Heterogeneous Metal–Organic-Framework-Based Biohybrid Catalysts for Cascade Reactions in Organic Solvent

Article abstract of DOI:10.1002/chem.201805680

In cooperative catalysis, the combination of chemo- and biocatalysts to perform one-pot reactions is a powerful tool for the improvement of chemical synthesis. Herein, UiO-66-NH₂ was employed to stepwise immobilize Pd nanoparticles (NPs) and Candida antarctica lipase B (CalB) for the fabrication of biohybrid catalysts for cascade reactions. Distinct from traditional materials, UiO-66-NH₂ has a robust but tunable structure that can be utilized with a ligand exchange approach to adjust its hydrophobicity, resulting in excellent catalyst dispersity in diverse reaction media. These attractive properties contribute to the formation of MOF-based biohybrid catalysts with high activity and selectivity in the synthesis of benzyl hexanoate from benzaldehyde and ethyl hexanoate. With this proof-of-concept, we reasonably expect that future tailor-made MOFs can combine other catalysts, ranging from chemical to biological catalysts for applications in industry.

Full text of DOI:10.1002/chem.201805680

A Journal of
Accepted Article
Title: Heterogeneous metal-organic frameworks-based biohybrid
catalysts for cascade reaction in organic solvent
Authors: Yangxin Wang, Ningning Zhang, En Zhang, Yunhu Han,
Zhenhui Qi, Marion Ansorge-Schumacher, Yan Ge, and
Changzhu Wu
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To be cited as: Chem. Eur. J. 10.1002/chem.201805680
Link to VoR: http://dx.doi.org/10.1002/chem.201805680
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Heterogeneous metal-organic frameworks-based biohybrid
catalysts for cascade reaction in organic solvent
Yangxin Wang,[a, b] Ningning Zhang,[b] En Zhang,[c] Yunhu Han,[d] Zhenhui Qi,*[a] Marion B. Ansorge-
Schumacher,*[b] Yan Ge,*[a] and Changzhu Wu*[e]
Abstract: In cooperative catalysis, the combination of chemo- and
biocatalysts to perform one-pot synthetic route is a powerful tool for
the improvement of chemical synthesis. Herein, UiO-66-NH2 was
employed to stepwise immobilize Pd nanoparticles (NPs) and
Candida antarctica lipase B (CalB) for the fabrication of biohybrid
catalysts for cascade reaction. Distinct from traditional materials, UiO-
66-NH2 has a robust but tunable structure which can be utilized with
a ligand exchange approach to adjust its hydrophobicity, resulting in
excellent catalyst dispersity in diverse reaction media. These
attractive properties eventually contribute the MOF-based biohybrid
catalysts with high activity and selectivity in the synthesis of benzyl
hexanoate from benzaldehyde and ethyl hexanoate. With this proof-
of-concept, we reasonably expect that future tailor-made MOFs can
combine more other catalysts, ranging from chemical to biological
catalysts for perspective applications in industry.
in protein cages for the efficient CO2 fixation.[3] This intriguing
nature design has initiated great efforts in bioinspired synthetic
chemistry.[4]
In this context, considerable progress has been made to mimic
biohybrid structure for remarkable cascade catalysis. These
include DNA-hybrid catalysts,[5] protein-based compartments,[6]
liposomes,[7] artificial metalloenzymes,[8] and polymer-based
capsules,[9] which have been extensively reviewed in the
literature.[10] Most of these catalysts are fabricated by
simultaneous or stepwise enzyme(s) loading into self-assembled
capsules that are typically water-soluble and mechanically soft.
Accordingly, they act as flexible cell-mimics in water, producing
system-level essential bioproducts from cascade reactions.[9d]
However, these “soft” biohybrid capsules are often limited by their
mechanic vulnerability, encountering difficulties in catalyst
recycling and process operation. Moreover, they are typically
solvent-incompatible,
thus
are
unable
to
proceed
Nature has evolved to create biohybrid catalysts, through the
integration of biocatalysts into biological scaffolds, to proceed
cooperative biotransformation in cellular machinery.[1] The value
of scaffolds is to provide spatial restriction and close confinement
around catalysts, which facilitates cascade bioreactions in a
cooperative and efficient fashion while minimizing the
decomposition of active intermediates.[2] An example of such
cooperativity is carboxysomes, which harbor two distinct enzymes
biotransformation where nonpolar substances are used. These
limitations present a great challenge to bring “soft” biohybrid
catalysts into industry.
To face the challenge, using mechanically robust scaffolds
becomes an alternative choice for biohybrid catalysts. In a
pioneering study, the Bäckvall group has promoted “hard”
biohybrid catalysts by embedding enzymes and metal
nanoparticles (NPs) into mesoporous silica.[11] This design allows
two active species to cooperatively catalyze dynamic kinetic
resolution in a solid matrix, which behaves similarly to the
cooperativity in these “soft” cell-mimics (e.g., liposomes). The
difference, however, is the use of solid carriers that facilitates
catalyst reuse while allowing to be performed in various reactions
media, including water, organic solvents, and even aqueous-
organic two-phase.[12] To date, a variety of solid particles have
been utilized for the fabrication of biohybrid catalysts, ranging
from silica[13] to reduced graphene oxide[14] and polymeric
matrix[15]. Despite this, unlike soft matters, these solid supports
only act as inert and “hard” carriers that have physically fixed
structure, thus lack of structure flexibility and tunability which are
crucial factors to the regulation of catalytic performances.
Therefore, up to now, a fundamental gap between robustness and
tunability remains when designing applicable biohybrid catalysts.
To fill this gap, we herein report for the first time metal-organic
frameworks (MOFs)-based biohybrid catalysts where metal
catalysts (Pd NPs) and biocatalysts (Candida antarctica lipase B)
are respectively immobilized in distinct compartments for cascade
[a]
[b]
Dr. Y. Wang, Associate Prof. Y. Ge, Prof. Z. Qi
Sino-German Joint Research Lab for Space Biomaterials and
Translational Technology, School of Life Sciences
Northwestern Polytechnical University
127 Youyi Xilu, Xi’an, Shaanxi 710072, P. R. China
E-mail: ge@nwup.edu.cn; qi@nwpu.edu.cn
Dr. Y. Wang, N. Zhang, Prof. M. B. Ansorge-Schumacher
Institute of Microbiology
Technische Universität Dresden
Zellescher Weg 20b, 01217 Dresden, Germany
E-mail: marion.ansorge@tu-dresden.de
E. Zhang
[c]
[d]
[e]
Department of Chemistry
Technische Universität Dresden
Bergstraβe 66, 01062 Dresden, Germany
Y. Han
Department of Chemistry
Tsinghua University
Beijing 100084, China
Prof. C. Wu
Danish Institute for Advanced Study (DIAS) and Department of
Physics, Chemistry and Pharmacy
University of Southern Denmark
5230 Odense, Denmark
catalysis. As
a coordination network, MOFs represent a
fascinating platform whose structure, porosity and functionality
can be finely tuned by judicious design of metal nodes and
organic linkers[16] or through post-synthetic methods.[17] MOFs
have shown great potential in the field of both chemocatalysis[18]
E-mail: wu@sdu.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.2018xxxxx.
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19]
and biocatalysis.[16d,
Incorporating two catalysts into MOFs,
NPs and CalB in/on hydrophobized MOFs is depicted in Scheme
1. To tune the hydrophobicity of Pd@UiO, lauric acid was applied
for ligand exchange in DMF solution, obtaining products
Pd@UiO-LA20 and Pd@UiO-LA50, during which 20 and 50 mM
lauric acid were used, respectively. After ligand change, water
contact angle of Pd@UiO increased from 16.3 ± 2.2 o to 26.9 ±
2.3 o (Pd@UiO-LA20) and 133.5 ± 1.4 o (Pd@UiO-LA50) (Figure.
1a). This hydrophobicity upsurge suggests that the surface
composition of Pd@UiO has been finely tuned. The ligand
exchange was further confirmed by analyzing components
released from Pd@UiO, Pd@UiO-LA20, and Pd@UiO-LA50 with
gas chromatography coupling with mass spectrometry (GC/MS)
(Figure. S2). The molecular ion peak at m/z = 200 clearly supports
the existence of lauric acid in Pd@UiO-LA20 and Pd@UiO-LA50,
but not in Pd@UiO. In order to quantify the respective content of
ligands in the MOF-based materials after ligand exchange, the
MOF-based materials were digested in deuterium DMSO
containing hydrofluoric acid, and then characterized with 1H NMR.
As shown in Figure S3, peaks from benzoic acid and 2-
aminoterephthalic acid are observed in the spectra of digested
pristine UiO-66-NH2 and Pd@UiO, and peaks from lauric acid
appears in the spectra of digested Pd@UiO-LA20 and Pd@UiO-
LA50, which again confirms the successful ligand exchange.
There are also some unidentified peaks observed in the aromatic
region in all the spectra of digested MOF-based materials. These
peaks are presumably derived from the 2-aminoterephthalic
acid.[28] Nevertheless, the molar ratio of lauric acid to benzoic acid
in Pd@UiO-LA20 and Pd@UiO-LA50 can be estimated from their
peak areas, which is about 0.69 and 0.92, respectively.
therefore, provides the biohybrid with sufficient robustness for
catalyst recycling, and tunable porous structure for substance
diffusion.[20] As is known, Pd NPs have been widely used as
catalyst in different types of reactions, such as reduction,
oxidation, racemization, and coupling reactions.[21] While CalB is
a well-known and easily available lipase which can efficiently
catalyze esterification, hydrolysis, and transesterification
reactions in a mild manner.[19m, 22] Therefore, various cascade
reactions can be achieved through the cooperative application of
Pd NPs and CalB. However, mutual inactivation of chemo- and
biocatalysts was regularly found in metal-containing biohybrid
catalysts, which inhibits their catalytic performances. In this
context, precise synthesis with MOFs as supporting carrier would
allow the chemo- and biocatalysts compartmentalized in different
locations, avoiding their mutual inactivation. The tiny Pd NPs will
be stabilized in the inner pores of MOFs, while CalB will be
immobilized on the surface of MOFs because of its larger sizes
(6.9 nm × 5.0 nm × 8.7 nm).[23] Moreover, with a ligand exchange
method, the surface hydrophobicity of MOFs catalysts can be
tailor-made to adapt to many reaction media of interests.
Therefore, we have proved the concept that a robust and tunable
MOFs platform can be developed to compartmentalize diverse
catalysts for the efficient cascade biotransformation.
To prepare biohybrid catalysts for cascade reactions, CalB was
physically adsorbed onto Pd@UiO, Pd@UiO-LA20, and
Pd@UiO-LA50, obtaining biohybrid catalysts, CalB-Pd@UiO,
CalB-Pd@UiO-LA20, and Cal-Pd@UiO-LA50, respectively. This
preparation allows to spatially separate Pd NPs in MOFs from
enzymes on the surface, thus benefiting by circumventing
possible mutual inactivation that often occurs between chemo-
and biocatalysts.[29] Bradford assay disclosed that CalB loaded
onto CalB-Pd@UiO, CalB-Pd@UiO-LA20, and CalB-Pd@UiO-
LA50 was 7.2, 16.8, and 12.1 mg g-1, respectively (Figure. S4).
No measurable amount of CalB from all these MOF-based
catalysts was detected in leaching test, suggesting that the
protein is strongly attached to the carriers (details in item 1.8,
supporting information). CalB-Pd@UiO-LA50 shows the
remarkable capability to disperse in different organic solvents of
a wide range of polarity (Figure. S5), implying that this MOF-
based biohybrid catalyst could be applied in various reaction
media of interests, which is an important achievement with
respect to reaction media engineering. We examined the changes
of zeta potential (ζ-potential) of MOF-based catalysts in the
presence of different concentrations of CalB (Figure 1b). When
there is no CalB, ζ-potential of Pd@UiO, Pd@UiO-LA20, and
Pd@UiO-LA50 is 19.5±0.9, 13.8±0.6, and 12.9±0.3 mV,
respectively. With the increasing concentration of CalB in solution,
ζ-potential gradually decreases because the positive charge is
neutralized by the negative charge of CalB. When the
concentration of CalB reaches above 15.8 μg mL-1, ζ-potential
approaches to an equilibrium plateau. These results suggests that
coulombic forces should play an important role in the
immobilization of CalB, which corroborates well with the findings
Scheme 1. Schematic illustration of the synthesis of CalB-Pd@UiO-LA20 and
CalB-Pd@UiO-LA50.
In this work, UiO-66-NH2 was chosen as “hard” scaffold owing
to its high stability and ready post-functionality.[24] Excess benzoic
acid was added during preparing UiO-66-NH2 following reported
protocol,[25] because it could not only lead to MOFs with small
sizes,[26] but also offer the opportunities for post-modification
through ligand exchange.[27] Initially, the as-synthesized UiO-66-
NH2 was employed for ligand exchange. The reaction was
performed in DMF solution of lauric acid (50 mM), and the product
was denoted as UiO-LA50. As shown in Figure S1, water contact
angle of UiO-LA50 is 112.2 ± 1.6 o, which is much larger than that
of the pristine UiO-66-NH2, indicating the success of ligand
exchange. But considering that the ligand exchange has an
influence on the surface property of MOF materials, it may further
influence the amount of subsequently immobilized Pd NPs, herein,
for the convenience of comparing the catalytic performances of
the biohybrid catalysts, Pd NPs were immobilized on MOFs
before the ligand exchange. The procedure of immobilizing Pd
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by Hupp and colleagues.[30] Meanwhile, the hydrophobicity of the
MOF materials also has an impact on the immobilization of CalB,
as hydrophobic interactions between carriers and enzymes are
regarded as
immobilization.[31] Elemental analysis and inductively coupled
plasma atomic emission spectroscopy (ICP-AES)
a convenient and effective way for enzyme
characterization were perform to analyze the chemical
components of the MOF-based materials, and the results are
summarized in Table S2. Pd content in CalB-Pd@UiO, CalB-
Pd@UiO-LA20, and Cal-Pd@UiO-LA50 was determined to be
28.7, 26.6, and 23.4 mg g-1, respectively. The slight variation of
Pd content may be caused by the trapped guest molecules, ligand
exchange process and enzyme immobilization.
Figure 2. (a) SEM image of CalB-Pd@UiO-LA50; (b) TEM image of CalB-
Pd@UiO-LA50 (inset: particle size distribution of Pd NPs).
To ascertain the details of chemical state of Pd NPs, X-ray
photoelectron spectroscopy (XPS) measurements were carried
out. As shown in Figure S13, the Pd 3d region is divided into two
spin-orbital pairs, indicating the presence of two types of surface-
bound palladium species. The binding energy peaks at 341.5 (Pd
3d5/2) and 336.0 (Pd 3d3/2) are ascribed from Pd(0) species, while
the peaks at 343.4 (Pd 3d5/2) and 337.8 (Pd 3d3/2) are assigned to
Pd(II) species. The ratio of Pd(0)/Pd(II) in Pd@UiO is 1.18,
estimated from corresponding peak areas. However, it decreases
to 0.47 and 0.30 in Pd@UiO-LA20 and Pd@UiO-LA50,
respectively. The Pd(II) species may be derived from the
reoxidation of Pd(0) during the air contact.[33] The similar tendency
was also observed that the ratio of Pd(0)/Pd(II) in CalB-Pd@UiO-
20 and CalB-Pd@UiO-LA50 is 0.34 and 0.46, respectively, while
the value is 1.05 in CalB-Pd@UiO.
Figure 1. (a) Water contact angle images of Pd@UiO, Pd@UiO-LA20, and
Pd@UiO-LA50; (b) Zeta potential of Pd@UiO, Pd@UiO-LA20, and Pd@UiO-
LA50 in the presence of CalB at 25 oC.
To visually prove the proteins were adsorbed on the surface of
MOFs, CalB was labeled with fluorescein isothiocyanate (FITC),
and subjected to the same procedure for preparing CalB-
Pd@UiO-LA50. Optical and fluorescence microscopic images
reveal that fluorescent CalB readily resided on MOFs after the
immobilization (Figure 3). Pd@UiO-LA50 was also incubated in a
solution of FITC, which only shows almost invisible fluorescence
after washed, excluding the possible influence of FITC on the
adsorption behavior of labeled CalB (Figure S14). Interestingly, in
addition to CalB, other functional proteins like green fluorescent
protein (GFP) and FITC-labelled glucose oxidase (GOD) could be
also adsorbed onto Pd@UiO-LA50 using the same method. We
notice that the isoelectric points (pI) of GFP (pI = 5.8), GOD (pI =
4.3) and CalB (pI = 5.0) are all negatively charged in neutral pH
condition, indicating that it is a relatively general phenomenon for
Pd@UiO-LA50 to adsorb negatively charged proteins. Therefore,
the successful immobilization of three distinct proteins indicates
that MOFs can be developed into a versatile tool for constructing
biohybrid catalysts from different biocatalyst sources.
Benzyl alcohol is an important precursor for synthesis of esters
in cosmetics and flavouring industries, and is also generally used
as solvent for inks and paints.[34] Reducing benzaldehyde with
molecular hydrogen involving Pd catalyst has turned out to be a
desirable way to produce benzyl alcohol due to its high efficiency,
minimum side reactions and environmental friendliness.[35]
Bearing this in mind, the catalytic performance of Pd@UiO,
Pd@UiO-LA20, and Pd@UiO-LA50 without CalB was initially
evaluated through the hydrogenation of benzaldehyde in toluene
at room temperature. As shown in Figure S15, when the reaction
was performed with 0.05 mmol benzaldehyde and 20 mg solid
catalyst in toluene, the turnover frequency (TOF) was 28.7, 16.3,
Thermogravimetric analysis (TGA), powder X-ray diffraction
(PXRD) and Fourier transform infrared spectroscopy (FTIR)
analysis were carried out, and the results show that the thermal
stability, crystallinity and characteristic vibration peaks of pristine
UiO-66-NH2 are well conserved after loading Pd NPs, ligand
change and immobilizing CalB (Figure S6, S7, and S8). Based on
N2 adsorption/desorption measurements, the total amount of
adsorbed N2, pore volume and Brunauer-Emmett-Teller (BET)
surface areas all decrease slightly after immobilizing CalB (Figure
S9 and Table S1). The decrease suggests the presence of
proteins on MOFs surface, probably blocking a small portion of
their porous cavities. According to the pore size distribution
curves, the pore diameter of all the MOF-based materials is
smaller than 5 nm, which proves that CalB (6.9 nm × 5.0 nm × 8.7
nm) should be immobilized on the surface of the MOFs.
Scanning electron microscope (SEM) images display that all
MOF-based samples are composed of tiny particles with an
average diameter of about 100 nm (Figure 2a and S10). These
nanoscale particle sizes are beneficial for reducing mass-transfer
limitations compared to micron-sized particles. Pd NPs in CalB-
Pd@UiO, CalB-Pd@UiO-LA20, and CalB-Pd@UiO-LA50 are
clearly observed in transmission electron microscope (TEM)
images (Figure 2b and S11). The average diameter of Pd NPs is
3.41±0.49 nm, which is similar to the previously reported Pd NPs
supported in MOF materials.[32] High-angle annular dark-field
scanning transmission electron microscopy (HAADF-STEM) and
elemental mapping images demonstrate the homogeneous
distribution of Pd elements throughout the supports without
obvious aggregation (Figure S12).
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and 14.8 h-1 for Pd@UiO, Pd@UiO-LA20, and Pd@UiO-LA50,
respectively. It was found that the TOF decreased with the
increment of hydrophobicity of catalysts. This is probably due to
that the reduction reaction is prohibited by the lipophilic
environment in hydrophobized MOF-based catalysts.[27b]
observed as a product when Pd@UiO-LA50 was used, and not
any product was observed when CalB@UiO-LA50 was applied,
illustrating the necessity of cooperation of Pd NPs and CalB for
this cascade reaction (Figure S16). Moreover, physically mixed
Pd@UiO-LA50 and free CalB was also employed to catalyze the
cascade reaction. As shown in Figure S17, the yield of final
product benzyl hexanoate is lower than that catalyzed by CalB-
Pd@UiO-LA50, possibly due to the aggregation of free CalB in
toluene, indicating the superiority of immobilizing enzyme on the
MOFs. Another important advantage of the enzyme
immobilization is the reusability, since free CalB is difficult to
recover from the reaction mixture. As solid heterogeneous
catalyst, reusability of CalB-Pd@UiO-LA50 was investigated.
After used for three times, the yield of benzyl hexanoate was still
maintained about 80% compared with that of the first run (Figure
S18). Leaching test after the first run showed that the leaching Pd
into reaction solution was only 1.08% out of the original CalB-
Pd@UiO-LA50, while no obvious leaching of CalB was observed
based on Bradford test. Structural stability of our MOF-based
catalyst was further confirmed from the unchanged FTIR
spectrum of reused CalB-Pd@UiO-LA50 (Figure S19). TEM
image shows that the average diameter of Pd NPs in CalB-
Pd@UiO-LA50 after used for 4 times increased slightly to
4.92±1.44 nm, but no obvious aggregation of NPs was observed
(Figure S20). Therefore, it is deduced that the enzyme
deactivation should be mainly accounted for the degradation of
catalytic performance during reuse. To confirm this, CalB-
Pd@UiO-LA50 after used for four times in cascade reactions was
applied to catalyze the transesterification reaction between benzyl
alcohol and ethyl hexanoate. As shown in Figure S21, the activity
of reused CalB-Pd@UiO-LA50 is much lower than that of fresh
one, indicating the denaturation of CalB during the cascade
reactions.
Figure 3. (a) Schematic shows that diverse proteins/enzymes could be
immobilized on the Pd@UiO-LA50. Optical (top) and fluorescence (bottom)
microscopic images of Pd@UiO-LA50 after adsorbing (b) FITC labeled CalB,
(c) GFP, and (d) FITC labeled GOD.
To demonstrate the merit of our MOF-based biohybrid catalysts,
a one-pot, two-step cascade reaction transferring benzaldehyde
into benzyl hexanoate was then chosen as a model reaction
(Figure 4a). Benzaldehyde was first reduced by molecular
hydrogen catalysed by Pd NPs into benzyl alcohol, which then
reacted with ethyl hexanoate catalysed by CalB to produce benzyl
hexanoate. This strategy offers an expedient route to prepare
esters for cosmetics or flavouring in one pot directly from
benzaldehyde in a mild manner. The reaction was performed in
toluene because lipophilic solution is favourable for
transesterification reaction. The curves of time-dependent yield of
benzyl hexanoate catalysed by different catalysts are given in
Figure 4b. When using CalB-Pd@UiO-LA50, an excellent yield of
92% of benzyl hexanoate was achieved in 6 h, and a 100% yield
was obtained when reaction time was prolonged to 8 h. While the
yield was only about 76% when either CalB-Pd@UiO or CalB-
Pd@UiO-LA20 was used at 8 h, respectively. By taking a close
look at the reaction, the yield of benzyl hexanoate for CalB-
Pd@UiO, CalB-Pd@UiO-LA20, and CalB-Pd@UiO-LA50 at initial
2 h is 17%, 22%, and 52%, respectively. In this regard, CalB-
Pd@UiO-LA50 obviously exhibits higher catalytic efficiency than
CalB-Pd@UiO and CalB-Pd@UiO-LA20. Considering the almost
same catalyst loading, the increased catalytic efficiency in CalB-
Pd@UiO-LA50 than others should be due to its improved
dispersibility in solvent. Accordingly, this proves the concept that
the tunability of MOFs structure can be utilized for efficient
catalysis. In control experiments, hydrophobized MOFs without
loading CalB (Pd@UiO-LA50) or Pd NPs (CalB@UiO-LA50,
details in item 1.6, supporting information) were also employed as
catalysts for the same reaction. However, only benzyl alcohol was
Figure 4. (a) one-pot cascade reaction to produce benzyl hexanoate from
benzaldehyde and ethyl hexanoate; (b) Time-dependent yield of benzyl
hexanoate catalysed by different biohybrid catalysts; (c) Yield of benzyl
hexanoate catalysed by different biohybrid catalysts at 2 h.
In summary, we describe for the first time the use of MOFs as
robust and tunable scaffolds for the construction of biohybrid
catalysts, in which Pd NPs and CalB were stepwise immobilized
in/on different compartments. The carrier in use, UiO-66-NH2, is
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Keywords: heterogeneous catalysis• metal-organic frameworks
(MOFs) • enzyme immobilization • cascade reactions • Pd
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Yangxin Wang, Ningning Zhang, En
Zhang, Yunhu Han, Zhenhui Qi,*
Marion B. Ansorge-Schumacher,* Yan
Ge,* Changzhu Wu*
Page No. – Page No.
Heterogeneous metal-organic
frameworks-based biohybrid
catalysts for cascade reaction in
organic solvent
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