High-yield gram-scale organic synthesis using accelerated microdroplet/thin film reactions with solvent recycling

Article abstract of DOI:10.1039/c9sc06265c

A closed system has been designed to perform microdroplet/thin film reactions with solvent recycling capabilities for gram-scale chemical synthesis. Claisen-Schmidt, Schiff base, Katritzky and Suzuki coupling reactions show acceleration factors relative to bulk of 15 to 7700 times in this droplet spray system. These values are much larger than those reported previously for the same reactions in microdroplet/thin film reaction systems. The solvent recycling mode of the new system significantly improves the reaction yield, especially for reactions with smaller reaction acceleration factors. The microdroplet/thin film reaction yield improved on recycling from 33% to 86% and from 32% to 72% for the Katritzky and Suzuki coupling reactions, respectively. The Claisen-Schmidt reaction was chosen to test the capability of this system in gram scale syntheses and rates of 3.18 g per h and an isolated yield of 87% were achieved.

Full text of DOI:10.1039/c9sc06265c

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High-yield gram-scale organic synthesis using
accelerated microdroplet/thin film reactions with
solvent recycling†
Cite this: DOI: 10.1039/c9sc06265c
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Honggang Nie,‡ab Zhenwei Wei,‡a Lingqi Qiu,a Xingshuo Chen,a Dylan T. Holdena
a
*
and R. Graham Cooks
A closed system has been designed to perform microdroplet/thin film reactions with solvent recycling
capabilities for gram-scale chemical synthesis. Claisen–Schmidt, Schiff base, Katritzky and Suzuki
coupling reactions show acceleration factors relative to bulk of 15 to 7700 times in this droplet spray
system. These values are much larger than those reported previously for the same reactions in
microdroplet/thin film reaction systems. The solvent recycling mode of the new system significantly
improves the reaction yield, especially for reactions with smaller reaction acceleration factors. The
microdroplet/thin film reaction yield improved on recycling from 33% to 86% and from 32% to 72% for
the Katritzky and Suzuki coupling reactions, respectively. The Claisen–Schmidt reaction was chosen to
test the capability of this system in gram scale syntheses and rates of 3.18 g per h and an isolated yield of
87% were achieved.
Received 10th December 2019
Accepted 3rd January 2020
DOI: 10.1039/c9sc06265c
rsc.li/chemical-science
small volumes provide high acceleration factors).20,29,41,45–47 (iii)
Large amounts of solvent are wasted which is undesirable from
green chemistry considerations.48
Introduction
Over the past decade, a large number of mass spectrometry and
uorescence based studies have described unusual reaction
behavior in small conned volumes, a topic that naturally
attracts wide interest because of the close relationship to single
cell biology,1–8 nanoscience9–12 and surface science.13–16 Reactions
in microdroplets17–26 and thin lms27–30 can be accelerated by
factors of 101 to 105, and this has potential value in chemical
synthesis. The partial solvation of reactants near the micro-
droplet–gas interface,9,15,31–33 the extremes in pH of micro-
droplets,9,20,22 fast solvent evaporation,29,34 special electric eld
and dipoles near interface10,14,35 and enhanced mass transfer36–40
make these reactions notably faster than in bulk. Although larger
acceleration factors have been achieved in microdroplets,31,41 the
small scale of the experiments18,29 and the failure to recycle the
solvent have to be addressed to make this a practical approach to
chemical synthesis. Specically, (i) microdroplet reaction yields
are restricted by the limited reaction time allowed due to the
short lifetimes of microdroplets generated by electrospray,42
pneumatic spray43 and ultrasonic spray.44 (ii) The reaction scale
suffers from the small volumes of the droplets (chosen because
To address the yield and scale issues, microdroplet collec-
tion experiments have been performed. In 2012, preparative
electrospray was used to scale up the Claisen–Schmidt
condensation reaction;27 the reaction mixture was electro-
sprayed at ow rate of 10 mL minꢀ1 and directed into a poly-
ethylene vessel containing glass wool to collect the product.
Once the microdroplets hit the wall of the vessel or the wool
ber, they form an electroneutral thin lm of reaction solution.
If reaction is incomplete in the droplets it then can occur in this
thin lm. Although the reported reaction acceleration factors in
thin lms27,28,49 are not as large as in microdroplets,41 the reac-
tion yields can be much higher due to the increased reaction
time, as conrmed by dropcast thin lm reactions.29 For this
rst 2012 preparative electrospray synthesis, the reaction scale
was 35.3 mg per h (four sprayers, 90% yield).18 In 2017, depo-
sition of uncharged microdroplets generated by sonic spray was
used to fabricate a dynamic thin lm for continuous synthesis.30
Again for Claisen–Schmidt reactions, the uncharged micro-
droplet and thin lm reactions showed similar kinetics and
yields to those in charged droplets, however, a larger reaction
scale (120 mg per h; one sprayer, 80% yield) could be achieved
due to the greater ow rate allowed in the sonic spray.
Commercial pneumatic sprayers can support even greater ow
rates, which means a much larger reaction scale, however, the
droplet size is then too large for signicant microdroplet reac-
tion acceleration. In 2018, by choosing mesh materials with
micrometer scale holes, a pneumatic sprayer was used to
aAston Labs, Department of Chemistry, Purdue University, 560 Oval Drive, West
Lafayette, IN, 47906-1393, USA. E-mail: cooks@purdue.edu
bBeijing National Laboratory for Molecular Sciences, College of Chemistry and
Molecular Engineering, Peking University, Beijing 100871, P. R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9sc06265c
‡ These authors contribute equally.
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generate size-controlled microdroplets at a very high ow rate (8
mL minꢀ1).43 A particular aldehyde oxidation reaction was run
at a scale of 630 mg per h (one sprayer, 66% yield). Multiplexing
is always a favorable strategy to achieve a larger scale. For
example, the scale of two-phase microdroplet reactions13 could
be increased by using multiple sprayers. Similarly, paper spray
microdroplet reactions can be multiplexed by using paper with
multiple tips.50
In light of this examination of earlier studies of scaled-up
microdroplet synthesis, we note that although a variety of scale-
up methods have been developed and larger scales have been
achieved recently, the limited reaction time and lack of solvent
recycling remain issues that are inadequately addressed. With
a focus on these issues, we describe a new system for micro-
droplet synthesis with major improvements in reaction yield,
product collection efficiency and solvent economy. The system
can operate on the mg per h to g per h scale.
Reaction conditions and MS measurement
All microdroplet reactions were performed at a concentration
of 10 mM with equimolar reactants. For the Claisen–Schmidt
reaction, 2 eq. of KOH were used to catalyze the reaction; for
the Suzuki reaction, 2 eq. of EtONa and 0.02 eq. Xphos G3
were used as catalyst. The corresponding bulk reactions were
run at these concentrations in 20 mL cap-sealed glass vials
containing 3 mL reaction mixture and placed in an incubator
and run at the desired temperatures (25 ꢁC for Claisen–
Schmidt and Katritzky reactions, 65 ꢁC for Schiff base and
Suzuki reactions). The microdroplet reactions used a ow rate
of 100 mL minꢀ1 to spray reaction mixture into the reaction
chamber housed in a water bath. The concentration of reac-
tion mixture and the chamber temperature were the same as
those used for the corresponding bulk reactions. At selected
times aer starting a reaction, the reaction mixture (the
sprayed reaction mixture plus the condensate) was quenched
by dilution with quenching solution (pH adjustment of
quenched solution was necessary for the Suzuki reaction;
detailed information on quenching steps is given in Table
S1†) prior to subsequent nanoelectrospray mass spectrometry
(nESI-MS) analysis under standard non-accelerating condi-
tions.30 By comparing the peak intensity of reactant and
product ions in these mass spectra, and correcting for the
difference in ionization efficiency, reaction yields were esti-
mated from eqn (1):
Results and discussion
As shown in Fig. 1a, a peristaltic pump is used to introduce the
reaction mixture from a reservoir, as well as to transfer the
condensate back to the microdroplet reaction chamber. High-
pressure nitrogen is used as a sheath gas to assist with nebuli-
zation and for protection of air/water sensitive reagents. As the
synthesis begins, valve 1 is open and valve 2 is closed; the reac-
tion mixture is transferred from the reservoir to the spray
chamber to perform microdroplet and thin lm reactions. The
condensation chamber is used to collect the reagent- and product-
containing vapors and nanodroplets. When the desired volume
of reaction mixture had been transferred, valve 1 was closed and
valve 2 opened, placing the system in the solvent recycling mode.
During this time, reaction condensate is transferred back to the
sprayer continuously to allow microdroplet and thin lm reac-
tions to proceed in the reaction chamber. This helps increase
reaction time and product yield. We have performed various
reactions using this new system, including typical C–C and C–N
bond formation reactions, ring opening and closing reactions
and coupling reactions, as listed in Fig. 1b.
IP
IP=IR
Yield ¼
¼
(1)
IP þ IR f
IP=IR þ f
where IP and IR are the peak intensities of the product and
reactant, respectively. The constant f reects the difference in
product and reagent ionization efficiency, dened as:
IP=IR
f ¼
(2)
½Pꢂ=½Rꢂ
Constant f was measured by spiking reactant into diluted
and quenched reaction mixture to measure the corresponding
peak intensities in the mass spectra (see ESI†).
Fig. 1 (a) System for microdroplet synthesis on the mg per h to g per h scale. (b) Reactions interrogated using the new scale-up synthesis system.
(b(i)) Claisen–Schmidt reaction; (b(ii)) Schiff base reaction; (b(iii)) Katritzky reaction; (b(iv)) Suzuki reaction.
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reaction shows a small AAF of 15 (only 15 times faster than
bulk!). For the Claisen–Schmidt reaction, a model reaction
oen examined in microdroplet/thin lm reaction acceleration
studies, we note that the AAF in this new system is 7700, which
is signicantly higher than our previously reported value of
1000 (compared in units of [P]/[R]) in microdroplet product
collection experiments.30 This improvement can be due to
enhanced microdroplet collection efficiency, especially more
efficient collection of the smallest droplets. It is important to
emphasize that the apparent acceleration factor in these
experiments, while a relative measure of rate constants,
includes droplets of a range of sizes. As already noted, there is
a strong inverse size effect on rate constants45 because reactions
at the microdroplet/air interface are the main contributors to
reaction acceleration.14–16,33,35,38,51 The closed reaction system
will, no doubt, increase the collection efficiency of small sized
droplets compared to ambient collection conditions (Fig. S2†)
and hence increase the apparent acceleration factor measured.
However, it must be acknowledged that not every reaction can
be dramatically accelerated in microdroplets and that the
mechanism behind this phenomenon is not completely clear.30
Empirically, it is clear that microdroplets are very effective at
facilitating and accelerating bimolecular reactions, especially
those involving the loss of small molecules such as condensa-
tion reactions. Moreover, solvent evaporation and the increased
concentrations of acids/bases in microdroplets, as well as the
super acidic/basic environment of microdroplets will facilitate
reactions such as the Claisen–Schmidt reaction. These consid-
erations help to explain acceleration in the Claisen–Schmidt,
Katritzky and Schiff base reactions. However, the Suzuki
coupling reaction could be different because it is a homogenous
reaction catalyzed by a Pd(0) complex, wherein the reaction rate
is highly dependent on the catalyst loading. The microdroplet
condition does not increase the catalyst loading but the fast
mass transfer in microdroplets can facilitate the renewal of
catalytic sites and so increase catalyst efficiency.
Microdroplet/thin lm reaction without solvent recycling
We investigated the kinetics and thermodynamics of micro-
droplet reactions in our system and made comparisons with
bulk reactions. Organic reactions are oen reversible so we
investigated their reaction kinetics in the kinetic control
regime, where the inuence of the back reaction can be ignored.
All four chosen reactions are considered as pseudo 2nd order
reactions to facilitate comparison between the different reac-
tions; note however that the order of Suzuki coupling is less
certain (see the ESI† for discussion on this point). Hence the
slope of the plot of [P]/[R] vs. reaction time t should be the
product of reagent concentration (c0) and rate constant (k). This
information can then be used to evaluate the apparent reaction
acceleration factor (AAF, AAF ¼ (c0k)droplet/(c0k)bulk) of the
different chemical systems. It is noteworthy that there is
a concentration effect on AAF.
As shown in Fig. 2, the slopes of the Claisen–Schmidt, Schiff
base, Katritzky and Suzuki coupling reactions in bulk are
0.000052 minꢀ1, 0.0014 minꢀ1, 0.0049 minꢀ1 and 0.0029 minꢀ1
,
respectively; the slopes derived from the microdroplet reactor
are 0.40 minꢀ1, 0.18 minꢀ1, 2.5 minꢀ1 and 0.050 minꢀ1
,
respectively. Taking the ratio of the slopes recorded under bulk
and microdroplet conditions, and noting that both sets of
experiments used the same initial concentrations, we note that
the Claisen–Schmidt reaction has a very large AAF of ca. 7700,
while the Schiff base and Katritzky reactions have moderate
AAFs of 510 and 130, respectively, and the Suzuki coupling
Fig. 3 describes the thermodynamics in the bulk and
microdroplet reactors. The rst column shows data for the bulk
reactions and the second column shows those for the micro-
droplet reactions. For all four microdroplet reactions, there is
a plateau in the plot of yield vs. reaction time that occurs within
10 min, indicating that the reactions approach equilibrium very
quickly. For example, the Claisen–Schmidt and Schiff base
reactions both have very large AAFs and reach a plateau
(maximum yield in microdroplet reaction) within 3 min. The
maximum yield aer 10 min is 58% for the microdroplet/thin
lm Claisen–Schmidt reaction however the yield of bulk reac-
tion is only 9%, even with 20ꢃ KOH and aer 24 hour reaction.
The maximum yield is 94% for the microdroplet/thin lm Schiff
base reaction while the yield in bulk is only 20% aer 1 hour
reaction. For the Katritzky and Suzuki reactions, with their
medium and small AAFs, the plateau in the microdroplet
reaction is not as well-dened. The yield aer 10 min micro-
droplet reaction vs. 60 min bulk reaction is 55% vs. 14% for
Katritzky reaction and 40% vs. 17% for the Suzuki reaction.
Although the yield was improved in the microdroplet reaction, it
is still some way from the maximum possible yield, likely due to
Fig. 2 Kinetics curves and apparent acceleration factors (AAF). In
order to obtain measurable kinetics curves in bulk, 20 equivalent KOH
had to be used as opposed to 2 equiv. in droplets.
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Table 1 Comparison of the parameters used in normal vs. solvent
recycling reactions
Parameters
Normal mode Recycling mode
Temperature (ꢁC)
65
0.3
10
3
65
3
10
3
Flow rate (mL minꢀ1
Concentration (mM)
)
Volume transferred (mL)
Reaction time (min)
10
10
Valve 1 (reaction solution reservoir) Always on
Valve 2 (condensation chamber) Always off
On (0 to 3 min)
On (3 to 10 min)
We see that for the Claisen–Schmidt and Schiff base reactions,
two reactions with large AAFs, the yields with and without
solvent recycling are similar and very high. However, for reac-
tions with smaller AAFs, solvent recycling improved the yields
dramatically, from 33% to 86% for the Katritzky reaction and
32% to 72% for the Suzuki coupling reaction. The higher yields
achieved in the solvent recycling reactions are due to the
increase of microdroplet reaction time. In the continuous spray
microdroplet reaction format, the reaction mixture is gradually
introduced to the reaction chamber to allow microdroplet
reactions. The later the reaction mixture is introduced, the less
microdroplet/thin lm reaction time there is. However, in the
solvent recycle mode, all reactants are introduced into the
chamber within 3 minutes; during the other 7 min, all of the
reactants are experiencing accelerated microdroplet and thin
lm reactions and thus a higher yield is achieved (Table 2).
Fig. 3 Yield vs. time behavior of the four reactions under consider-
ation. In order to obtain measurable kinetics curves in bulk, 20
equivalent KOH had to be used as opposed to 2 equiv. in droplets.
Scale-up synthesis with solvent recycling
the lack of reaction time. This is a general drawback of the
continuous microdroplet reaction format, which becomes
a serious problem in reactions with intrinsically small acceler-
ation factors. In traditional microdroplet/thin lm reaction
format, reaction time is dependent on spray time and the later
the reactants are introduced, the lower is the reaction time. The
radical solution to this problem is separation of reagent intro-
duction and solvent introduction into the system so that one
can control the reaction scale and microdroplet reaction time
appropriately.
We chose the Claisen–Schmidt reaction to test the capability to
perform reactions on the gram per hour scale. The photos in
Fig. 4 show the instrumental setup, the reaction chamber
during reaction/aer reaction and the puried product
acquired aer the reaction. In this experiment 30 mL of the
fresh mixed reaction solution (0.2 M 6-hydroxyindanone, 0.2 M
2-methoxybenzaldehyde and 0.4 M KOH) was transferred into
reaction chamber at a ow rate of 2 mL minꢀ1. Aer 15 min,
solvent recycling was started and run for 15 min. In total, the
reaction took half an hour. All of the mixture in the reaction
chamber was then washed with 15 mL 2 M hydrochloride
solution twice and then with 15 mL water once. The washed
product was dried in an incubator at 35 ꢁC overnight. The dried
powder was weighed as 1.38 g (isolated yield of 87%). A small
fraction of the powder was diluted by MeOH (with 1 mM DMAP
for ionization in negative mode) to 1 mM for nESI-MS analysis.
Comparison of microdroplet/thin lm reaction with and
without solvent recycling
To solve the above question, instead of separate introduction of
reagents and solvent we added a solvent recycling capability to
our microdroplet reaction system. We then compared the
microdroplet reaction with and without the solvent recycling
option. To compare these two methods, the reagent concen-
trations (10 mM), reaction time (10 min), reaction scale (3 mL,
Table 2 Recycling/no recycling 10 min reactions
ꢁ
30 mmol) and temperature (65 C) were kept the same. For the
Yield (%)
simple microdroplet reaction, the ow rate was set to 0.3
mL minꢀ1 so that 30 mmol of each reactant solution was
deposited aer 10 min. For the solvent recycling version of the
microdroplet reaction, the ow rate was 1 mL minꢀ1. In the rst
3 min, 3 mL reaction solution (30 mmol) was deposited. Table 1
compares reaction yields with and without the solvent recycling.
Reaction type
Normal mode
Recycling mode
Claisen–Schmidt reaction
Katritzky reaction
Schiff base formation
Suzuki coupling reaction
92
33
98
32
93
86
100
72
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Fig. 4 Photos of (a) the scaled-up microdroplet/thin film reaction system for Claisen–Schmidt reaction, (b) reaction chamber during/after
reaction and (c) purified product.
The MS is shown in Fig. S3.† Another small fraction of the performed the experiments. L. Qiu helped in product purica-
product was dissolved deuterated DMSO for NMR analysis. The tion and characterization. X. Chen and D. T. Holden helped
H-NMR and 13C-NMR spectra are shown in Fig. S4 and S5.† All with performing the reactions. The authors acknowledge
the spectra indicate a very high purity of the isolated product.
support from US. Defense Advanced Research Projects Agency
W911NF-16-2-0020 and National Science Foundation 1905087.
H. Nie thanks the nancial support from National Natural
Science Foundation of China 21405006 and 21527809 and
China Scholarship Council 201806015051.
Conclusions
We have designed a semi-closed system for accelerated micro-
droplet reactions with solvent recycling capabilities. In this
system, microdroplet reactions occur in a chamber housed in
a water bath, which is separated from the ambient environment
by a cold trap housed in a dry ice bath. The semi-closed system
improves microdroplet reaction yields in three ways: (i) the
reaction chamber increases the collection efficiency of small
micro- or nanodroplets, enhancing the reaction acceleration
factor relative to open systems; (ii) the cold trap allows carrier
gas to pass into the air but captures microdroplets entrained
reagents, products and solvents, and works with the peristaltic
pump to recycle the condensate so improving the isolated yield
in synthesis; (iii) solvents can be recycled to achieve longer
microdroplet reaction times, which increases yields, especially
for those reactions with small acceleration factors. This system
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