Two-Phase Reactions in Microdroplets without the Use of Phase-Transfer Catalysts

Article abstract of DOI:10.1002/anie.201612308

Many important chemical transformations occur in two-phase reactions, which are widely used in chemical, pharmaceutical, and polymer manufacturing. We present an efficient method for performing two-phase reactions in microdroplets sheared by sheath gas without using a phase-transfer catalyst. This avoids disadvantages such as thermal instability, high cost, and, especially, the need to separate and recycle the catalysts. We show that various alcohols can be oxidized to the corresponding aldehydes and ketones within milliseconds in moderate to good yields (50–75 %). The scale-up of the present method was achieved at an isolated rate of 1.2 mg min^?1 for the synthesis of 4-nitrobenzylaldehyde from 4-nitrobenzyl alcohol in the presence of sodium hypochlorite. The biphasic nature of this process, which avoids use of a phase-transfer catalyst, greatly enhances synthetic effectiveness.

Full text of DOI:10.1002/anie.201612308

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International Edition: DOI: 10.1002/anie.201612308
German Edition: DOI: 10.1002/ange.201612308
Synthetic Methods Very Important Paper
Two-Phase Reactions in Microdroplets without the Use of Phase-
Transfer Catalysts
Xin Yan, Heyong Cheng, and Richard N. Zare*
Abstract: Many important chemical transformations occur in
two-phase reactions, which are widely used in chemical,
pharmaceutical, and polymer manufacturing. We present an
efficient method for performing two-phase reactions in micro-
droplets sheared by sheath gas without using a phase-transfer
catalyst. This avoids disadvantages such as thermal instability,
high cost, and, especially, the need to separate and recycle the
catalysts. We show that various alcohols can be oxidized to the
corresponding aldehydes and ketones within milliseconds in
moderate to good yields (50–75%). The scale-up of the present
method was achieved at an isolated rate of 1.2 mgminÀ1 for the
synthesis of 4-nitrobenzylaldehyde from 4-nitrobenzyl alcohol
in the presence of sodium hypochlorite. The biphasic nature of
this process, which avoids use of a phase-transfer catalyst,
greatly enhances synthetic effectiveness.
Therefore, using current methods, one cannot avoid
problems associated with phase-transfer catalysts, such as
thermal instability, cost, and, especially, the need to separate
and recycle the catalysts.[9] PTCs for anions are often
quaternary ammonium salts (Q+). The recovery is usually
accomplished by extraction, distillation, adsorption, or bind-
ing to an insoluble support.[10] Most methods employ an
organic layer containing about 90% Q+, which must be
recycled at least ten times with no loss of Q+.[9] Removing
residual traces of Q+, usually by ion-exchange, can be difficult
and expensive, but it is often required for the synthesis of
drugs and Q+-sensitive products.[9] We present a methodology
that avoids using a phase-transfer catalyst but still enables the
two-phase reaction to occur within milliseconds in yields of
50–75%.
Recent studies have shown many single-phase reactions
can be dramatically accelerated in microdroplets[11] created by
spray-based ionization,[12] surface drop-casting,[13] and micro-
fluidics.[14] Microdroplets as microreactors have a strikingly
different reactive environment from that of the corresponding
bulk phase.[15] How exactly the reaction is accelerated in
microdroplets, however, remains to be fully understood, given
both the size and time scales involved. Many factors are
thought to contribute to the reaction acceleration such as
microdroplet evaporation, confinement of reagents, altera-
tion of pH of the microdroplet surface, and probably one of
the most important features, the high surface-to-volume ratio
of the microdroplet.[11] A reaction/adsorption model describ-
ing adsorption of molecules at interfaces in small droplets
plays an important role in reaction acceleration in micro-
droplets.[14] The observation of additional acceleration for p-
methylbenzaldehyde in a microdroplet reaction with 6-
hydroxy-1-indanone by cooperative interactions between p-
methylbenzaldehyde and p-nitrobenzaldehyde supported the
above model based on the assumption that more reagents
stayed at the interface than in the bulk.[16]
In this work, we provide a strategy for performing
superfast two-phase reactions in microdroplets without
using a phase-transfer catalyst. A bulk liquid–liquid system
was dispersed as small aerosol droplets so that the interfacial
area between the two phases is increased by many orders of
magnitude.[15] We also used the extreme case, reactions that
only occur at the interface, to elucidate the important role of
the microdroplet interface in two-phase reaction acceleration.
Stevens oxidation[17] without using a phase-transfer catalyst
(Scheme 1) was chosen as a proof of concept. Sodium
hypochlorite (NaOCl) was used to oxidize 4-nitrobenzyl
alcohol (1) to 4-nitrobenzaldehyde (2).
O
rganic reactions in systems containing two immiscible
liquid phases appear in a number of important applications in
chemical, pharmaceutical, and polymer synthesis.[1] The
reaction between two substances located in different phases
of a mixture is often inhibited because of the inability of
reagents to come together. Traditionally, a phase-transfer
catalyst (PTC) is used to enhance reaction rates, making
feasible a wide range of synthetic reactions not possible in
a single phase.[2] The most common arrangement for PTCs
involves the transport of a water-soluble reactant into an
immiscible organic solvent (Starks extraction mechanism[3])
or the transport of a reactant at the interface of two
immiscible solvents (Makosza interfacial mechanism[4]) with
an appropriate hydrophobic phase-transfer catalyst. Two-
phase reactions are carried out between immiscible phases;
thus, the nature of the interface and the physical properties of
the reacting compounds at the interface become very
important in promoting the desired reaction at a satisfactory
rate. Methods that can increase the interfacial contact area
between the two phases should effectively improve mass
transfer, resulting in better product conversion in less time.[5]
Available methods such as vigorous magnetic or mechanical
stirring,[6] ultrasonic irradiation,[7] and use of a rotor-stator
homogenizer[8] accelerate two-phase reactions to some extent,
but a phase-transfer catalyst is still necessary in those
methods.
[*] Dr. X. Yan, Dr. H. Cheng, Prof. R. N. Zare
Department of Chemistry, Stanford University
333 Campus Drive, Stanford, CA 94305-5080 (USA)
E-mail: zare@stanford.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612308.
Figure 1a shows our experimental design. Two high-speed
streams of microdroplets of 1 (0.2m) in ethyl acetate (EtOAc)
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ence in product formation (Supporting Information, Fig-
ure S1). This observation indicated that the reactions were
not mediated by the collection surface. The travel distance of
the microdroplets determined the degree of product con-
version in previously reported reactions.[12a] We changed the
distance between the spray emitters and collection surface
from 5 to 10 cm and did not find a change in product yield
(Supporting Information, Figure S2), which shows the fast
reaction occurred in the microdroplets before they landed on
the surface. Compressed air and helium gas were also tried as
the sheath gas with no apparent changes in the yields
(Supporting Information, Figure S3). Three control experi-
ments were performed in bulk (Figure 1c), drop-casted
millimeter-size droplets (Figure 1d), and droplets generated
using a 29 nL micro-T-junction (Figure 1e) with reaction
times of 10 min or more (see Supporting Information for
details). GC confirmed that no reaction occurred under any of
these three conditions (Figure 1 f). A previous study also
showed that no oxidation occurred in the absence of the
phase-transfer catalyst in bulk solution.[17b]
The sharp contrast between the two-phase reaction
behavior in microdroplets from that in the bulk and large
droplets (100 mm to 5 mm) emphasized the importance of
droplet size (surface-to-volume ratio) in driving the two-
phase reactions. With a decrease of the droplet size from mm
to micrometer, the surface-to-volume ratio increases three
orders of magnitude.[15] We decreased the size of the droplets
by either fixing the pressure of the sheath gas and using
capillaries with inner diameters (i.d.) of 50, 100, and 250 mm
(outer diameter of 360 mm) to generate microdroplets with
different initial sizes; or fixing the diameter of the capillary
and changing the sheath gas pressure from 50 to 150 psi (1
psi = 6894.76 Pa) to decrease the droplet size by increasing
the shearing force (Supporting Information, Figure S4).
Slightly increased product formation was observed for
a capillary of 50 mm i.d. and under 150 psi (Supporting
Information, Figure S5). This suggests that below a certain
droplet diameter, further decrease of droplet size has no
significant effect on the two-phase reactions.
Scheme 1. Stevens oxidation of 4-nitrobenzyl alcohol (1) with NaClO in
ethyl acetate and water to form 4-nitrobenzaldehyde (2) without using
a phase-transfer catalyst.
and NaOCl (12.5%) in water were generated by the
nebulization of the respective bulk solutions with a turbulent
gas (N2). Oxidation was initiated by the rapid mixing of
droplets containing each reactant at the spray emitters and
progressed as the microdroplets travelled through the air. The
resulting products in the merged plumes were collected using
a glass separation funnel for 10 min. Exhaust gas was pumped
out from the bottom, while glass wool was used to cover the
gas outlet, avoiding loss of products. The distance and angle
between the two microdroplet spray emitters influenced the
formation of products, as described later. The reaction
mixture was extracted with EtOAc and analyzed by gas
chromatography (GC). The product 4-Nitrobenzaldehyde (2)
was detected by GC in 72% yield, as shown in Figure 1b.
Other materials such as aluminum foil and Teflon were also
investigated as collection surfaces, with no apparent differ-
To explore other intrinsic factors that facilitate the liquid–
liquid reaction in microdroplets, different methods of gen-
erating microdroplets and ways of interacting between the
two-phase droplets were investigated. In Figure 2a, a fused
silica capillary fed with 1 in EtOAc was inserted into
a concentric capillary fed with NaOCl aqueous solution to
produce an annular flow. The bottom of the inner capillary
was first kept at the same level with that of the outer capillary.
Two phases came into contact only when they entered the tip
of the spray emitter. GC shows that a yield of 18% (Fig-
ure 2g) was obtained. When we set the inner capillary back to
the outer concentric capillary (Figure 2b), a better yield
(27%) resulted. To further increase the contact time of the
two phases, we mixed them by cross flow in a micro-T-
junction and kept the droplet segments flowing through
a length of capillary followed by spraying of the droplets onto
the surface (Figure 2c). Fairly good conversion from 1 to the
product was obtained in some trials. However, the yield
varied (from 30–58%) in different batches. Possible reasons
for the unsteady formation of the products might be related to
Figure 1. a) Two-phase oxidation reaction between 4-nitrobenzyl alco-
hol (1) with NaOCl performed in microdroplets generated by the
atomization of respective bulk solutions with a turbulent nebulizing
gas (dry N2) at 120 psi; b) gas chromatogram of a two-phase oxidation
reaction under (a) conditions showing the formation of the product 4-
nitrobenzyladehye (2) in 72% yield. c) Two-phase reagents were mixed
in bulk and stirred vigorously for 10 min. d) Millimeter-size droplets of
the two reagents were drop-casted on top of each other. e) Two
streams of droplets were mixed in a micro-T-junction and then
directed to a collection funnel. f) Gas chromatogram of two-phase
oxidation reaction under the conditions shown in (c). Similar traces
were obtained under the conditions shown in (d) and (e). GC yields
were determined using standard curves generated from a series of
known standards referenced to the internal standard benzaldehyde.
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initiated by sheath gas instead of either one or both being
initiated by an electric field as in the extractive electrospray[18]
or microdroplet fusion[12b] experiments. There is a thin
intervening gas film between the surfaces of two droplets. If
the collision kinetic energy (mainly gained from sheath gas)
of the two droplets is not sufficient to penetrate this gas layer,
the droplets bounce off each other, resulting in no physical
contact between two liquid droplets.[19] This behavior can be
seen from the gas chromatograms obtained when the distance
between two spray emitters (d) exceeded 80 mm. Almost no
product was formed in such microdroplet reactions. The
optimized distance d of 1.5 mm with an angle a of 808
between two spray emitters pointing to the surface enabled
effective collisions (coalescence, disruption, or/and fragmen-
tation[19]) between microdroplets to occur. A representative
gas chromatogram obtained under this configuration is shown
in Figure 1b with an overall product yield of 72%.
Encouraged by these results, we further examined the
microdroplet two-phase oxidations of several other alcohols
including benzyl alcohols with different substituents, 1,4-
benzenedimethanol and secondary alcohol as shown in
Table 1. In all cases tested, the desired oxidation products of
individual alcohols were obtained without using phase-trans-
fer catalysts in moderate to good yields.
Figure 2. a) Two-phase annular flow was generated by inserting the
capillary tube fed with 1 in EtOAC into the capillary tube fed with
aqueous NaOCl and nebulized by sheath gas. The bottom of the inner
capillary was first kept at the same level with that of the outer capillary.
b) Inner capillary was set back to the outer concentric capillary. c) Two-
phase cross flow was formed by mixing 1 and NaOCl in a micro-T-
junction and sprayed. d) Microdroplets of 1 in EtOAc were sprayed
onto the collection surface followed by spraying NaOCl in water onto
the layer of 1. e) Microdroplets of aqueous NaOCl were sprayed onto
the collection surface followed by spraying 1 in EtOAc onto the layer of
NaOCl. f) Dual spray of 1 in EtOAc and aqueous NaOCl at distance d
and angle a onto the collection surface. g) Gas chromatogram of two-
phase oxidation reaction under the conditions in (a, green; b, blue; c,
yellow; d, purple; e, red; and f, black).
Table 1: Oxidation of various alcohols in two-phase microdroplets.
Reagent[a]
Product
Yield [%]
64
75
52
[a] 1,4-Benzenedimethanol has poor solubility in EtOAc. Its oxidation
was performed in acetonitrile, which still formed two phases when mixed
with aqueous NaOCl (12.5%).
the effect of the high-pressure sheath gas on mixing two-phase
droplets before and after their exiting the capillary. More
studies are ongoing for this device, while a key clue obtained
here was that NaOCl did not come in contact effectively with
1 when it was in the microdroplets in the low yield batches. To
verify this hypothesis, we divided the microdroplet reaction
into two types: 1) Microdroplets of 1 in EtOAc were
deposited onto the surface followed by spraying aqueous
NaOCl onto the layer of 1 (Figure 2d) or 2) vice versa
(Figure 2e). GC analysis showed repeatable product conver-
sions for both setups, although the yields were relatively low
(33% and 38%, respectively). This behavior was caused by
the fact that the interfacial area of one reagent on the
collection surface was not fully used to interact with the other
and droplets were partially fused upon their deposition onto
the surface.
To demonstrate the practical utility of the present two-
phase microdroplet synthesis method, a preparative-scale
experiment was performed. Four pairs of dual microdroplet
sprayers were arranged radially and converged at the tips of
spray emitters (Figure 3). Two-phase liquids were introduced
through the five-port mixers to the spray emitters. Sheath gas
(N2) was delivered using two gas manifold systems. Accord-
ingly, a rate of 1.2 mgminÀ1 was realized for the synthesis of 4-
nitrobenzylaldehyde (2) with an isolated yield of 64%. Its 1H-
NMR spectrum is provided after purification (Supporting
Information, Figure S5).
In summary, we have demonstrated that two-phase
reactions can be carried out in microdroplets rapidly and
with good yields without using phase-transfer catalysts.
Various alcohols including primary and secondary alcohols
were oxidized to their corresponding aldehydes and ketones.
Therefore, we forced microdroplets of the two phases to
collide with each other in a Y-shape intersection without
touching any other surface before they were collected (Fig-
ure 2 f). Note that both of the two-phase spray plumes were
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Conflict of interest
The authors declare no conflict of interest.
Keywords: liquid–liquid reactions · microdroplet synthesis ·
phase-transfer catalysis · Stevens oxidation · two-phase reactions
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Experimental Section
For the two-phase microdroplet synthesis of 4-nitrobenzaldehyde
(2), 4-nitrobenzyl alcohol (1, 0.2m) in ethyl acetate and aqueous
sodium hypochlorite (12.5%) were loaded at equal volume into two
airtight glass syringes and were delivered with a syringe pump
(Harvard Apparatus) at a flow rate of 15 mLminÀ1 to two separate
capillaries with an i.d. of 100 mm and o.d. of 360 mm. The ends of the
capillaries were equipped with two sheath-gas-assisted spray emitters.
The angle between the two spray sources was set between 608 and 808.
The distance between the two capillaries was set in a range of 0.5–
2 mm, depending on the angle of the two spray sources. The dry N2
gas, which served as the sheath gas, was operated at 120 psi. A glass
surface was used to collect the merged plumes from two spray sources.
Upon completion of the reaction, ethyl acetate was used to extract the
product from water and the product was dried by sodium sulfite. The
product yield was determined by GC. For further information on the
instrument, see the Supporting Information.
[15] S. Banerjee, E. Gnanamani, X. Yan, R. N. Zare, unpublished
results.
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3433 – 3437; Angew. Chem. 2016, 128, 3494 – 3498.
Acknowledgements
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1980, 45, 2030 – 2032; b) G. A. Mirafzal, A. M. Lozeva, Tetrahe-
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2044.
We thank Katherine Walker who made available to us the GC
instrument in the Waymouth laboratory. H. C. appreciates the
financial support from the China Scholarship Council
(201508330736) and the National Natural Science Foundation
of China under project No. 21405030. This work was
supported by the Air Force Office of Scientific Research
through Basic Research Initiative grant (AFOSR FA9550-16-
1-0113).
[19] M. Orme, Prog. Energy Combust. 1997, 23, 65 – 79.
Manuscript received: December 19, 2016
Revised: February 6, 2017
Final Article published: && &&, &&&&
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Communications
Synthetic Methods
X. Yan, H. Cheng,
R. N. Zare*
&&& — &&&
Two-Phase Reactions in Microdroplets
without the Use of Phase-Transfer
Catalysts
It’s all about the interface: Biphasic
reactions are carried out in microdroplets
without using a phase-transfer catalyst.
Reactions occur within milliseconds in
moderate to good yields.
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5
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