Pickering Emulsion-Derived Liquid-Solid Hybrid Catalyst for Bridging Homogeneous and Heterogeneous Catalysis

Article abstract of DOI:10.1021/jacs.8b11860

We describe a novel method to prepare a liquid-solid hybrid catalyst via interfacial growth of a porous silica crust around Pickering emulsion droplets, which allowed us to overcome the current limitations of both homogeneous and heterogeneous catalysts. The inner micron-scaled liquid (for example, ionic liquids) pool of the resultant catalyst can host free homogeneous molecular catalysts or enzymes to create a true homogeneous catalysis environment. The porous silica crust of the hybrid catalyst has excellent stability, which makes it amenable to packing directly in fixed-bed reactors for continuous flow catalysis. As a proof of concept, the enzymatic kinetic resolution of racemic alcohols, Cr^III(salen) complex-catalyzed asymmetric ring opening of epoxides and Pd-catalyzed Tsuji-Trost allylic substitution reactions were used to verify the generality and versatility of our strategy for bridging homogeneous and heterogeneous catalysis. The hybrid catalyst-based continuous flow system exhibited a 1.6a16-fold enhancement in activity relative to homogeneous counterparts even over 1500 h, and the afforded enantioselectivities were completely equal to those obtained in the homogeneous counterpart systems. Interestingly, the catalytic efficiency can be tuned through rational engineering of the porous crust and the dimensions of the liquid pool, resulting in features of an innovatively designed catalyst. This contribution provides a new method to design efficient catalysts that can bridge the conceptual and technical gaps between homogeneous and heterogeneous catalysis.

Full text of DOI:10.1021/jacs.8b11860

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Article
A Pickering Emulsion-Derived Liquid-Solid Hybrid Catalyst
for Bridging Homogeneous and Heterogeneous Catalysis
Xiaoming Zhang, Yiting Hou, Rammile Ettelaie, Ruqun Guan, Ming Zhang, Yabin Zhang, and Hengquan Yang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11860 • Publication Date (Web): 18 Feb 2019
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A Pickering Emulsion-Derived Liquid-Solid Hybrid Catalyst for
Bridging Homogeneous and Heterogeneous Catalysis
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Xiaoming Zhang,†,§ Yiting Hou,†,§ Rammile Ettelaie,# Ruqun Guan,† Ming Zhang,† Yabin Zhang† and
Hengquan Yang*,†
† School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
# Food Colloids Group, School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, U.K.
Supporting Information
ABSTRACT: We describe a novel method to prepare a liquid-solid hybrid catalyst via interfacial growth of a porous silica
crust around Pickering emulsion droplets, which allowed us to overcome the current limitations of both homogeneous
and heterogeneous catalysts. The inner micron-scaled liquid (for example, ionic liquids) pool of the resultant catalyst can
host free homogeneous molecular catalysts or enzymes to create a true homogeneous catalysis environment. The porous
silica crust of the hybrid catalyst has excellent stability, which makes it amenable to packing directly in fixed-bed reactors
for continuous flow catalysis. As a proof of concept, the enzymatic kinetic resolution of racemic alcohols, CrIII(salen)
complex-catalyzed asymmetric ring opening of epoxides and Pd-catalyzed Tsuji-Trost allylic substitution reactions were
used to verify the generality and versatility of our strategy for bridging homogeneous and heterogeneous catalysis. The
hybrid catalyst-based continuous flow system exhibited a 1.6~16-fold enhancement in activity relative to homogeneous
counterparts even at more than 1500 h, and the afforded enantioselectivities were completely equal to those obtained in
the homogeneous counterpart systems. Interestingly, the catalytic efficiency can be tuned through rational engineering of
the porous crust and the dimensions of the liquid pool, resulting in features of an innovatively designed catalyst. This
contribution provides a new method to design efficient catalysts that can bridge the conceptual and technical gaps
between
homogeneous
and
heterogeneous
catalysis.
catalysts on or in solid supports, may be closest to
realizing this goal because of the structural integration
of homogeneous and heterogeneous catalysts.19–25
Unfortunately, immobilized molecular catalysts often
suffer from decreased or unpredictable activity and
selectivity because of alternation of the preferred
structures, the steric hindrance arising from the support
surfaces or the disturbance of homogeneous
microenvironments.21,26–28 Another milestone in this
direction is the supported liquid phase catalyst in which
a layer of liquid that dissolves homogeneous catalysts is
adsorbed onto porous solid materials.29–32 This method,
however, requires the liquid layer to be very thin and is
1. INTRODUCTION
The discovery of efficient catalysts is of paramount
importance since most chemical reactions in industry
involve catalysis. Combining the merits of both
homogeneous and heterogeneous catalysts is considered
an important goal for the design of powerful catalysts.1–5
An ideal catalyst should feature well-defined active sites,
high activity and exquisite selectivity like homogeneous
catalysts, and insoluble solid characteristics that can be
used in industrially favorable continuous flow reactors,
like conventional heterogeneous catalysts.6–8 Such a
catalyst is expected to bridge the conceptual and
technical gaps between homogenous and heterogeneous
catalysis.2
unable
to
provide
an
ideal
homogeneous
microenvironment. Although encapsulated liquid
catalysts have also been prepared with a surfactant-
stabilized emulsion method or simple sol-gel process,
these methods often lead to cracked shells or no regular
morphology due to the inherent drawbacks of this
emulsion with low stability or uncontrollable silica gel
formation.33–35 Recently, our group developed a method
for continuous flow catalysis reactions by confining
Motivated by this goal, researchers have proposed
many important concepts such as single site catalysts,
single atom catalysts and immobilized molecular
catalysts.9–18 Although significant advances in the design
of catalysts and fascinating catalytic results have been
achieved, these concepts still face key challenges. For
example, the immobilized molecular catalysts that are
prepared by anchoring or encapsulating molecular
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homogeneous catalysts within Pickering emulsion
consists of a molecular catalyst (or enzyme)-containing
droplets.36,37 Nevertheless, this system has a limited
working window since high substrate concentrations,
high temperatures or high pressures lead to droplet
coalescence, which fails to satisfactorily achieve the
combined advantages of typical heterogeneous and
homogeneous catalysis.
ionic liquid (IL) pool and a porous solid outer crust.
These types of catalyst particles are dozens of
micrometers in size and are amenable to being packed
in industrially preferred fixed-bed reactors for
continuous flow reactions, which is analogous to
conventional solid catalysts. During the reaction,
reactants pass through the porous crust and encounter
the molecular catalysts (or enzymes) hosted inside the
IL pool, where “homogeneous” reactions occur. As
exemplified by the enzymatic kinetic resolution of
alcohols, CrIII(salen)-catalyzed asymmetric ring opening
of epoxides and Pd-catalyzed Tsuji-Trost reactions, our
expectations of the superior performance of this system
not only were fulfilled successfully but also were
surpassed. Interestingly, the catalytic efficiency can be
modulated by rationally engineering liquid-solid hybrid
catalysts, which is not possible for typical homogeneous
or heterogeneous catalysts.
The above limitations urge us to seek a more ideal
system in which the “microenvironment” of
homogeneous catalysis, namely, “free” catalysts along
with the reaction medium, are trapped within a crack-
free but permeable inorganic capsule through a reliable
method. Herein, we detail an unprecedented method to
prepare solid-liquid hybrid catalysts based on a solid
particle-stabilized emulsion (Pickering emulsion). This
surfactant-free method allows us to obtain a high-
quality solid-liquid hybrid catalyst that is suitable for
continuous flow chemical and enzymatic reactions. The
proposed catalyst particle, as shown in Figure 1A,
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Figure 1. Construction of liquid-solid hybrid catalysts for bridging homogeneous and heterogeneous catalysis. (A)
Illustration of the concept of a liquid-solid hybrid catalyst and its utilization in continuous flow reactions. (B) Schematic
of the preparation procedure of a liquid-solid hybrid catalyst.
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particles with dimethyldichlorosilane. Transmission
2. RESULTS AND DISCUSSION
2
electron microscopy (TEM) images, N2 sorption
isotherms and thermogravimetric analysis (TG) are
provided in Figure S1 in the Supporting Information (SI).
The methyl loading was 0.85 mmol g-1. The air-water
contact angle of the particle surfaces was 130o, as shown
in Figure S2] As Figure 1B illustrates, the preparation
process consists of two steps: 1) emulsification to obtain
an IL-in-oil Pickering emulsion and 2) an interfacial sol-
gel process for growing a porous crust around the IL
droplets. Trimethoxysilane (TMS) or tetramethoxysilane
(TMOS) was utilized as the silica precursor because they
were found to be easily hydrolyzed under mild
conditions and are able to form a perfect crust.
Scanning electron microscopy (SEM) images reveal
that the prepared solid-liquid hybrid material comprises
discrete microspheres that are 28±12 µm with smooth,
crack-free surfaces (Figures 2a and b). The empty
structure (after the inner liquid was removed) is visible
in the SEM image of the deliberately crushed sample
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2.1. Fabrication and Characterization of the Liquid-
Solid Hybrid Capsule. We first demonstrate the
preparation of the liquid-solid hybrid capsules. We
chose ILs as the inner liquid, considering their readily
tailored structure and properties that enable dissolution
of a wide range of homogeneous catalysts, enzymes and
organic reactants.38,39 For example, [BMIM]PF6 (1-butyl-
3-methylimidazolium hexafluorophosphate) [mixed
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with
a
small amount of [BMIM]BF4 (1-butyl-3-
methylimidazolium tetrafluoroborate) and water for
growing the crust] was used as the IL phase. Solid
nanoparticles were chosen as emulsifiers to stabilize the
IL droplets in octane (the oil phase) because of the
higher stability of Pickering emulsions and more easily
tunable droplet sizes compared with surfactant-
stabilized emulsions.40–43 After screening, hydrophobic
silica nanoparticles that were 20 nm in size were found
to be good emulsifiers for this IL-oil mixture. [The
emulsifier was prepared by modifying commercial silica
Figure 2. Characterizations of the liquid-solid hybrid capsules (prepared at a shearing speed of 15000 rpm). SEM images
of (a) the capsules at low magnification, (b) a single capsule, (c) a single deliberately broken capsule revealing the hollow
interior, and (d) a cross-sectional view of the outer crust. TEM images of (e) a single capsule and (f) a segment of the
capsule crust. (g) Element mappings of C, N, F and P. (h) Nitrogen adsorption-desorption isotherms of the capsule at 77 K.
(i) BJH pore size distribution calculated from the adsorption branch of the isotherm. (j) TG curve.
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(Figure 2c). The thickness of the silica curst is
formation during the course of the interfacial sol-gel,
approximately 130 nm, as estimated from the cross-
sectional image (Figure 2d). Interestingly, two distinct
layers were observed to be present on the silica crust.
The outer layer was distributed with emulsifier particles
and was relatively spongy, while the inner layer was
compact. This indicates that the sol-gel process occurs
mainly at the inner surfaces of IL droplets. This is
because the hydrogen bonding interactions between the
hydrolyzed Si-OH and the anion of the IL at the inner
interfaces direct the condensation process to occur
around the inner surfaces of the droplets, as illustrated
in Figure 1B.44 The spherical structure of the capsules
was further confirmed by the TEM image (Figure 2e). A
higher level of detail of the microstructures becomes
visible from the magnified TEM image (Figure 2f).
Irregular pores of a few nanometers are present on the
crust. The empty capsules exhibit a type-IV N2 sorption
isotherm with a H4-type hysteresis loop, which is
characteristic of a mesoporous structure (Figure 2h).
The BET surface area is as high as 266 m2 g-1, which is
much higher than that of the silica emulsifier (120 m2 g-1).
This high surface area is attributed to the pore
and the pore size calculated by the BJH method is
centered at approximately 2-10 nm, which is in
agreement with the TEM observation (Figure 2i).
Notably, these pores were generated in the absence of
any extra templates. The pore formation may originate
from the interfacial sol-gel process in the presence of
ILs.17,44
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Elemental
mappings
revealed
homogeneous
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distributions of C, N, F and P elements throughout the
liquid-solid hybrid material, confirming the successful
encapsulation of the IL (Figure 2g). This material was
then characterized by TG analysis (Figure 2j). Below 180
oC, no weight loss was observed, indicating a good
thermal stability (without decomposition and liquid
o
evaporation). From 180 to 250 C, there was an 8.8%
weight loss, which is attributed to the condensation of
o
silanols on the silica crust. Between 250 and 450 C,
there was a major degree of weight loss up to 83.5%,
which is caused by the decomposition of IL. This weight
loss is broadly consistent with the elemental analysis
results (88.2%). Such a high loading of IL is virtually
unattainable for the existing supported liquid phase
Figure 3. Fluorescence microscopy as a function of time for the diffusion of probe molecules into/out of liquid-solid
hybrid capsules with different crust thicknesses. (a)–(c) SEM images showing the cross-sections of silica crusts and series
of time-dependent confocal fluorescence microscopy images showing the diffusion of Nile Red (2.5 µM) into the capsules.
The crusts were prepared with different TMS amounts, (a) 0.04 g, (b) 0.08 g, (c) 0.12 g, which correspond to average
thicknesses of 80, 130 and 210 nm, respectively. Scale bar = 100 nm. (d) Fluorescence intensity as a function of time for the
diffusion of Nile Red into hybrid capsules. (e) Fluorescence intensity as a function of time for the diffusion of FITC-I out
of the hybrid capsules.
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method.30,45,46 To our knowledge, this is the first
materials was recorded upon addition of a small aliquot
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production of a crack-free IL-containing capsule. The
key to this success is the utilization of unique interfaces
and high stability of Pickering emulsions.
of Nile Red-containing solution (Figures 3a-c). For
instance, upon contacting the capsule with 80 nm of
crust thickness, the fluorescent molecules (initially
present outside the hybrid capsule) began to pass
through the silica crust and enter the inner IL pool.
After only 0.5 min, fluorescent signals were clearly
observed inside the IL pool. During the following 3.0-
15.0 min, the fluorescent intensity increased gradually as
more fluorescent molecules were present in the IL pool
(Figure 3d). Meanwhile, to visualize the molecular
transport out from the hybrid material, a separate
fluorescent experiment was conducted. A fluorescent
probe FITC-I was first encapsulated within the hybrid
capsule during the preparation (see SI). When the FITC-
I-containing hybrid material was dispersed in ethanol
(Figures 3e and S7), the fluorescent intensity in the
interior IL pool was observed to decline with time,
suggesting that the probe molecules diffused out of the
capsules. After 4 min, the fluorescent intensity in the IL
pool had nearly stabilized. These findings confirm that
the outer crust of the material has a good ability to
exchange molecules with the surrounding medium.
To determine the impact of the curst thickness on the
molecular exchanges, we examined two other hybrid
materials with increased crust thicknesses of 130 and 210
nm. The results (Figures 3b-e and S7) showed that the
rate of molecular exchanges was correlated with the
curst thickness. As the curst thickness increased, the
rate decreased due to the increased tortuosity and
longer diffusion pathways. This finding can further
guide the design of hybrid catalysts with controllable
permeability.
2.2. Tuning of the Capsule Size and Crust
Thickness. We tuned the capsule size and crust
thickness by modifying the synthesis protocol. It is well
documented that a higher stirring speed applied during
emulsification leads to smaller droplets.47 When stirring
at 5000 rpm, the resultant hybrid capsule was 55±15 µm
in size (Figures S3 and S4). When a stirring speed of
15000 rpm was applied, the hybrid capsule size
decreased to 28±12 µm. Still, a higher stirring speed of
20000 rpm led to even smaller capsules (16±7 µm).
Interestingly, for each sample, the final capsule size was
almost the same as its “mother” droplet size, indicating
template effects. Moreover, the crust thickness can also
be tailored by varying the TMS amount. As Figure S5
shows, upon increasing the amount of TMS from 0.04 to
0.08 and then further to 0.12 g, although the hybrid
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capsules had
a similar morphology and particle
diameter, the crust thickness remarkably increased from
80 to 130 and then to 210 nm (see the first panels of
Figures 3a-c for their textural parameters and see N2
sorption characterization in Figure S6). As these results
confirmed, our strategy allows the dimensions of the IL
pool and the crust thickness to be adjusted in a
controlled way.
2.3. Permeability of the Capsules. Fluorescent
probes were employed to evaluate the permeability of
the hybrid material. A time-dependent fluorescence
confocal microscopy (CLSM) image of the hybrid
Figure 4. Flow behavior and stability of the liquid-solid hybrid capsules in a column reactor. (a) The flow rate of the
mobile phase as a function of time under 1.0 MPa with the inset showing the appearance of the hybrid capsule materials
before and after 72 h of continuous flow. (b) and (c) SEM images of the liquid-solid hybrid capsules after 72 h of
continuous flow, scale bar = 20 µm for b and 2 µm for c. (d) Microscopic image of the capsules after thermal treatment at
120 oC for 5 h, scale bar = 100 µm. (e) Microscopic image of the capsules after stirring in methanol (30 min), scale bar = 30
µm.
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2.5. Kinetic Resolution of Alcohols in the
2.4. Mechanical Strength. To examine the
mechanical stability, the liquid-solid hybrid material
was packed in a fixed-bed reactor. An oil phase at a high
velocity (55 mL h-1) was pumped into this reactor under
1.0 MPa. The flow velocity of the eluent from the outlet
was monitored. To our satisfaction, over a period of 72 h,
the flow velocity remained unchanged (Figure 4a). No
leakage of IL was observed, and the height of the packed
column did not alter after this treatment (Figure 4a,
inset). The capsules remained intact and maintained
their structural integrity, as evident by the SEM images
(Figures 4b and c). These experiments demonstrate that
the hybrid capsules are sufficiently mechanically robust
to withstand the flowing liquid even at relatively high
flow velocities under pressurized conditions. In contrast,
their precursor IL droplets (without growing a silica
crust) were observed to flow out from the column when
the applied pressure was above 0.3 MPa (Figure S8). The
high stability against mechanical compression is
attributed to the unique structure, where the inner IL
pool supports the silica crust when there is external
stress. Moreover, the hybrid capsules can withstand
thermal treatment and tolerate polar solvents,
significantly beyond the stability exhibited by the
Pickering emulsion droplets (Figures S9 and S10). As
Figures 4d and e show, after 5 h of thermal treatment at
Continuous Flow System. Based on the above results,
we then examined the liquid-solid hybrid catalyst in
continuous flow reactions. We first chose an enzyme to
investigate because it is highly used within the IL field
for various organic transformations.37,48 Following the
above procedure, a lipase CALB was trapped within the
capsules by adding a given amount of CALB before
formulating the Pickering emulsions. To check the
distribution of CALB within the IL pool, we labeled
CALB with a fluorescent probe, Rhodamine B. The
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fluorescence-labeled
CALB
was
homogeneously
distributed inside the IL pool, as judged from the
fluorescent signals (Figure S11). No fluorescent signals
were found outside the capsules, which is indicative of
the quantitative entrapment of CALB.
The kinetic resolution of the alcohol catalyzed by
CALB, which is an important method to produce chiral
alcohols and esters, was examined.49,50 Being micron-
sized microspheres, the CALB-containing hybrid
catalyst could be directly packed in a fixed-bed column
reactor, as anticipated. A solution of racemic 1-
phenylethyl alcohol and vinyl acetate (acylation reagent)
in octane was fed from the inlet of the reactor, and the
product-containing stream was collected on the outlet
side. Notably, the concentrations of these two reactants
of as high as 0.35 and 1.40 M were applied here. Such
high reaction concentrations are impossible in our
previously reported Pickering emulsion system since
o
120 C or treatment with methanol under stirring, the
structural integrity of the capsules was still well
preserved.
Figure 5. CALB-catalyzed kinetic resolution of the alcohols over the liquid-solid hybrid catalyst-based continuous flow
system. Pink points represent the yielded ester, blue points represent the alcohol product, and purple points represent
productivity (grams of the converted substrate per enzyme). (a) 1-Phenylethyl alcohol as the substrate. (b) SEM images of
the catalyst after 1500 h of continuous flow reaction. (c) TG curve of the catalyst after 1500 h of continuous flow reaction.
Different alcohols as the substrate: (d) 1-indanol, (e) 4-phenyl-2-butanol, (f) 4-methyl-2-pentanol. Reaction conditions:
5.0 g of liquid-solid hybrid material (CALB concentration, 0.64 mg g-1), a solution of racemic alcohol (0.35 M) and vinyl
acetate (1.40 M) in octane as the mobile phase, 45 oC, 2.3~2 mL h-1 (a) and 1 mL h-1 (d, e and f).
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concentrated polar substrates cause breakage of
flow system was calculated to be 0.11 M, whereas the km
2
droplets. The enantiomeric excesses (ee values) of the
alcohol and the produced ester are plotted as a function
of time in Figure 5a. The ee values of the two
compounds rapidly increased to 99%. Impressively,
these high ee values were well maintained over 1500 h
on stream although the flow velocity was adjusted from
the initial 2.3 mL h-1 to the final value of 2.0 mL h-1. The
results confirm the long-term stability of our liquid-
solid hybrid catalyst in the continuous flow system.
After this long period of time, the morphology and size
of the capsules were found to be virtually unchanged, as
shown in the SEM image (Figure 5b). No significant loss
of IL occurred, which was supported by the TG analysis
of the spent catalyst (Figure 5c, an IL loss of
approximately 6.3 wt% was observed compared with the
above fresh catalyst, based on the weight loss between
for the conventional biphasic system was 0.05 M.
Although different, they are still close, indicating that
the enzyme in these two systems shares a similar
microenvironment. However, the Vmax in the flow
system was 3.2×10-3 M min-1, which was 26.0-fold higher
than that in the homogeneous system (1.23×10-4 M min-1).
Additionally, the kcat in the flow system was 26.4-fold
higher than that for the homogeneous reaction. The
significant decrease in product inhibition arising from
timely and efficient removal of the product from the
flow reaction system may be one main causes of the
enhancements.
A crucial factor in realizing the efficient exchange of
molecules may be the huge reaction areas created by the
micron-sized capsules. To corroborate this, we
investigated the impact of the capsule size on the
catalysis efficiency. As shown in Figures 6 (c1 and c2),
under exactly the same conditions, the ee values of the
alcohol at the steady state differ considerably,
depending on the capsule size. As the capsule size
increased from 16±7 to 28±12 and to 55±15 µm, the ee
value of the alcohol at steady state decreased from 89 to
56 and to 16%, while the corresponding specific activity
of the enzyme decreased from 5.65 to 3.30 and to 1.01 U
mg-1. The observed specific activity as a function of the
capsule size can be explained in terms of the surface
area and diffusion distance. Increasing the capsule size
results in a decrease in the interface area and an
increase in the diffusion distance to reach the interior of
the IL pool. Moreover, the crust thickness also
influences the observed specific activity. As the crust
thickness decreased from 210 to 130 and to 80 nm, the ee
value of the alcohol at steady state significantly
increased (Figures 6, d1 and d2), and the observed
specific activity increased from 1.27 to 3.30 and finally
5.40 U mg-1. This increase is attributed to the improved
permeability resulting from the decreased tortuosity,
which is in agreement with our aforementioned
fluorescent experimental results.
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o
200-300 C). The good preservation of the IL within the
capsules should be attributed to the combination of the
confinement arising from the silica crusts and the
immiscibility of IL with the mobile oil phase. The CALB
productivity (grams of product per mg enzyme) was
found to increase linearly with time (Figure 5a). The
productivity was estimated to be as high as 83.6 g mg-1
after 1500 h. Therefore, 1 g of enzyme can resolve 83.6 kg
of racemic 1-phenylethyl alcohol, highlighting the
extremely high level of productivity.51 Moreover, for
other substrates, such as racemic 1-indanol, 4-phenyl-2-
butanol and 4-methyl-2-pentanol, the ee values of the
corresponding alcohols and esters were also maintained
at 99% over 220 h (Figures 5d, e and f), confirming the
good substrate scope.
To benchmark the catalytic activity of the hybrid
catalyst, we compared it to CALB in a batch system that
represents
a homogeneous catalysis reaction. To
determine the kinetic parameters of CALB in these two
systems, different concentrations of 1-phenylethyl
alcohol (from 0.05 to 0.5 M) were applied (Figures 6a
and S12). For the homogeneous system with 0.05 M
alcohol, the ee value of 1-phenylethyl alcohol that was
achieved after 60 min was only 6.1%. The ee value
showed no further increase after 60 min, which was
caused by the usual strong product inhibition effect.52,53
The specific activity of CALB was estimated to be 0.16 U
mg-1. In contrast, the hybrid catalyst in the continuous
flow system produced ee values of approx. 64% at the
steady state, and the specific activity was estimated to
be 2.04 U mg-1. This is a 12.8-fold enhancement
compared with the homogeneous system. Such a
striking enhancement was also observed at other
concentrations (Figure S12). Based on these results at
different concentrations, we calculated the kinetic
parameters of CALB in these two systems, including the
apparent Michaelis-Menten constant, km (affinity of
enzyme to the substrate), the maximal reaction rate,
Vmax (the reaction rate when the active sites are
saturated with substrate) and the turnover number, kcat
(see Figure S13). As displayed in Figure 6b, the km for the
Furthermore, the CALB specific activity was related
to its loading in the liquid-solid hybrid catalyst (Figures
6, e1 and e2). By varying the amount of CALB introduced,
its loading was steadily tuned upward from 0.08 to 0.64
mg g-1. Upon increasing the enzyme loading, the ee
values of the alcohol increased from 37.5% to 98.5%,
while the observed specific activities decreased from 5.51
to 1.38 U mg-1. To rationalize these results, we
established a theoretical model (more details are
included in SI). Under steady state conditions, the
amount of product C generated within an IL pool will be
the same as the amount coming out of it, namely:
C
r
C
r
(1)
4 R2DICL
 4 R2DOC
R
R
where R is the radius of the IL pool, r is the radial
distance from the center of the IL pool, C represents
DICL
DOC
are the
concentration of the product C,
and
diffusion coefficients of product C in the dispersed IL
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Figure 6. Kinetic resolution of 1-phenylethyl alcohol over the liquid-solid hybrid catalyst in continuous flow systems or
over CALB in biphasic batch systems. The specific activity (U mg-1) is expressed as µmol of substrate converted per min
per mg enzyme (i.e., µmol min-1 mg-1). The specific activity for the batch reaction was calculated over the first 20 min, and
that for the flow reaction was calculated at steady state. (a) Comparison of the continuous flow (magenta) and batch
(cyan) reactions using a concentration of 0.05 M for 1-phenylethyl alcohol. (b) Km, Vmax and kcat for CALB in the liquid-
solid hybrid catalyst-based continuous flow system and in the batch reaction system. Batch reaction conditions are
included in Figure S12. Continuous flow reactions conditions: 1.0 g liquid-solid hybrid catalyst (CALB loading, 0.16 mg g-1),
1-phenylethyl alcohol (0.05, 0.10, 0.30 or 0.50 M), vinyl acetate (0.2, 0.40, 1.20 and 2.00 M) in n-octane, 45 oC, 1.2 mL h-1. (c)
Comparison of the kinetic resolution of alcohols over different-sized liquid-solid hybrid catalysts (c1, alcohol ee values
with time; c2, their specific activity). The reaction conditions were the same as in b except that the mobile phase was a
solution of 1-phenylethyl alcohol (0.10 M) and vinyl acetate (0.40 M). (d) Comparison of the kinetic resolution of alcohols
over the liquid-solid hybrid catalysts with different crust thicknesses (d1, alcohol ee values with time; d2, their specific
activity). The reaction conditions were the same as in c. (e) Comparison of the kinetic resolution of the alcohols over the
liquid-solid hybrid catalysts with different enzyme loadings (e1, alcohol ee values with time; e2, their specific activity). The
reaction conditions were the same as in c. (f) Theoretical results of the enzyme activity as a function of the enzyme
loadings. (g) Illustration of the variation of reaction region  (represented by the distance from boundary to inner dashed
line) with increasing enzyme loadings.
phase and continuous oil phase, and R- and R+ refer to
points infinitely close to the internal and external IL
pool surface respectively. Then, by substituting the
results for the variation of C with r in and out of the IL
pool (see SI), the rate of the generated product per IL
pool
4 R2DICL
was
calculated
to
be
(2)
C
r

R

 8nDICL sinh(R / )  cosh(R / )


R



where n is the integration constant, the value of which
was obtained by considering the boundary conditions at
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the interface of the IL pool, at its center and far away
backward reaction in IL,
and
are the partition
C
A
from it (also see SI), and  represents a length scale of
the reaction region thickness. Then, the rate of product
generated inside an IL pool can be expressed as per
amount of enzyme contained within the same IL pool,
leading to the theoretical enzyme activity (or Tea for
short). With the appropriate value of n substituted in (2)
constants of A and C between IL and oil phases.
Specifically, as a crucial prediction of this theory,  is
K1BI0L K2
calculated to be
. It is now reasonable that
 2


DIAL
DICL
both K1 and K2 increase in proportion with Cez, whereas
(as seen from the above equation). Hence,
 1/ Cez
we arrive at:
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0

2 











although the rate of reaction is increased by addition of
more enzyme, when R >   the reaction becomes
constrained in a smaller, more confined volume inside
the IL pool. For a given reaction system, after
substituting the appropriate numerical values for
various parameters into equation (3), the enzyme
activity as a function of enzyme concentration can be
plotted, as shown in Figure 6f. The theoretical enzyme
activity significantly decreases with increased enzyme
loading and then decreases slowly at high loadings,
K1BIL
(3)
DA A0  DcC0 1

o 
o
o
o


DIAL
3DoA
R2Cez
0
o

Tea

A 
0
0
K1BIL
A K1BIL 2

2 

DoA 1
 Doc

DIAL
C DIcL






In this equation, Cez is the concentration of the enzyme,
and are diffusion coefficients of substrate A in oil
DOA
DIAL
0
0
IL
0
0
AO0 BO
CO0
A
and IL, respectively,
,
and
and
,
and
BIL CIL
are the concentrations of substrates A, B and product C
in oil at distances far from the IL pool and in the IL
phase, K1 and K2 are the rate constant of the forward and
Figure 7. The ARO reactions of different epoxides over the liquid-solid hybrid catalyst in the continuous flow system or
CrIII(salen)-based batch system. (a) Molecular structure of the CrIII(salen) catalyst and its corresponding liquid-solid
hybrid catalyst. (b) Comparison of the catalysis efficiencies in the continuous flow and batch systems using cyclopentene
oxide as a substrate. Reactions with different epoxides: (c) cyclopentene oxide, (d) cyclohexene oxide, (e) 2,3-epoxybutane,
(f) 1,2-epoxyoctane, (g) 1,2-epoxyhexane and (h) 1,2-epoxybutane. Pink points are epoxide conversions, and blue points are
ee values of azido silyl ether products. The liquid-solid hybrid catalyst consists of 4.5 g [BMIM]PF6, 1.2 g [BMIM]BF4 and
45 mg CrIII(salen). Reaction conditions: epoxide (0.04 M) and TMSN3 (0.0.044 or 0.024 M) in n-octane, room temperature,
0.6-1.2 mL h-1.
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which is consistent with the experimental results. Such
a change is understandable in terms of the diffusion-
reaction process occurring inside the IL pool. As the
ARO reactions over the hybrid catalyst can be further
extended to terminal epoxides, such as 1,2-epoxyoctane,
1,2-epoxyhexane and 1,2-epoxybutane. For these
substrates, conversions of approximately 45%, 51% and
53% were maintained over a period of 300 h (the
theoretical maximum conversions were approx. 50% for
these substrates54), and corresponding ee values were
approximately 94-96%, 93-95% and 92-95%. After
continuous running of 300 h, the conversions and
enantioselectivities showed no apparent decrease. These
results constitute additional proof for the effectiveness
of our strategy in dealing with homogeneous catalysts.
2.7. Tsuji-Trost Reactions in the Continuous Flow
System. To further examine the generality of the
concept, the palladium-catalyzed Tsuji-Trost reaction
which is often used to construct C-heteroatom bonds
was investigated.57,58 The molecular catalyst [Pd(OAc)2]
and the ligand, TPPTS [(triphenyl phosphine-3,3’,3’’-
trisulfonic acid trisodium salt)], were co-trapped within
the IL pool of the hybrid catalyst according to the above
procedure (Figure S15a). The prepared catalyst likewise
showed high activity and long-term stability in the
allylic substitution of (E)-1, 3-diphenylallyl acetate with
morpholine or piperidine as N-nucleophiles. Compared
with the batch reaction counterparts, the continuous
flow system exhibited enhanced catalysis efficiency (3.60
vs. 2.23 mol mol−1 h−1; see kinetic plots in Figure S15b).
The conversions of (E)-1, 3-diphenylallyl acetate at
steady state were more than 99% over a period of 800 h,
and the total TON reached up to 2640 mol mol−1
(Figures S15c, d). Notably, almost no Pd or TPPTS were
detected in the effluent. This may be attributed to the
strong interactions between the Pd/TPPTS and the IL
surroundings, keeping the former securely within the
capsules. These results once again consolidate the
generality and adaptability of the method proposed in
this work.
enzyme loading was increased,  became progressively
smaller (Figure 6g). Thus, only a portion of the enzymes
took part in the reaction, and the rest closer to the
center of the IL pool were idle because the slow
diffusion limits the timely supply of substrates to the
more inner parts of the IL pool. In contrast, at low
enzyme loadings,  was larger than the IL pool size. This
means all enzymes in the entire body of the pool take
part in the reactions, leading to an optimum value for
special activity. The experimental and theoretic findings
both suggest that there is still a diffusion effect
underlying the working conditions of the continuous
flow catalysis reactor, despite the homogeneous
microenvironment. Importantly, the consistency
between experimental and theoretical results implies
that the catalytic performance of the hybrid catalyst is
predictable and even rationally designed.
Taken together, as the above experimental and
theoretical results corroborated, our strategy allows the
catalysis efficiency of the hybrid catalyst to be finely
tuned via rational engineering of the dimension of the
IL droplets, the crust thickness and the enzyme loading.
These merits are inaccessible for homogeneous or
heterogeneous catalysts alone and are unachievable for
existing methods.
2.6. Asymmetric Ring Opening (ARO) of Epoxides
in the Continuous Flow System. We then checked the
applicability of our method to homogeneous molecular
catalysts. For instance, CrIII(salen)-catalyzed ARO of an
epoxide with trimethylsilyl azide (TMSN3), a typical
asymmetric reaction, was investigated.54 Using the
procedure described above, CrIII(salen) molecules were
“trapped” within the IL pool of the hybrid catalyst
(Figure 7a). In a batch reaction, a 19.7% conversion of
cyclopentene oxide was afforded within 12 h (kinetic
plots are provided in Figure S14). The catalysis efficiency
(moles of converted reactants per mole of catalyst per h)
was calculated to be 0.0865 mol mol−1 h−1 (Figure 7b). In
contrast, in the hybrid catalyst-based continuous flow
system, full conversion was achieved at steady state, and
the catalysis efficiency was 0.674 mol mol−1 h−1, which is
7.8-fold higher than that of the batch reaction.
Additionally, the greater than 99% conversion and 93%
enantioselectivity were well maintained even after a
period of 600 h (Figure 7c). The total TON was as high
as 337 mol mol−1, which has been difficult to achieve for
previously reported systems.55,56 For other epoxides, the
hybrid catalyst also worked well (Figures 7d-h).
Cyclohexene oxide was completely converted and the ee
values of the generated azido silyl ether were
maintained at 85~88% over a time of 300 h on stream.
For 2,3-epoxybutane, 66~70% conversions and 84~88%
ee values were obtained. Apart from meso-epoxides, the
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3. CONCLUSION
We successfully developed a Pickering emulsion method
to prepare a liquid-solid hybrid catalyst, which allowed
us to overcome the limitations of the existing methods
and efficiently bridge the gaps between homogeneous
and heterogeneous catalysis in an unprecedented
manner. As a hybrid homogeneous and heterogeneous
catalyst, this type of catalyst consists of a crack-free
permeable silica outer crust and an IL pool, which was
confirmed to be powerful for hosting enzymes and
homogeneous molecular catalysts. The thickness and
permeability of the crust and the dimensions of the
inner IL pool are highly tunable. Crucially, the hybrid
catalyst not only has
a
homogeneous catalytic
environment but is also amenable to continuous flow
catalysis. As exemplified by the enzymatic kinetic
resolution of alcohols, the catalysis efficiency was
improved by over an order of magnitude compared with
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continuous flow. Impressively, the catalysis efficiency
and selectivity showed no significant decrease over 1500
h. The CrIII(salen)-catalyzed asymmetric ring opening of
the epoxides and the Pd-catalyzed Tsuji-Trost allylic
substitution reaction further corroborated the versatility
and adaptability of our method in dealing with
homogeneous catalysts. Furthermore, their catalytic
performances can be regulated by rationally engineering
the catalyst structure. We believe that our method
provides a new direction for filling the gap between
homogeneous, heterogeneous and biological catalysis
and brings new opportunities for practical applications
of enzymes and homogeneous catalysts.
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ASSOCIATED CONTENT
Supporting Information
Experimental details; TEM images; Water contact angles;
Optical microscopy images; SEM images; Confocal
fluorescence microscopy images; Appearance of the
Pickering emulsions; Theoretical investigation; Equation
derivation process; Reaction kinetics monitoring; MS
and NMR data for products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*hqyang@sxu.edu.cn
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the Natural Science
Foundation of China (21733009, 21603128, 21573136, and
U1510105) and the Program for Youth Sanjin Scholar.
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