Scale-up of microdroplet reactions by heated ultrasonic nebulization

Article abstract of DOI:10.1039/c9sc03701b

Dramatically higher rates for a variety of chemical reactions have been reported in microdroplets compared with those in the liquid bulk phase. However, the scale-up of microdroplet chemical synthesis has remained a major challenge to the practical applic

Full text of DOI:10.1039/c9sc03701b

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Scale-Up of Microdroplet Reactions by Heated Ultrasonic
Nebulization
Chengyuan Liua, ‡, Jia Lia, ‡, Hao Chenb, Richard N. Zarea,*
Received 00th January 20xx,
Accepted 00th January 20xx
Dramatically higher rates for a variety of chemical reactions have been reported in microdroplets compared with those in
the liquid bulk phase. However, the scale-up of microdroplet chemical synthesis has remained a major challenge to the
practical application of microdroplet chemistry. Heated ultrasonic nebulization (HUN) was found as a new way for scaling
up chemical synthesis in microdroplets. Four reactions were examined, a base-catalyzed Claisen–Schmidt condensation, an
oximation reaction from a ketone, a two-phase oxidation reaction without the use of phase-transfer-catalyst, and an
Eschenmoser coupling reaction. These reactions show one to three orders of magnitude of acceleration (122, 23, 6536, and
62) in HUN microdroplets compared to the same reactions in bulk solution. Then, using the present method, scale-up of the
reactions was achieved at an isolated rate of 19 mg min-1 for the product of the Claisen–Schmidt condensation, 21 mg
min-1 for the synthesis of benzophenone oxime from benzophenone, 31 mg min-1 for the synthesis of 4-
methoxybenzaldehyde from 4-methoxybenzyl alcohol, and 40 mg min-1 for the enaminone product of the Eschenmoser
coupling reaction.
DOI: 10.1039/x0xx00000x
flow microfluidic devices.33-36 Recently, many organic
reactions1, 3, 4, 6, 13, 14, 37-40 have been demonstrated to occur on
Introduction
A number of recent studies1-11, including work of our own,12-16
have reported the acceleration of reaction rates in
microdroplets formed in the course of spray-based ionization4,
the millisecond timescale in microdroplet reactions in air
generated in electrospray ionization mass spectrometry (ESI-
MS). However, the flow rate (ca. 10 μL/min) for microdroplet
reaction in ESI-MS is not high enough for preparative organic
synthesis. Although multiplexed ESI sprayer tips3, 16 have even
13, 17
19
and microfluidics.18,
Microdroplets show a strikingly
different reactive environment from that of the corresponding
bulk phase.5, 18, 20 The alteration of pH21, the accumulation of
reagents5 on the microdroplet surface, solvent evaporation,
confinement of reagents, and the high surface-to-volume ratio
of the microdroplet are thought to contribute to the reaction
acceleration.1 The acceleration phenomena in confined
volumes have also been reported in Leidenfrost levitated
droplets22 and thin films.23, 24 The applicability of microdroplets
in organic chemical synthesis is attracting increasing attention
because in addition to reaction rate acceleration, sometimes
microdroplet reactions can also proceed well without the use
of a catalyst.12, 16
been used as
a preparative method, the scale-up of
microdroplet reactions in air is still challenging.
Ultrasonic nebulization (UN), i.e., the emission of a fog of
microdroplets from an acoustically excited liquid–air interface,
has been well-known since the landmark work report by Wood
and Loomis in 1927.41 Since then, UN has been used
commercially in air humidifiers, medical nebulizers, and other
such devices. UN has also been used as a method of sample
atomization for subsequent ionization such as inductively
coupled plasma,42,
electrospray ionization (ESI),44,
43
45
extractive electrospray ionization,46 and photoionization47, 48 in
MS. Ultrasonically generated microdroplets have also been
used as microreactors for the synthesis of semiconductor
nanoparticles,49 porous carbon powders,50 and other
nanostructured materials.51 Ambient ionization MS was even
applied for the real-time monitoring of microreactions in
acoustically levitated droplets for which at least an order of
magnitude faster reaction rate was observed.52 Herein, we
demonstrate the use of heated, UN-generated microdroplets
(HUN) to perform the scale-up of four different chemical
syntheses.
The droplets in microfluidic channels can be used as
chemical microreactors for performing many reactions on a
small scale.25-28 Thus droplet-based microfluidics has been
widely used for the high-throughput screening of diverse
chemical and biochemical reactions.29-32 Preparative organic
synthesis in microemulsions can be facilitated by continuous-
a. Dr. C.Y. Liu, J. Li, Prof. R. N. Zare
Department of Chemistry, Fudan University, Shanghai 200438, China Email:
rnz@fudan.edu.cn
Figure 1 presents the experimental design for HUN
microdroplet synthesis. When the ultrasonic nebulizer (Model
402AI, Yuwell Medical Equipment & Supply Corp., Suzhou,
China) is switched on, the reactant solution in the nebulization
cell can be continuously atomized into large amounts of
b. Prof. H. Chen
Department of Chemistry & Environmental Science, New Jersey Institute of
Technology, Newark, NJ 07102, USA
C.Y. Liu and J. Li contributed equally to this work.
‡
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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investigated. As presented in Figure S3, the ratio of product 3
DOI: 10.1039/C9SC03701B
and reactant 1 increased only twofold when the temperature
microdroplets due to the so-called “ultrasonic fountain”.
Compared with the traditional ESI sprayer, the HUN setup
enabled the reuse of reactant solution for microdroplet
reaction. The working frequency of the transducer of the
ultrasonic nebulizer is 1.7 MHz ± 10 %. The glass nebulization
cell consists of a cylindrical upper part (I.D. 35 mm, height 90
mm) and lower part (I.D. 22 mm, height 15 mm). A thin
polyethylene membrane transparent to ultrasonic waves,
which is fixed by nylon cable ties, covers the bottom of the
nebulization cell. Water between the polyethylene membrane
and the transducer transfers the ultrasonic waves. In addition,
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was increased from 30 C to 50 C in bulk phase. Compared
with bulk phase, the increased temperature in HUN can
decrease the size of microdroplets, which was measured by a
laser diffractometer (Sympatec HELOS, Sympatec, Germany).
The experimental setup and results were shown in Figure S3.
As the temperature was increased from 30 C to 50 C, the
average droplet size was decreased from 6.9 μm to 5.4 μm,
which is closer to the microdroplet size (2-3 μm) in ESI.
Previous reports39, 55, 56 have indicated that the droplet size has
a large effect on the reaction rate in microdroplets; thus we
speculate that the increased reaction rate in HUN at higher
temperature is caused by the smaller droplet size. The
following three reactions were also conducted at 50 C. The
a
temperature-controlled heating tape (ZhengLong
Electrothermal Technology Co., Ltd., China) is wound around
the nebulization cell to assist in the microdroplet reaction. For
comparison, all the bulk reactions were conducted at the same reaction in the nebulization cell is accelerated by the
continuously atomized microdroplets from the reactant
solution. The effect of reaction time on the yield of product 3
for the Claisen-Schmidt condensation reaction in HUN
microdroplets was also examined (Figure S4). The ratio of
product 3 and reactant 1 increased during the initial 120 s due
to the recycling of the reactant solution and remained
unchanged at longer reaction times (up to 300 s). The
influence of the volume of reactant solution in nebulization cell
on the conversion efficiency was also tested. As shown in
Figure S5, as the volume was increased from 1.2 mL to 2.4
mL, the ratio of product 3 and reactant 1 gradually decreased.
It is speculated that the greater probability of recombination of
microdroplets resulted in the lower reaction rate and lower
conversion efficiency when higher volume reactant solution
was nebulized into larger amounts of microdroplets in the
confined space of ultrasonic the nebulization cell.
temperature. In the present design, no electric potential is
applied but for some cases charging the microdroplets can be
advantageous.
Figure 1. The heated ultrasonic nebulization (HUN) system used to
generate continuously microdroplets in which chemical reactions are
accelerated.
Results and discussion
At first, the base-catalyzed Claisen-Schmidt conden-
sation between 6-hydroxy-1-indanone 1 and benzaldehyde 2
was investigated as a model reaction (See Figure 2). The
acceleration of a similar system has been well-characterized
53
by paper spray,23,
ESI,3 thin film,24 and the Leidenfrost
droplet reaction.22 A recent study reported that moderate heat
can accelerate the solvent evaporation from microdroplets and
improve the reaction rate of the ESI microdroplet reaction.54
The influence of temperature on the microdroplet reaction in
the HUN system was investigated at first. As shown in Figure
S1, temperature is quite an important factor, and the ratio of
the MS product (6-hydroxy-2-benzyliden-1-indanone 3) signal
at m/z 235 to the reagent (6-hydroxy-1-indanone 1) signal at
m/z 147 increased markedly with elevation of the temperature
from 30 C to 50 C. However, when increasing further the
heating from 50 C to 60 C, no higher signal intensity of
product 3 was observed and byproducts emerged. Thus, 50
Figure 2. Base-catalyzed Claisen–Schmidt condensation of 6-hydroxy-1-
indanone 1 with benzaldehyde 2 to form the product 3: (a) reaction
schematic; negative ion mode mass spectra of the condensation reaction in
(b) bulk phase and (c) HUN microdroplets after 2 min. Plots of 1/Ct vs time
C was selected as the heating temperature for HUN for second-order reaction kinetics driving the reaction rate constant to be
(d) 9.0x10-3 L mol-1 s-1 in bulk and (e) 1.1x100 L mol-1 s-1 in HUN
microdroplets.
microdroplet reactions, and the same temperature was used
for the control experiments in bulk phase. The effect of
temperature for this reaction in bulk phase was also
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According to MS peak intensities of the reactant 1 and significant rate acceleration.58 However, the ratVeiewoAfrtpicrleoOdnulincet
DOI: 10.1039/C9SC03701B
product 3, we can calculate the remaining concentration of production obtained by the microdroplet reaction was too
reactant 1 (Ct) and yield of product 3 (Ycalculated). The reactant small (less than 50 μg min-1).58 Figures 3b and 3c show
was found to ionize 2.2 times more efficiently than the product, respectively the HPLC chromatograms of the oximation
resulting in
a greater signal intensity for the same reaction in bulk phase and HUN microdroplets after 2 min. The
concentration of material (Figure S6). By monitoring the concentration of hydroxylamine 5 in this experiment was
reaction with time, we calculated the reaction rate constants in maintained 20 times higher than that of benzophenone 4; thus,
bulk (kbulk) and HUN microdroplets (kHUN). The ratio between the oximation reaction followed pseudo first-order kinetics.
kHUN and kbulk gives the acceleration factor (AF). Section 4 of Figures 3d and 3e present plots of ln(Ct/C0) vs time (Ct and C0
the Supporting Information describes the details of these represent the remaining and initial concentrations of reactant
calculations.
4) of this reaction in bulk phase and HUN microdroplets,
Figures 2b and 2c present the mass spectra of the respectively. As listed in Table 1, the reaction rate constant in
condensation reaction in bulk phase and HUN microdroplets HUN microdroplets (kHUN) is 23-fold higher than that in bulk
after 2 min. Compared to the 2-min yield in bulk phase (1.6%), (kbulk). For preparative synthesis, 41.5 mg benzophenone
a much higher 2-min yield (87.6%) can be obtained by the oxime was synthesised from benzophenone within 2 minutes
HUN microdroplet reaction. The reaction rate constants in bulk (ca. 21 mg min-1) by the setup shown in Figure S17.
phase (kbulk) and HUN microdroplets (kHUN) at 50 C were
calculated by plotting the reciprocal of the remaining
concentration of reactant 1 (1/Ct) against reaction time in
Figures 2d and 2e. The HUN microdroplet reaction showed an
acceleration factor of 122 over the bulk phase reaction. An
industrial nebulization plate with 10 ultrasonic nebulizers
(Figure S17) was used for the scale-up experiment, and 37.2
mg product was produced within 2 minutes (ca. 19 mg min-1).
M
ultiplexed ESI sprayer tips (25 μL/min per spray tip) have been
used previously for the preparative synthesis of products from the
Claisen-Schmidt condensation reaction in microdroplets, but
only 0.588 mg min-1 product was produced.3 The highest yield
for the preparative synthesis of the product of this
condensation reaction in confined volume was ever achieved
by a thin film, and only 98 mg h-1 (ca. 1.6 mg min-1) was
reached.24 Thus, HUN is a promising new method for the
scale-up of microdroplet chemical synthesis. Table 1 lists the
results for the condensation reaction.
The oximation reaction of benzophenone
4
with
Figure 3. Oximation reaction of benzophenone 4 with hydroxylamine 5 to
form benzophenone oxime 6: (a) reaction schematic; HPLC chromatograms
of oximation reaction in bulk phase (b) and HUN microdroplets (c) after 2
min. A higher yield of product 6 was obtained in HUN microdroplets. Plots
of ln(Ct/C0) vs time deriving the pseudo first-order reaction rate constant to
be (d) 9.1×10-4 s-1 in bulk and (e) 2.1×10-2 s-1 in HUN microdroplets.
hydroxylamine 5 (Figure 3a) was also investigated to yield the
corresponding benzophenone oxime 6, which is an important
reaction material for amide synthesis by the Beckman
rearrangement reaction.57 This reaction has previously been
investigated using an ESI sprayer (10 μL/min) and showed a
Table 1. Reaction rate constants (kbulk and kHUN) and acceleration factors (AF) for different reactions in bulk phase and HUN microdroplets. Ycalculated is the
calculated reaction yield based on MS and HPLC mesurements, and Yisolated is the isolated yield.
Isolated
amount*
Reaction type
Claisen–Schmidt condensation
Oximation reaction
AF
122
23
k
k
Y
Y
isolated
bulk
HUN
calculated
87.6%
92.4%
75.4%
78%
1.1×100 L mol-1 s-1
2.1×10-2 s-1
37.2 mg
78.8%
84.3%
68.4%
67%
9.0×10-3 L mol-1 s-1
9.1×10-4 s-1
41.5 mg
93 mg
Two-phase reaction
1.1×10-6 s-1
7.3×10-3 s-1
6536
62
Eschenmoser coupling reaction
1.4×10-3 L mol-1 s-1
8.7×10-2 L mol-1 s-1
140 mg
* The isolated amount is obtained by using 10 reactors based on an industrial nebulization plate. All the reactions were conducted at 50 C. The reaction
times for the Claisen-Schmidt condensation, the oximation reaction, the two-phase reaction and the Eschenmoser coupling reaction are 2 min, 2 min, 3
min and 3.5 min, respectively. The reactant solution volumes for the Claisen-Schmidt condensation, the oximation reaction, the two-phase reaction and
the Eschenmoser coupling reaction are 1.2 mL, 1 mL, 1.1 mL, and 1 mL, respectively.
When a bulk liquid-liquid two-phase system is nebulized as phase reaction was readily facilitated without the use of a
small microdroplets, the interfacial area of the two-phases can phase-transfer-catalyst (PTC) in ESI microdroplets16, 54, which
be increased by many orders of magnitude. Thus, the two- meets the requirement of green chemistry and sustainable
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synthesis. In this study, the two-phase reaction of 4- microdroplets. As noted in previous reports,5,
the
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DOI: 10.1039/C9SC03701B
methoxybenzyl alcohol 7 in ethyl acetate (EtOAc) with acceleration of reaction rate in microdroplets can be largely
aqueous NaClO (Figure 4a) was examined without using PTC. attributed to the accumulation of reactants on the surface of
microdroplets. For this reaction, the concentrated NaClO on
HUN microdroplets can also change the pH on the
microdroplet surface. According to the previous report,60 the
byproduct, 4-chloroanisole, formed by ipso substitution of 4-
methoxybenzyl alcohol with hypochlorite (ClO-) is strongly
affected by pH. Thus, we speculate that the special pH
microenvironment in HUN microdroplets inhibited the ipso
substitution and at the same time, the production of another
product, 3-chloro-4-methoxybenzaldehyde, was avoided by
the short reaction time in HUN microdroplets.
In this two-phase reaction, the concentration of sodium
hypochlorite (NaClO) was much higher than that of 4-
methoxybenzyl alcohol 7. Consequently, this reaction is
presumed to proceed as a pseudo first-order reaction, which
was confirmed by the kinetic analysis with reactant 7 at
different initial concentrations (Figure S9). The reaction rates
in bulk and HUN microdroplets were derived by plotting
ln(Ct/C0) of reactant 7 vs time, as shown in Figures 4d and 4e.
Figure 4. Synthesis of 4-methoxybenzaldehyde 8 by a two-phase oxidation
reaction between 4-methoxybenzyl alcohol 7 in ethyl acetate (EtOAc) and
aqueous NaClO without the use of PTC: (a) reaction schematic; HPLC
chromatograms of two-phase oxidation reaction in (b) bulk phase and (c)
HUN microdroplets after 3 min. Plots of ln(Ct/C0) vs time deriving the pseudo
first-order reaction rate constant to be (d) 1.1×10˗6 s-1 in the “initial-rate
region” of bulk phase and (e) 7.3x10˗3 s-1 in HUN microdroplets.
The acceleration factor for this reaction in HUN microdroplets
was determined to be 6536. In the HUN system, 93 mg
product (4-methoxybenzaldehyde 8) of the two-phase reaction
with 68.4% yield was produced within 3 min (31 mg min-1),
which is a large advance for the scale-up of microdroplet
reactions compared with that (1.2 mg min-1)16 obtained by a
previous multiplexed ESI sprayer method (15 μL/min per spray
Figures 4b and 4c show respectively the HPLC
chromatograms of the two-phase reaction in bulk phase and
HUN microdroplets after 3 min. In sharp contrast with that
(0.1%) in bulk phase, a strikingly higher yield (75.4%) of
product (4-methoxybenzaldehyde 8) can be obtained by the
HUN microdroplet reaction. The bulk reaction was also
investigated for a longer reaction time, and we found that there
were abundant byproducts (such as 4-chloroanisole and 3-
chloro-4-methoxybenzaldehyde) in addition to the oxidation
reaction product 8 in the two-phase reaction without the use
of PTC in bulk phase (Figure S11). Gas chromatography mass
spectrometry and nuclear magnetic resonance (NMR)
enabled the identification of these byproducts (Figure S12 and
S13). The bulk reaction was monitored by HPLC for 7 h, and
Figure S14 presents the temporal peak area profiles of
reactants and products. According to previous studies,59, 60 the
possible reaction pathway for the two-phase reaction in bulk
phase is proposed to be as shown in Scheme S1. In the initial
stage, reaction of 4-methoxybenzyl alcohol with NaClO
resulted in 4-chloroanisole through ipso substitution in addition
to the oxidation product (4-methoxybenzaldehyde), which is
consistent with a previous report.60 Then the chlorination
reaction of the newly formed 4-methoxybenzaldehyde with
NaClO generated 3-chloro-4-methoxybenzaldehyde.59 After 7
h of bulk reaction, the yield of 4-methoxybenzaldehyde 8 was
determined to be only 11.3% (owing to the formation of
byproducts) by using a standard calibration curve of 4-
methoxybenzaldehyde. These results also indicate that in
addition to rate acceleration, highly selective synthesis of 4-
tip
)
.
Encouraged by these results, we further examined the
applicability of this new method for a new reaction, i.e., the
preparative synthesis of enaminone by the Eschemoser coupling
reaction, which has not been examined previously by microdroplet
reaction. Enaminones are important building blocks in organic
synthesis and the Eschemoser coupling reaction has been
extensively employed in the construction of enaminones.61,
62
However, the coupling reaction often requires a long reaction
time.63-65
methoxybenz-aldehyde
8
was facilitated by HUN
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19-40 mg min-1 products were synthesized in HUN microdroplets.
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DOI: 10.1039/C9SC03701B
The above results indicate that microdroplet chemistry shows
promise for the semi-preparative synthesis of many different
compounds.
Experimental
For the Claisen-Schmidt condensation reaction, 50 mM 6-
hydroxy-1-indanone, 50 mM benzaldehyde and 1.8 M KOH
were mixed in equal volumes and methanol was the solvent.
For the Oximation reaction, 50 mM benzophenone and 1 M
hydroxylamine dissolved in 1 M NaOH were mixed in equal
volumes and methanol was used as solvent. For the two-
phase oxidation reaction, 200 mM 4-methoxybenzyl alcohol in
EtOAc and aqueous NaClO (11-14%) were mixed at a volume
ratio of 5:6. For the Eschenmoser coupling reaction, 87 mM 1-
methylpyrrolidine-2-thione, 130 mM diethyl bromomalonate
and 87 mM Na2CO3 were mixed and CH3CN/H2O (v:v=9:1)
was used as the solvent.
Figure 5. The Eschenmoser coupling reaction of 1-methylpyrrolidine-2-
thione 9 with diethyl bromomalonate 10 to form the enaminone product 11:
(a) reaction schematic; HPLC chromatograms of Eschenmoser coupling
reaction in (b) bulk phase and (c) HUN microdroplets after 3.5 min. Plots of
Microdroplet reactions were conducted in nebulization cell
with the temperature of heating tape set at 50 C. For
comparison, bulk reactions were conducted in a 50 C water
bath. Upon completion of the reaction, the products were
collected and diluted for subsequent analysis by using a LTQ
XL Orbitrap hybrid mass spectrometer (Thermo Fisher
Scientific, Germany) or an Agilent 1260 high-performance
liquid chromatography (HPLC) (Agilent, USA). The size of
microdroplets in nebulization cell was measured by a laser
diffractometer (Sympatec HELOS, Sympatec, Germany).
Additional experimental details on each reaction system can
be found in the Supporting Information (Sections S1 and S2).
Preparative synthesis of the microdroplet reactions was
facilitated by using an industrial nebulization plate with 10
ultrasonic nebulizers (A10D48-001, Dongguan RunYang
Electronic Co., Ltd., China).
0
t
0
1/(C09 ― C100)ln [ C9 ― C11 /(C10 ―Ct11)]
(
)
vs time deriving the second-order
reaction rate constant to be (d) 1.4×10˗3 L mol-1 s-1 in the bulk phase and (e)
8.7x10˗2 L mol-1 s-1 in HUN microdroplets.
Figure 5a shows the reaction schematic of the Eschemoser
coupling reaction between 1-methylpyrrolidine-2-thione 9 and
diethyl bromomalonate 10 to form the enaminone product 11. The
HPLC chromatograms of the Eschemoser coupling reaction in bulk
phase and HUN microdroplets after 3.5 min were shown in Figures
5b and 5c, respectively. In comparison with the 3.5-min yield in bulk
phase (6.2%), the 3.5-min yield (78%) obtained by the HUN
microdroplet reaction is much higher. The initial concentration of
C0
diethyl bromomalonate 10 ( 10) in this experiment was 1.5 times
C0
higher than that of 1-methylpyrrolidine-2-thione 9 ( 9) and thus this
reaction proceed as a second order reaction with reactants at
different initial concentrations. The reaction rate constants in bulk
phase (kbulk) and HUN microdroplets (kHUN) were calculated by
1/(C0 C100)ln [ C9 ― C11 /(C10 Ct )]
Ct
vs reaction time (
11
0
t
0
(
)
-
-
11
plotting
9
Conflicts of interest
There are no conflicts to declare.
represents the concentrations of product 11) in Figures 5d and 5e.
An acceleration factor for this reaction in HUN microdroplets was
calculated to be 62. By using the HUN scale-up setup, 140 mg
product was produced within 3.5 min with 67% yield (40 mg min-1).
Its 1HNMR spectrum is provided after purification (Figure S16).
Acknowledgements
We would like to thank Prof. Yan Xia for useful discussions and
comments. This work was supported by the Scientific Research
Startup Foundation (Grant IDH1615113) of Fudan University. C.Y.
Liu thanks the funding of the China Postdoctoral Science
Foundation (No. 2018M640329).
Conclusions
In summary, we have developed a new method for the scale-up
of microdroplet reactions based on the HUN system. Four reactions
including a base-catalyzed Claisen–Schmidt condensation, an
oximation reaction, a two-phase reaction without the use of a phase
transfer catalyst, and an Eschenmoser coupling reaction were
examined. The rates of these reactions can be markedly
accelerated in HUN microdroplets by one to three orders of
magnitude higher than the corresponding bulk reactions. In addition
we demonstrated that these reactions could be scaled up by an
industrial nebulization plate with multiple nebulizers. By this means,
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