Accelerating Electrochemical Reactions in a Voltage-Controlled Interfacial Microreactor

Article abstract of DOI:10.1002/anie.202007736

Microdroplet chemistry is attracting increasing attention for accelerated reactions at the solution–air interface. We report herein a voltage-controlled interfacial microreactor that enables acceleration of electrochemical reactions which are not observed in bulk or conventional electrochemical cells. The microreactor is formed at the interface of the Taylor cone in an electrospray emitter with a large orifice, thus allowing continuous contact of the electrode and the reactants at/near the interface. As a proof-of-concept, electrooxidative C?H/N?H coupling and electrooxidation of benzyl alcohol were shown to be accelerated by more than an order of magnitude as compared to the corresponding bulk reactions. The new electrochemical microreactor has unique features that allow i) voltage-controlled acceleration of electrochemical reactions by voltage-dependent formation of the interfacial microreactor; ii) “reversible” electrochemical derivatization; and iii) in situ mechanistic study and capture of key radical intermediates when coupled with mass spectrometry.

Full text of DOI:10.1002/anie.202007736

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Accepted Article
Title: Accelerating Electrochemical Reactions in a Voltage-Controlled
Interfacial Microreactor
Authors: Heyong Cheng, Shuli Tang, Tingyuan Yang, Shiqing Xu, and
Xin Yan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007736
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Accelerating Electrochemical Reactions in a Voltage-Controlled
Interfacial Microreactor
Heyong Cheng,[a, b], Shuli Tang,[a] Tingyuan Yang,[a] Shiqing Xu,[a] and Xin Yan*[a]
Abstract: Microdroplet chemistry is attracting increasing attention
spectrometer, therefore microdroplet reactions can be monitored
in real time, and structures of intermediates and products as well
as reaction kinetics can be analyzed in situ.[1a, 1c]
for accelerated reactions at the air/solution interface. We report here
a
novel voltage-controlled interfacial microreactor allowing
acceleration of electrochemical reactions which are not observed in
bulk or conventional electrochemical cells. The microreactor is
formed at the interface of the Taylor cone in an electrospray emitter
with a large orifice. This allows continuous contact of the electrode
and the reactants at/near the interface. As a proof-of-concept,
electro-oxidative C–H/N–H coupling and electro-oxidation of benzyl
alcohol were shown to be accelerated by more than an order of
magnitude compared to the corresponding bulk reactions. The new
electrochemical microreactor has unique features that allow i)
voltage-controlled acceleration of electrochemical reactions
achieved by voltage-dependent formation of the interfacial
microreactor; ii) “reversible” electrochemical derivatization; and iii) in
situ mechanistic study and capture of key radical intermediates when
coupled with mass spectrometry.
Reactions that have been studied in microdroplets include C–
[6c, 11]
C,[6a, 9] C–N,[2, 10] and C–O
bond formation, however, up to
now
a large and significant category of reactions not
demonstrated in microdroplets is the electrochemical reaction.
Modern electrochemistry has undergone a revival during the last
few decades that results in many benefits over traditional
reagent-based transformations.[12] For example, electricity is
used instead of stoichiometric amounts of redox reagents for
chemical conversions; oxidizing and reducing potentials can be
precisely controlled to enable highly chemoselective
transformations. In spite of these benefits, electrochemical
reactions often suffer from long reaction times, typically around
2–38 h.[13] Such an obstacle prevents them from wide and
efficient use. Thus, we are motivated to develop a microreactor
that can be used to accelerate electrochemical reactions.
The challenge of developing spray-based microdroplet
reactors applicable to electrochemical reactions is obvious. In
the ESI process, electrochemical reactions are terminated in
microdroplets, because reactants in the electrosprayed
microdroplets lose contact with the ESI electrode when droplets
are formed.
Microdroplets have recently emerged as a unique form of
chemical reactor that has gained significant attention due to the
interfacial chemistry that produces reaction acceleration.[1] Many
studies have shown that reactions in microdroplets exhibit
acceleration of reaction rates by one or more orders of
magnitude compared to the corresponding bulk reactions.[2] This
effect is associated with reactions at the solution–air interface,
where partial solvation of the reagents is one factor that reduces
the critical energy for reaction.[1b] These findings have stimulated
the applications of microdroplet chemistry in chemical
derivatization,[3] reaction mechanistic studies,[4] high-throughput
reaction screening,[5] and rapid small-scale, green and
sustainable synthesis.[6]
Microdroplets are readily generated by various spray
methods,[1] drop-casting thin film,[6d, 7] ultrasonic nebulization,[6b]
and Leidenfrost levitation.[8] Electrospray ionization (ESI)-based
microdroplets are most commonly used in performing
accelerated reactions,[1] where electrostatic force is applied to a
solution of reaction mixture. The jet of finite conductivity, known
as the Taylor cone, breaks up into a plume of charged droplets
where increased surface areas of microdroplets allow the
acceleration of reactions. It is worth noting that such spray-
based microdroplet reactors can be directly coupled with a mass
ESI can be coupled with a separate electrochemical (EC) flow
15]
reactor[14] or directly used as an electrochemical cell[3c,
for
various
studies
such
as
identification
of
reaction
intermediates[14d-f], examination of electrochemical reactions[14a,
15b]
,
and to mimic biologically relevant electrochemical
reactions.[16] However, the electrochemical reactions occurring in
such electrochemical cells or ESI emitters reflect the reaction
behavior in the bulk phase and do not possess the acceleration
phenomenon. Molecules that are easy to oxidize or reduce by
one-electron transfer can quickly form a predictable species in
the ESI process and the scope of such reactions is very
limited.[15a] This approach does not apply to a broad range of
slower reactions such as the transformations of Csp3–H, Csp2–H,
C=C, -OH, and C=O groups.
In this work, we develop a novel electrochemical interfacial
microreactor that allows continuous contact of the electrode and
reactants, and acceleration of electrochemical reactions in a
confined volume (Figure 1). The unique microreactor is formed
at the solution-air interface of the Taylor cone in the ESI emitter
with a large (139 μm) orifice, when the spray voltage is tuned to
form a meniscus that has a large surface area (4500 μm2) using
a low ESI flow rate (a few tens of nL min-1). The reactants at or
near the meniscus can receive or lose electrons from/to the
electrode upon the application of voltage, and the reaction
products are immediately formed at the interface. This feature is
not found in the standard ESI source with a small orifice (less
than 10 μm) nor conventional EC-MS. Moreover, the
electrochemical interfacial reactor is voltage-dependent, and the
occurrence of reactions can be controlled by tuning voltages.
[a]
[b]
Dr. H. Cheng, S. Tang, T. Yang, Prof. S. Xu, Prof. X. Yan
Department of Chemistry,
Texas A&M University,
580 Ross St., College Station, TX 77845.
E-mail: xyan@tamu.edu
Dr. H. Cheng
College of Material Chemistry and Chemical Engineering,
Hangzhou Normal University, Hangzhou, 311121, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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were less than 5% of the dominant product peak (m/z 318.1)
after 7 s and remains constant. Two control experiments were
performed. When no voltage was applied to the electrode, and
the spray was initiated by pneumatic force (sonic spray), the
reactants, PTA (m/z 199.1), its in-source fragment by the loss of
sulfur (m/z 167.1), and DMA (m/z 122.1) were the major signals
in the mass spectrum and no products were observed (Figure
2b). This result indicates that the C–H/N–H coupling was
voltage-dependent. The corresponding bulk reaction was
performed in an undivided electrochemical cell (see Supporting
Information S1.4.2) using the same concentrations of the
reactants and electrolytes, which led to the formation of product
in a much lower intensity (Figure 2c and Figure S5). A large
amount of PTA (m/z 199.1), its in-source fragment (m/z 167.1),
and DMA (m/z 122.1) remained in the solution. The apparent
acceleration factor (AAF, defined as the conversion ratio of
products and reactants in microdroplet reaction versus that in
bulk at the same reaction time)[6d] was calculated to be 67. The
above experiments demonstrate the acceleration of electro-
oxidative C–H/N–H coupling in the newly developed
electrochemical interfacial microreactor.
Figure 1. Schematic diagram of the interfacial microreactor for accelerating
electrochemical reactions. The microreactor is formed at the solution-air
interface of the Taylor cone in an ESI emitter with a large (139 μm) orifice,
when the spray voltage (2 kV) is tuned to form a meniscus that has a large
surface area (4500 μm2) using a low ESI flow rate (a few tens of nL min-1).
We demonstrate the feasibility of this electrochemical
interfacial microreactor using the electro-oxidative C–H/N–H
cross-coupling of N,N’-dimethylaniline (DMA) and phenothiazine
(PTA) (Scheme 1) as a proof-of-concept. Such a method of
construction of aryl C–N bonds provides green and sustainable
synthesis of various natural products, pharmaceuticals,
agrochemicals and materials.[17]
Scheme 1. Electro-oxidative C–H/N–H coupling of DMA (1) with PTA (2).
We dissolved DMA (1) (400 μM), PTA (2) (100 μM), and the
electrolyte lithium triflate (LiOTf) (100 μM) in acetonitrile and
water (1:1, v:v). The mixed solution was immediately loaded into
the modified ESI emitter (orifice diameter of 139 μm) that was
coupled with a mass spectrometer. Upon the application of a
voltage of 2 kV to the ESI electrode (Pt), the large surface of
meniscus was observed to be formed. A very fine spray of
droplets was formed at the front of the meniscus and carried the
reaction mixture to the MS inlet. The radical species of the
coupling product (3) at m/z 318.1, and its in-source fragment ion
at m/z 303.1 by the loss of methyl (Figure 2a) were observed
immediately. The structures were confirmed by high resolution
(Figure S2) and tandem mass spectra (Figure S3a) in
comparison with the spectra of the purified product (Supporting
Information S8). The signals of reactants PTA at m/z 199.1 and
DMA dimer (N,N,N’,N’-tetramethylbenzidine, TMB) at m/z 240
Figure 2. Mass spectra of the electro-oxidative coupling of PTA with DMA (a)
in the interfacial microreactor at 7 s reaction time, (b) by sonic spray, and (c) in
bulk at 7 s reaction time. The bulk reaction was performed in an undivided
electrochemical cell (see Supporting Information S1.4.2 for the bulk reaction
conditions and mass spectra collected at 5 min and 30 min reaction times).
[Product-CH3]+ and [PTA-S]+ are the in-source fragments. TMB is the DMA
dimer.
The fact that the electrochemical interfacial microreactor is
coupled with MS facilitates the study of reaction mechanisms by
detecting transient intermediates. In previous work on the
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10.1002/anie.202007736
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COMMUNICATION
mechanism of electro-oxidative C–H/N–H coupling of PTA and
DMA,[17] an electron paramagnetic resonance experiment was
carried out to show reactant oxidation during electrolysis, while
no further evidence was provided to demonstrate the reaction
pathway.[17] In our study, the key intermediates in accelerated
electro-oxidative C–H/N–H coupling were captured by MS, and
the mechanism is shown in Figure 3. DMA (1) was first oxidized
to generate a radical cation (4). Homo-coupling of radical cation
(4) could lead to the formation of its dimer TMB (4a). At the
same time, 2 was also oxidized to generate a nitrogen radical (5)
that can further lose one electron to form a nitrogen radical
cation (5a). C–N bond was formed by radical/radical cross-
coupling of radical cation (4) and nitrogen radical (5).
Subsequent deprotonation of intermediate (6) afforded the final
amination product (3). Our results provide direct evidence for the
plausible mechanism proposed by the Lei group,[17]
demonstrating the power of the electrochemical microreactor
with the capability of reaction mechanistic study.
switchable feature was realized by performing accelerated and
non-accelerated electrochemical reactions during different
voltages.
To prove this concept, we tested direct MS analysis of benzyl
alcohol in the new electrochemical microreactor. Alcohols are
not well detected using standard ESI-MS.[12d, 19] Our strategy is
to enable a one-step electro-oxidation of benzyl alcohol and
couple it with Girard T (GT, a quaternary ammonium hydrazine
salt) for in-situ formation of the charged hydrazone (BGT)
(Scheme 2).[20] Without performing the electrochemical reaction,
benzyl alcohol was not detectable by MS with or without added
GT reagent (Figure 4a). After we set the voltage to 2 kV, the
derivatized benzyl alcohol in the form of the charged hydrazone
(BGT) was detected immediately in the spectrum (Figure 4b).
Compared with the bulk reaction (Figure S6), the
electrochemical derivatization in the interfacial microreactor
showed an apparent acceleration factor of 111. Then we tested
the switchable feature by quickly changing the voltage between
2 kV (with interfacial reactor) and
Scheme 2. Electrochemical derivatization of benzyl alcohol with GT reagent in
the electrochemical interfacial microreactor.
Figure 3. Plausible mechanism of electro-oxidative C–H/N–H coupling of DMA
and PTA. The m/z of each intermediate and product observed in the mass
spectra (Figure 2) is shown under its structure.
Encouraged by the accelerated electro-oxidative C–H/N–H
coupling of DMA and PTA in the electrochemical microreactor,
we quickly found other applications in online chemical
transformations and demonstrated the unique feature of this
microreactor in an on-demand chemical derivatization and in situ
characterization of analytes that cannot be ionized and so
cannot be studied by conventional mass spectrometry. The
electrochemical reactions performed in the microreactor can be
switched on/off by applying different ESI voltages. This was
inspired by our recent work of locating double bonds in lipids
using a voltage-dependent electro-epoxidation.[3c]
Derivatization has been widely used in the analysis of
chemicals that have no/low responses to mass analyzers due to
their un-ionizable properties or low ionization efficiencies.[18]
Derivatization is commonly irreversible and one cannot switch
between derivatized molecules and native molecules during a
single analysis. The switchable feature of our microreactor
makes the derivatization “reversible”, which allows one to
observe the native and derivatized compounds in the same run.
This might be beneficial to a mixture analysis in which some
analytes need to be derivatized while others do not. The
Figure 4. Mass spectra showing a one-step electrochemical derivatization of
benzyl alcohol in the presence of GT reagent (a) by sonic spray without
appling voltage; and (b) in the interfacial microreactor. (c) Chronogram of the
MS intensity ratio of BGT to GT upon varying the ESI votage between 2 kV
and 3 kV, showing the rapid switchable electrochemical derivatization in the
microreactor.
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3 kV (normal ESI without interfacial reactor) (Figure 4c). The
chronogram of MS intensity ratio of derivatized benzyl alcohol
(BGT) to GT reagent vs. time shows that the electrochemical
derivatization of benzyl alcohol was turned on at 2 kV and turned
off at 3 kV. This result further confirms that electrochemical
reactions can be significantly accelerated in the interfacial
microreactor, and provides an example of switchable
electrochemical derivatization for chemical analysis as well.
To clarify the inherent mechanism for acceleration in the
electrochemical interfacial microreactor, attention was paid to
the geometry of the meniscus formed in the ESI process that is
specific to the spraying mode, and is dependent on the voltage,
flow rate, and orifice diameter. As shown by the microscopic
images (Figure S14) and the videos (Table S2) recorded by a
microscopic camera, the electrospray from an emitter of a 139
μm orifice successively underwent the dripping, microdripping,
spindle, cone jet (standard ESI mode) and multijet modes when
the applied voltage was increased from 1.85 kV to 3.50 kV. We
observed that the electrochemical reactions could be
accelerated most in the microdripping mode (Supporting
Information S6) which maintains a large surface area (Figure 5a
and b). In the ESI with an orifice less than 10 μm, however, the
electrospray immediately responded to the cone jet without the
other modes (dripping, microdripping and spindle) on gradually
increasing the voltage (Figure 5c and d), which led to no obvious
accelerated reactions in those ESI emitters. This indicates that
the interfacial effect of the large-area meniscus in the
microdripping mode of electrospray plays a key role in the
accelerated electrochemical reactions. Similar results have been
observed in additional reactions (Supporting Information S3-S5).
Furthermore, we added a neutral surfactant Triton X-100 to
the electrochemical reaction of PTA and DMA in the interfacial
microreactor. With the increased amount of Triton X-100 (from
0.001% to 0.1%, v/v), we observed decreased conversion ratios
and acceleration factors (Figure 5e), which further demonstrates
the role of the interface in reaction acceleration as Triton X-100
blocks the surface and diminishes accelerated product formation
(see Supporting Information S7.4). Then we changed the
distance between the ESI emitter and the MS inlet to vary the
possible reaction time in the electrosprayed microdroplets. The
reaction conversions of the electrochemical coupling of PTA and
DMA were similar at different distances (Figure S16), which
suggests that the electrochemical reaction acceleration does not
occur to a major extent in the electrosprayed microdroplets, but
at the interface of the Taylor cone. In addition, we found that the
distance between the electrode and air/solution interface of the
Taylor cone is very important in the electrochemical interfacial
reactor. A distance of 0.6–5 mm allows the reactants at or near
the interface to receive or lose electrons from/to the electrode
upon the application of voltage (Figure 5f, SI section 7.2). The
above results suggest that the electrochemical reaction is
initiated at the electrode and is accelerated at the air/solution
interface close to the electrode.
In conclusion, we present
a
novel voltage-controlled
interfacial microreactor that can accelerate electrochemical
reactions. This microreactor is formed at the solution-air
interface of the Taylor cone in the ESI emitter of a 139 μm orifice.
The electro-oxidative C–H/N–H coupling of DMA and PTA, and
electrochemical derivatization of benzyl alcohol performed in
such an electrochemical microreactor show the acceleration
factors of 67 and 111 compared to the corresponding bulk
reactions, respectively. The coupling of microreactors with MS
allows us to capture the key radical intermediates in a
mechanistic study of electro-oxidative C–H/N–H coupling of
DMA and PTA. The electrochemical derivatization can be
switched on and off by changing the spray voltage, which allows
the collection of mass spectra before and after derivatization in a
single
run.
The
demonstrated
fast
electrochemical
transformations, on-demand derivatization and in situ
mechanistic study allow this novel interfacial microreactor a wide
use in the electrochemistry related research.
Acknowledgements
We acknowledge the support and start-up funds from Texas
A&M Universtiy and the Department of Chemistry. Dr. Heyong
Cheng appreciates the financial support from the National
Natural Science Foundation of China under project No.
21974048. We thank for the help from Dr. Zhenwei Wei with the
TOC figure.
Figure 5. Microscopic images showing the ESI tip shapes of a 139 μm-emitter
(a) before spraying, (b) in the microdripping mode; the ESI tip shapes of a 3
μm-emitter (c) before spraying and (d) in the cone-jet mode; (e) Effects of
Triton X-100 (% represents volume of Triton X-100/volume of reaction solution)
on the conversion ratios (solid black) and apparent acceleration factors (AAFs,
dotted gray) of the electrochemical coupling of PTA with DMA in the interfacial
microreactor; (f) Effects of the electrode-to-interface distance on the
conversion ratios (solid) and AAFs (dotted) of the electrochemical coupling of
PTA with DMA in the interfacial microreactor. The measurement of each
accelerated reaction was repeated 5 times. The error bars represent the
standard deviation of five measurements.
Conflict of interest
The authors declare no conflict of interest.
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Sathyamoorthi, R. N. Zare, Angew. Chem. Int. Ed. 2017, 56,
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Keywords: interfacial microreactor • electrochemical reaction •
electrospray • reaction acceleration • mass spectrometry
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This article is protected by copyright. All rights reserved.

10.1002/anie.202007736
Angewandte Chemie International Edition
COMMUNICATION
Table of Contents
COMMUNICATION
Heyong Cheng, Shuli Tang, Tingyuan
Yang, Shiqing Xu, and Xin Yan
Page No. – Page No.
Accelerating Electrochemical
Reactions in a Voltage-Controlled
Interfacial Microreactor
A novel interfacial microreactor was developed to achieve accelerated electrochemical reactions. The formation
of the interfacial microreactor can be voltage-dependent and used for on-demand electrochemical derivatization
and in-situ mechanistic study of electrochemical reactions.
This article is protected by copyright. All rights reserved.