020
Published: February 3, 2021
https://dx.doi.org/10.1021/jacs.0c12512
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© 2021 American Chemical Society
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aliquot sampled at 5 min after starting the reaction to directly
capture and detect the aforementioned carbocations (1−8,
Figure 2) in the liquid DESI-MS.24 Figure 3 shows ion signals
of those different types of carbocation species detected in the
positive ion mode DESI-MS (Table S1). The high mass
accuracy and resolution of the MS instrument allowed reliable
identification of these transient fleeting intermediates (m/z
accuracy ≤1 ppm) from the corresponding reactions (Table
S1). We also calculated the spectral accuracy, wherever
possible, by matching the simulated and experimental isotopic
distribution patterns (Figure S2). Figure S3 shows the
extracted ion chronogram of the tert-butyl carbocation as a
representative example indicating that the carbocation was
detected immediately upon dispensing the reaction aliquot in
the DESI source. This observation suggests that the same
species was absent in the blank background. No carbocation
signal was detected from the control experiments (no reagent
added) with the precursor solution (Figure S4) and some
typical products (Figure S5). We also intercepted the above
carbocations at different time intervals, and their ion signal
intensities were plotted against the reaction time, providing us
with temporal profiles (insets of Figure 3a−h) of the
carbocation abundance (normalized to 1) during the reaction.
We further confirmed the feasibility of the water microdroplets
for intercepting the same carbocation species from different
reactions by changing the reagents added to a typical substrate.
For example, exo-norborneol was considered as the substrate
for two different reactions, such as elimination (Figures 2 and
3d) and a substitution (Figure S6). Detection of the 2-
norbornyl cation from both these reactions suggests that this
carbocation detection using water microdroplets in DESI-MS
is likely to be a general method, although the detection
efficiency should depend on the carbocation concentration in
the reaction.
Figure 2. Model reactions performed to generate various types of
short-lived carbocations 1−8 as intermediates (Table S1). The
theoretical m/z value of each carbocation is shown in red next to their
respective structures.
Figure 3. Microdroplets generated in the DESI source (Figure 1) rapidly transferred the elusive carbocations from the reaction aliquot to the mass
spectrometer for their subsequent detection (a−h, Table S1). The insets show the temporal evaluation of the carbocation formation (intensity
normalized to 1) allowing their real-time monitoring.
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In another set of experiments, we screened microdroplets of
different solvents to examine their carbocation-capturing
efficiencies. We selected seven different types of electrospray-
friendly solvent systems25 (Table S2) for capturing four typical
carbocations (1, 2, 4, and 6 in Figure 2), and the results are
presented as histograms in Figure 4a−d. The data indicated the
The electrospray voltage is known to contribute charges in
the microdroplet,26 and that can also contribute to increased
focusing of charged microdroplets into the MS inlet. To
investigate the effect of DESI spray voltage, we tuned the
voltage from 0 to +5 kV for the detection of the above
carbocations (Figure 4e−h). We observed that the carbocation
detection efficiency improved on increasing the voltage of the
water spray. However, the opposite effect was observed for
carbocations wherever detected by the acetonitrile spray
(Figures 4g,h), indicating better carbocation detection with
no voltage applied to the acetonitrile spray. This result has also
been separately shown in Figure S7, which could be attributed
to the high volatility of the acetonitrile and its rapid droplet
evolution involved in the DESI process (Supplementary Note
4).
All the above observations collectively suggested that water
microdroplets outperformed the organic microdroplets con-
sidered in this study for the capture and detection of several
short-lived and elusive carbocation intermediates. One may
wonder why the intermediate carbocations survived in the
aqueous microdroplet although they are highly susceptible to
be attacked by the nucleophilic water forming alcohol. It
appears that this microdroplet phenomenon is strikingly
different from that of the corresponding bulk phase.7,27−29
Indeed, this observation can be attributed to the emerging field
of microdroplet chemistry demonstrating the unusual process
that could occur in a tiny droplet.9−11,13,27,30−33
Although we are unable to conclusively establish the
mechanism of the carbocation interception at present, we
rationalize a viable mechanism for the same (Figure 4i) based
on what has been presented. An electrospray microdroplet,
produced under a positive potential, is highly acidic because of
the accumulation of protons by the solvent oxidation.25,26
Unlike a normal Brønsted acid, these protons lack their
counteranions (conjugate base) in the droplet. Moreover,
these protons are likely distributed on or nearer to the
microdroplet surface with equidistant spacing to minimize the
potential energy.34,35 This unique polar environment of the
air−liquid interface possibly facilitates the carbocation capture.
When the charged microdroplet impacts the reaction aliquot
on the microscope glass slide, it causes the splashing of
secondary microdroplets encapsulating the chemical and
reactive intermediate species from the reaction aliquot. A
charged species can be destabilized inside the charged
microdroplet by a huge Coulomb force of repulsion imparted
by the surface protons.31 Therefore, the carbocation (R+) can
exist as an intimate or tight ion pair in association with a
counteranion X− (e.g., the leaving group or other anions)
inside the charged microdroplet, or R+ can also exist
preferentially on the charged surface to minimize the Coulomb
force of repulsion. The existence of intimate ion pairs inside
charged microdroplets was also proposed before by Fenn.34
The mechanism of DESI suggests that secondary micro-
droplets evolve through repeated solvent evaporation and the
Coulomb fission assisted by the flow of a sheath gas and the
heated MS inlet capillary (Figure 1).36 When the intimate ion
pair (R+X−) in the vanishing charged droplet encounters the
surface by its Brownian dynamics, the attractive interaction
between the counteranion (X−) and surface protons might
weaken the interaction between R+ and X− (Figure 4i). The
thermal activation (kT) and Coulomb repulsion may
subsequently provide sufficient energy to desorb the intrinsi-
cally charged carbocation species (R+) from the highly charged
Figure 4. Screening of spray solvents and voltages to elucidate the
mechanism of carbocation interception. Four typical species, e.g.,
tertiary (1), secondary (2), nonclassical (4), and benzylic (6)
carbocations, were considered in the assessment of DESI spray
solvents (a−d) and voltages (e−h). Ion intensities are presented as
mean
SD from the triplicate analysis. An ion evaporation
mechanism is illustrated in the lower panel (i) to demonstrate the
feasibility of intercepting short-lived carbocations using positively
charged aqueous microdroplets.
superior performance of microdroplets composed of water
compared to that of organic or binary aqueous−organic
solvents in intercepting the carbocation species from an
ongoing reaction. For example, the highly unstable tert-butyl
carbocation was only detected by water spray, while other
solvent sprays failed (Figure 4a) to do so. The tuning of
solvent flow rate (5−50 μL/min) and sheath gas flow (100−
170 psi back pressure) could not establish the better
performance of organic microdroplets than that of aqueous
microdroplets (data not shown). This phenomenon can be
ascribed by the high polarity of water and its microdroplet
surface, which is discussed later. Relatively less polar solvents
(methanol, acetonitrile, and their binary mixtures) either could
not intercept (Figure 4a,b) or poorly intercepted (Figure 4c,d)
the intermediate carbocation species depending on the nature
and stability of the carbocation. For example, carbocation
intermediates 4 and 6 are somewhat better stabilized by
resonance when compared with 1 and 2 and thereby detected
with less polar solvents, albeit poorly, as mentioned above.
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droplet surface with concomitant neutralization of the
counteranion (X−) by binding with a proton on the surface
(Supplementary Note 5).
AUTHOR INFORMATION
■
Corresponding Author
Shibdas Banerjee − Department of Chemistry, Indian Institute
of Science Education and Research Tirupati, Tirupati
517507, India; orcid.org/0000-0002-3424-8157;
Email: shibdas@iisertirupati.ac.in
When we investigated the influence of different spray
solvents on carbocation interception, we found that the
carbocation signal was highest from water spray, and in some
instances, the carbocation was only captured by water or water
containing organic solvent spray (Figure 4a−d). This result
appears anomalous because, in contrast to other organic
solvents (Table S2), water is a better nucleophile for attacking
the carbocation and thereby decreasing its average lifetime.
However, this phenomenon can be attributed to the high
charge (H+) density12 and electric field26,35 on the aqueous
microdroplet surface, leading to effective desorption of
carbocations (Supplementary Note 6). Moreover, the reactivity
of carbocations with water is likely to be decreased on the
microdroplet surface, where water density sharply vanishes
within a nanometer.37−41
Authors
Anubhav Kumar − Department of Chemistry, Indian Institute
of Science Education and Research Tirupati, Tirupati
517507, India
Supratim Mondal − Department of Chemistry, Indian
Institute of Science Education and Research Tirupati,
Tirupati 517507, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12512
Notes
That the positively charged microdroplet surface has a
crucial role in the carbocation capture is further supported by
the voltage-dependent study as discussed before (Figure 4e−
h). The detection of the resonance stabilized carbocations
(Figure 4g,h) at 0 V, the temporal evaluation of the
carbocation formation (insets of Figure 3a−h), and absence
of the carbocation signal at the zero time point (insets of
Figure 3a−h) and in the control study (Figures S4 and S5)
collectively suggest that those carbocations were indeed the
intermediates in the original reactions (Figure 2), which is
consistent with the literature reports.14−16 We were not able to
detect carbocations (data not shown) from the same reactions
(Figure 2) when we sprayed negatively charged water
microdroplets at −5 kV in the DESI-MS. This result further
substantiates the importance of the positive charges (protons)
for providing the stability to the carbocation in the
microdroplet (Figure 4i). In some cases, though not for all,
the reduction of the spray solvent (water) pH improved the
carbocation detection efficiency (Supplementary Note 7,
Figures S8 and S9). Moreover, the carbocation (1) was also
found to undergo hydrogen−deuterium exchange when
captured by the microdroplets of heavy water (Figure S10).
It should be noted that this study is not intended to measure
the absolute concentration of carbocations in the original
reaction aliquot, which is experimentally challenging, and also
might suffer from the possibility of the loss of a fraction of
carbocations by their reactions during the DESI spray.
Nevertheless, this anomalous carbocation chemistry in
aqueous microdroplets inspires us to further explore the
mysterious power of aqueous microdroplets in the future. This
study lays the foundation of a fairly straightforward MS
method for directly detecting elusive carbocation intermediates
using inexpensive water spray on a minimal amount of reaction
aliquot.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by SERB, India (grant numbers SB/
S2/RJN-130/2017 and ECR/2018/001268). The authors
thank S. Mutyam for his help with the HRMS instrumentation.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12512.
Supplementary notes, materials and methods, and mass
spectral data (PDF)
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