Dynamic kinetic resolution of amines by using palladium nanoparticles confined inside the cages of amine-modified MIL-101 and lipase

Article abstract of DOI:10.1016/j.jcat.2018.04.006

Dynamic kinetic resolution (DKR) of amines is an important strategy for the synthesis of chiral drugs and their building blocks; however, improving the matchability of metal-catalyzed racemization and enzymatic resolution is still a task. In this paper, P

Full text of DOI:10.1016/j.jcat.2018.04.006

Journal of Catalysis 363 (2018) 9–17
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Dynamic kinetic resolution of amines by using palladium nanoparticles
confined inside the cages of amine-modified MIL-101 and lipase
⇑
Sen Xu, Meng Wang, Bo Feng, Xinchen Han, Zijie Lan, Huajun Gu, Hexing Li, Hui Li
The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Dynamic kinetic resolution (DKR) of amines is an important strategy for the synthesis of chiral drugs and
their building blocks; however, improving the matchability of metal-catalyzed racemization and enzy-
matic resolution is still a task. In this paper, Pd nanoparticles (NPs) were encapsulated inside the cages
of ethylenediamine-grafted MIL-101 (ED-MIL-101), giving highly efficient catalysts (Pd/ED-MIL-101)
for the racemization of primary amines. The racemization can be combined with lipase-catalyzed resolu-
tion in a one-pot DKR of rac-1-phenylethylamine leading to optically pure product (>99% ee value) with
an excellent conversion and selectivity up to 99% and 93%, respectively, superior to other catalysts, such
as Pd/MIL-101, Pd/MCM-41 and commercially available Pd/C. Furthermore, the heterogeneous chemoen-
zymatic catalyst combination can be recovered and recycled 8 times without significant loss of efficiency.
The enhance catalytic performances were found to depend on the amine modification of MIL-101 that not
only endows the surface of its cages with basic property, but also enables efficiently confining Pd NPs in
the cages. In addition, the matchability of such chemoenzymatic catalyst combination can be further
enhanced by conducting the DKR process under microwave irradiation.
Received 28 February 2018
Revised 31 March 2018
Accepted 3 April 2018
Keywords:
Dynamic kinetic resolution
Chiral amine
Palladium
Lipase
MOFs
Ó 2018 Elsevier Inc. All rights reserved.
1. Introduction
tions, resulting in the rate-determining racemization step in one-
pot DKR process. To ensure the matchability of the racemization
There is an ever increasing requirement for chiral amines, pri-
marily for use as pharmaceuticals, but also for use as important
key intermediates in fine chemical and agrochemical industries
[1]. Despite great achievements in catalytic asymmetric synthetic
transformations [2–4], kinetic resolution (KR) of racemic starting
materials is still the most common approach to obtaining enan-
tiomerically pure amines in industrials [5]. The enzyme-aided KR
is one of the most widely utilized methods for the synthesis of chi-
ral amines [6]. However, the resolution process is generally limited
to a maximum yield of 50%. The combination of KR and in situ
racemization of the remaining enantiomer results in a dynamic
kinetic resolution (DKR) process (Scheme 1), which is an option
to tackle this problem. This modification increases the theoretical
yield to 100% of a single enantiomer starting from a racemic mix-
ture [7–11]. Furthermore, one-pot DKR that combining of racem-
ization catalyst and enzyme into a single reaction vessel usually
increases the profitability and efficiency of the process by reducing
costs, time, as well as labor efforts [12]. In general, racemization of
amines is difficult to achieve and requires harsh reaction condi-
reaction with the enzyme-aided KR, a sufficiently high racemiza-
tion rate is demanded for the continuous feed of the faster-
reacting enantiomer to the enzyme catalyst. Several racemization
methods have been developed using basic catalysts, enzymes, or
transition-metal catalysts [13]. The former two kinds of racemiza-
tion are relatively infrequent and thus, not applied in DKR process.
In the development of one-pot DKR processes for amines, homoge-
neous Shvo-type ruthenium complexes played a key role. The most
efficient DKR applications utilizing homogenous Ru-based racem-
ization catalysts have been pioneered by the group of Bäckvall
[14,15]. However, homogeneous transition-metal catalysis also
presents a number of drawbacks, particularly including the cata-
lyst reusability and the environmental pollution from heavy metal-
lic ions [16,17]. The development of heterogeneous racemization
catalysis system with high efficiency is preferred due to the easier
work-up protocols, simple product isolation, as well as catalyst
recycling [18]. The first example of heterogeneous DKR of amine
was reported by Reetz and Schimossek using Pd/C for the racem-
ization and lipase (CALB, NovozymÒ 435) for the enzymatic resolu-
tion [19]. This combination required long reaction time (8 days) to
provide excellent ee value (99%) and moderate yield (75–77%) in
the one-pot DKR of 1-phenylethylamine. Generally, the activity
⇑
Corresponding author.
E-mail address: lihui@shnu.edu.cn (H. Li).
https://doi.org/10.1016/j.jcat.2018.04.006
0021-9517/Ó 2018 Elsevier Inc. All rights reserved.

10
S. Xu et al. / Journal of Catalysis 363 (2018) 9–17
Scheme 1. DKR of rac-amine.
of Pd is primarily determined by its dispersion, thus the synthesis
of Pd nanoparticles (NPs) on a few nanometer scale is of great
important. Kim et al. [20] reported an improved process using a
modified lipase-Pd combination, in which Pd NPs in the range of
2–3 nm entrapped in aluminum hydroxide [21], Pd/AlO(OH), was
employed as the racemization catalyst. The racemization of (S)-1-
phenylethylamine by Pd/AlO(OH) proceeded much more rapidly
compared to the commercially available Pd/Al2O3, most likely
because of the high dispersion of the metallic Pd active sites. The
one-pot DKR of 1-phenylethylamine was done by the combination
of Pd/AlO(OH) and CALB in the presence of molecular sieves, giving
a good yield (92%) and a high optical purity (98% ee) at shorter
reaction time (3 days) [20]. Jacobs [22] and De Vos [23] utilized
Pd/BaSO4 in combination with CALB for the DKR of 1-
phenylethylamine, obtaining good conversion (91%) and selectivity
(94%) with high ee value (99%) of the acetylated amine product
within a more shorter reaction time (24 h). Another important
aspect of one-pot DKR of amines is the control of selectivity
towards the target products. Jacobs and De Vos found the main
byproducts in amine racemization to be a result of competing con-
densation reactions to secondary amine and its subsequent
hydrogenolysis to ethylbenzene (EB) (Scheme 2) [22,23]. Such side
product formation could be strongly suppressed when alkaline
earth salts were used as supports for Pd [22,23]. In their next work,
Pd on amine-functionalized silica proved to be more selective for
the racemization of 1-phenylethylamine relative to Pd on bare sil-
ica [24]. They demonstrated that the acid-base properties of the
supports for Pd catalysts evidently influences the formation of
by-products and should be modestly basic to enable suppress the
formation of byproducts [24]. By incorporating alkalic salt, Jin
et al. [25] prepared K2CO3-modified Pd catalysts, which could effi-
ciently suppress side reactions during the racemization and thus
enhance the yield in the DKR of 1-phenylethylamine in combina-
tion with NovozymÒ 435; however, their stability was unclear
due to the lack of durability studies. Recently, several multifunc-
tional hybrid materials containing Pd NPs loaded on basic support
and enzymes were constructed, and served as catalysts for one-pot
DKR of amines [26,27], whereas the stability or efficiency is still an
open task. Despite these advances, one-pot DKR protocols with
efficient catalysts would be highly desirable.
Scheme 2. Reaction mechanism for racemization of (S)-1-phenylethylamine.
both in terms of activity and durability. The enhanced catalytic
performances of Pd/MIL-101 were found to depend on the specifi-
cal texture of MIL-101 matrix which impeded the agglomeration of
Pd NPs while maintaining efficient substrate transport owing to
the porous nature of the material. Additionally, Férey and cowork-
ers conferred basic properties to MIL-101 by grafting amine groups
onto the chromium(III) coordinatively unsaturated sites (CUSs) in
their mesoporous cages and, then, used the resulting modified
solid as a host for further loading of Pd NPs in the internal pores
[35]. In the present work, Pd NPs were encapsulated inside the
cages of both the bare and the the amine-grafted MIL-101 via a
facile incipient wetting procedure followed by reduction with
hydrogen, giving highly efficient racemization catalysts for primary
amines. The racemization can be combined with enzymatic KR in
a one-pot process leading to optically pure products from racemic
amines, showing superior catalytic efficiency when compared to
other catalysts, such as Pd/MCM-41 and commercial Pd/C. On the
basis of various characterizations, the correlation of catalytic
observations to the structural characteristics has been tentatively
established, especially, getting an insight into the effect of amine
modification of MOFs on catalytic performances.
2. Experimental section
Presently, metal-organic frameworks (MOFs) have drawn
tremendous attention owing to their abundant diversity in struc-
ture and composition and thus specific applications [28–30]. In
the domain of catalysis, besides the well-demonstrated catalytic
activity of pure MOFs, these materials are also attractive candi-
dates for catalyst supports because of their unique porous features
[31–33]. In previous work, we have used MIL-101 as support to
encapsulate Pd NPs in its cages and applied the as-prepared Pd/
MIL-101 for one-pot indole synthesis from 2-iodoaniline and
phenylacetylene in aqueous media [34]. Our results exemplified
the superiority of Pd/MIL-101 over other conventional Pd catalysts,
2.1. Catalyst preparation
All of the chemicals used in this experiment were obtained from
commercial sources and used without any other treatments.
NovozymÒ 435 (immobilized lipase B from Candida antarctica),
( )-1-phenylethylamines, (S)-1-phenylethylamines, and 1%-Pd/C
were purchased from Sigma-Aldrich Inc. (USA). Other reactants
were purchased from Aladdin Industrial Co., Ltd. (Shanghai, China).
MIL-101 was synthesized following the method reported by
Férey et al. [36]. Ethylenediamine (ED) grafted MIL-101 were

S. Xu et al. / Journal of Catalysis 363 (2018) 9–17
11
synthesized according to the method reported by Hwang et al. [35],
and designated as ED-MIL-101. All the supported Pd catalysts were
achieved via the procedure, as we described previously [34]. First, a
certain amount of Pd(acac)2 was dissolved into 1.0 mL of chloro-
form. A calculated amount of activated MIL-101 type material
was then impregnated with the Pd precursor solution. The mixture
was sonicated for 20 min with an ultrasonic batch (60 W) and stir-
red vigorously for 24 h in Argon flow. After being dried at 423 K for
8 h, the impregnated MIL-101 samples were reduced in a 10% H2/
Ar flow at 493 K for 2 h. The as-prepared samples were designated
as x%-Pd/MIL-101 or x%-Pd/ED-MIL-101, where x % denotes the
nominal Pd loading. For comparison, the reference 1.5%-Pd/MCM-
41 catalyst was prepared through the same incipient wet impreg-
nation followed by the reduction method.
The reaction system was stirred vigorously (800 rpm) to eliminate
the diffusion effect. The reaction mixture was sampled at intervals
for product analysis by the GC as mentioned above. After cooling to
room temperature at the end of the reaction, the catalyst was sep-
arated by centrifugation and washed with toluene for further char-
acterizations and applications. Microwave-assisted DKR was
carried out in a closed glass tube by using a commercially available
microwave synthesis equipment (MAS-1 SINEO). The reaction mix-
ture was flushed with a 5% H2/Ar flow before vial was closed. The
hydrogen partial pressure inside vial was 0.015 MPa. The reaction
temperature was controlled by a continuous focused microwave
power delivery system with power from 0 to 1360 W and a micro-
wave frequency source of 2450 MHz.
3. Results and discussion
2.2. Catalyst characterization
3.1. Catalyst characterization
Fourier transform infrared (FTIR) spectra were obtained using a
Thermo Nicolet Magna 550 spectrometer. The Pd loading was ana-
lyzed by means of inductively coupled plasma optical emission
spectrometry (ICP-OES; Varian VISTA-MPX). The crystalline struc-
ture was investigated by X-ray diffraction (XRD; Rigaku D/Max-
RB with Cu Ka radiation). The material shapes and morphologies
were observed by both field emission scanning electron micro-
scopy (FESEM; HITACHI S-4800) and transmission electron micro-
scopy (TEM, JEOL JEM2100). The surface electronic states were
determined by X-ray photoelectron spectroscopy (XPS; ULVAC-
PHI PHI5000 VersaProbe system using Al Ka radiation). All of the
binding energy (BE) values were calibrated by using C 1 s = 284.
6 eV as a reference. N2 adsorption–desorption isotherms were
obtained at 77 K using a Micromeritics TriStar II apparatus. By N2
The FTIR spectra reveal that, besides those absorbance bands
observed in the bare MIL-101 (Fig. 1a), the ED-grafted MIL-101
(ED-MIL-101) displays additional absorbance bands at 2950 and
2890 cmÀ1, corresponding to the asymmetric stretching and sym-
metric stretching vibrations of aliphatic CAH bonds [37]. More
importantly, obvious red shift can be observed for these aliphatic
C-H bond stretching vibrations, as observed when the ED mole-
cules were linked to the chromium(III) CUSs [35]. This results con-
firm the successful grafting of ED groups onto the Lewis acid sites
at the center of mesoporous cages.
The low-angle XRD pattern of the as-prepared MIL-101 (Fig. 2a)
is in excellent agreement with the simulated pattern reported by
Férey et al. [36]. The ED-grafted MIL-101 also displays similar
XRD pattern (Fig. 2b) to the bare MIL-101, demonstrating that
the resulting ED-MIL-101 preserved the crystallinity. Compared
with both the hosts, the almost unchanged XRD patterns of 1.5%-
Pd/MIL-101 (Fig. 2c) and 1.5%-Pd/ED-MIL-101 (Fig. 2d) mean that
the Pd NPs incorporation occurred with no apparent loss of struc-
ture integrity, but with some slight variations of the Bragg intensi-
ties. Furthermore, no significant diffraction peak characteristic of
Pd species is detected from the wide-angle XRD pattern from
1.5%-Pd/MIL-101 and 1.5%-Pd/ED-MIL-101 (Fig. 3), which might
be related to the embedding of Pd NPs into the cages of MOF hosts.
This observation is very similar to the results reported by EI-Shall
et al. [38], where the incorporation of Pd in MIL-101 produced
hardly significant signals of Pd in the XRD pattern unless the Pd
loading was >4.9 wt%.
adsorption, the Brunauer–Emmett–Teller (BET) surface area (SBET
)
was calculated by using the multiple-point BET method in the rel-
ative pressure range of P/P0 = 0.05–0.2. The pore size distribution
curve were obtained by the Barrett–Joyner–Halenda model. The
active surface area (SPd) was measured by the CO chemisorption
at room temperature, which was performed on a Micromeritics
AutoChem II 2920 instrument using a dynamic pulse method.
The sample was purged under an argon flow (purity of 99.997%,
treated with an Alltech Oxy-Trap column) at 423 K for 2 h. The pre-
treated sample was cooled down to room temperature under argon
atmosphere, and CO pulses were injected at 303 K until the calcu-
lated areas of consecutive pulses were constant. According to the
CO chemisorption, Sact of the as-prepared catalyst was calculated
assuming Pd/CO = 1 and a Pd surface density of 1.27 Â 1019
atoms mÀ2
.
ICP-OES analysis confirmed the presence of Pd species in all the
supported Pd catalysts, and it also revealed that the Pd loadings in
all the Pd-containing samples were very similar to the nominal Pd
contents in the preparation precursors (see Table 1). XPS spectra
(Fig. 4) further demonstrate that almost all the Pd species in the
2.3. Catalytic performances test
Racemization reactions were carried out in 15-mL stainless
steel autoclaves containing a catalyst (0.75 mg Pd), 0.13 mmol of
(S)-1-phenylethylamine, 4 mL of solvent, and 0.005–0.030 MPa of
hydrogen at 343 K. To easily obtain hydrogen pressures below
0.1 MPa, a 5% hydrogen dilution in argon was used as reactive
gas. The processes were monitored on a gas chromatography (Shi-
madzu GC-17A) with a CP-CHIRASIL-DEX CB chiral column (25 m
(a)
 0.32
lm, CP7503) and FID detection using n-heptane as an inter-
(b)
nal standard. DKR reactions were performed under the same con-
ditions as above but with 0.13 mmol of rac-1-phenylethylamine
as reactant, 37.5 mg of NovozymÒ 435 as acylation catalyst and
0.13 mmol of ethyl methoxy acetate as acyl donor. In a typical
experiment, the one-pot DKR of racemic 1-phenylethylamine was
carried out in a 15-mL stainless steel autoclave containing 1.5%-
Pd/ED-MIL-101 (0.75 mg Pd), 37.5 mg of NovozymÒ 435, 0.13
mmol of rac-1-phenylethylamine, 0.13 mmol of ethyl methoxy
acetate, 4 mL of toluene, and 0.015 MPa of hydrogen at 343 K.
sC-H
asC-H
4000 3500 3000 2500 2000 1500 1000 500
Wavenumber (cm-1)
Fig. 1. FTIR spectra of (a) MIL-101 and (b) ED-MIL-101.

12
S. Xu et al. / Journal of Catalysis 363 (2018) 9–17
Pd 3d
335.1
(c)
(a)
(b)
(b)
(a)
(c)
(d)
2
4
6
8
10
330
335
340
345
350
2
(degree)
Binding energy (eV)
Fig. 2. Low-angle XRD patterns of (a) MIL-101, (b) ED-MIL-101, (c) 1.5%-Pd/MIL-
Fig. 4. XPS of (a) 0.5%-Pd/ED-MIL-101, (b) 1.5%-Pd/ED-MIL-101, and (c) 3%-Pd/ED-
101, and (d) 1.5%-Pd/ED-MIL-101.
MIL-101.
by Hwang et al. [35]. Upon Pd loading, marked decrease in both the
SBET (see Table 1) and the average pore size (Fig. 4b) was noted for
1.5%-Pd/MIL-101 and 1.5%-Pd/ED-MIL-101, mainly because of the
occupation of the cages of MIL-101 and ED-MIL-101 supports by
the monodisperse Pd NPs.
(a)
(b)
As shown in FESEM image (Fig. 6a), the as-prepared MIL-101 is
present in the form of octahedral shape on the micrometer scale,
which is in agreement with the previous reports [38,39]. FESEM
image of ED-MIL-101 (Fig. 6b) also displays similar octahedral
morphology to the bare MIL-101. From the TEM images of the
as-prepared MIL-101 (Fig. 6c) and ED-MIL-101 (Fig. 6d), the cubic
symmetry of both the materials is also reflected in the shape of the
crystals. These observations demonstrated that grafting of ED did
not change the characteristic morphology of MIL-101. TEM images
of 1.5%-Pd/MIL-101 (Fig. 6e) and 1.5%-Pd/ED-MIL-101 (Fig. 6f)
reveal similar morphology and pore structure to the parent sup-
ports, further confirming that the structural integrity of MIL-101
hosts was preserved after the Pd incorporation. After deposition
of 1.5 wt% Pd on both the supports, only a few NPs appear on the
outside surface of the parent supports (Figs. 6e and f), demonstrat-
ing that most of the formed metallic Pd NPs were confined in the
cages of the hosts [34,35]. This is in distinct contrast to the result
of 1.5%-Pd/MCM-41 where much larger Pd particles were located
at the external surface (Fig. S1), mainly due to the absence of the
confinement effect of nanocages since MCM-41 possesses only
straight channels.
It is worth noting that encapsulation of Pd NPs in the cages of
MIL-101 type materials results in the difficulty measuring estimat-
ing the Pd particle size from TEM micrographs because of the poor
particle-support contrast [34]. Therefore, CO chemisorption exper-
iment was used to determine the Pd dispersion degree and subse-
quently calculate the Pd particle size [41]. Compared with 1.5%-Pd/
MCM-41, both 1.5%-Pd/MIL-101 and 1.5%-Pd/ED-MIL-101 exhibit
much higher Pd dispersion degree regardless of similar Pd loadings
(Table 1). It can further verify the nanocage confinement effect on
the formation of the Pd NPs in the range of 2.1–3.3 nm, in agree-
ment with the cage diameters. For 1.5%-Pd/MCM-41, in contrast,
the measured Pd size (3.7 nm) is much larger than the pore diam-
eter of parent MCM-41 (2.4 nm), suggesting that most of Pd parti-
cles aggregated on the outer surface of MCM-41 support. This
observation once again demonstrated the absence of remarkable
confinement effect of straight channels in MCM-41 material.
Accordingly, a portion of the formed Pd particles might emigrate
out the pore channels of MCM-41, and agglomerate on the outer
surface during the preparation procedure. Additionally, the CO
chemisorption data (Table 1) also confirmed that, with nearly the
same Pd loading, the surface amine functionalities had remarkable
impact on the dispersion degree of the Pd NPs. The formation of
(c)
(d)
10
20
30
40
(degree)
50
60
70
80
2
Fig. 3. Wide-angle XRD patterns of (a) MIL-101, (b) ED-MIL-101, (c) 1.5%-Pd/MIL-
101, and (d) 1.5%-Pd/ED-MIL-101.
Table 1
Some structural properties of the as-prepared samples.
a
Sample
Pd loading
(wt %)
SBET
SPd
dPd
(m2/g)
(m2/g)
(nm)
MIL-101
–
3820
3589
3313
3200
3459
3256
3030
2730
810
–
–
0.5%-Pd/MIL-101
1.5%-Pd/MIL-101
3%-Pd/MIL-101
ED-MIL-101
0.48
1.4
2.9
–
0.49
1.4
2.8
1.3
138
150
191
–
221
238
250
135
3.6
3.3
2.6
–
2.3
2.1
2.0
3.7
0.5%-Pd/ED-MIL-101
1.5%-Pd/ED-MIL-101
3%-Pd/ED-MIL-101
1.5%-Pd/MCM-41
a
Calculated as 6/(
qSPd),
q
= 12.02 g/cm3.
x%-Pd/ED-MIL-101 were present in the metallic state with the BE
about 335.1 eV in the Pd 3d5/2 core level, which is same as our pre-
vious reports on Pd/MIL-101 [34].
The N2 adsorption-desorption isotherms and the pore size dis-
tribution profiles of the as-prepared MIL-101, ED-MIL-101, 1.5%-
Pd/MIL-101, and 1.5%-Pd/ED-MIL-101 are shown in Fig. 5. The SBET
of MIL-101 was calculated to be 3820 m2 gÀ1, which is close to the
reported value [36,38–40]. The isotherms of MIL-101 have sec-
ondary uptakes around p/p0 = 0.1 and 0.2 (Fig. 5a), indicating the
existence of two kinds of nanopores [39]. The pore size distribution
curve of MIL-101 also displays two different pore sizes, 1.7 and 2.2
nm (Fig. 4b), which is similar to the result reported by Pan et al.
[40]. Compared with the bare MIL-101, ED-grafted MIL-101 exhi-
bits significant decrease in both the SBET (3459 m2 gÀ1) and the
average pore size (1.5 and 2.0 nm), which could be due to the cov-
erage of the cage surface with the amine functionalities as reported

S. Xu et al. / Journal of Catalysis 363 (2018) 9–17
13
(a)
(b)
6
MIL-101
2000
1500
1000
500
1.5%-Pd/MIL-101
ED-MIL-101
1.5%-ED-MIL-101
5
4
3
MIL-101
2
1.5%-Pd/MIL-101
ED-MIL-101
1.5%-ED-MIL-101
1
0.0 0.2 0.4 0.6 0.8 1.0
p/p
1
2
3
4
5
6
Pore diameter (nm)
0
Fig. 5. (a) N2 adsorption-desorption isotherms and (b) pore size distributions of MIL-101, ED-MIL-101, 1.5%-Pd/MIL-101, and 1.5%-Pd/ED-MIL-101.
gen pressure could strongly slow down the racemization because
the hydrogenation of intermediate imine could not proceed com-
pletely (Table S1, entries 2, 5, 6). Moreover, nonpolar toluene
seemed to be the best solvent for the racemization of (S)-1-
phenylethylamine in the presence of 1.5%-Pd/MIL-101 but the
racemization rate slowed down greatly in polar solvents
(Table S1, entries 2, 7–10). In general, the less polar intermediate
imine is stabilized to a greater extent than the more polar starting
material amine in the presence of a nonpolar solvent, and thus the
racemization proceeds faster. Preliminary study also revealed that
the optimal racemization of (S)-1-phenylethylamine was obtained
on Pd catalyst with 1.5 wt% loading (Table S1, entries 2, 11, 12).
The 1.5%-Pd/MIL-101 was therefore selected for the following
studies. Despite similar Pd loading, 1.5%-Pd/MIL-101 was much
more active than 1.5%-Pd/MCM-41 (Table S1, entry 13). Obviously,
the higher reactivity over 1.5%-Pd/MIL-101 may be mainly attribu-
ted to its higher SPd (Table 1), which would provide more Pd active
sites for the dehydrogenation and hydrogenation steps. Addition-
ally, the conversion over 1.5%-Pd/MIL-101 was 20% higher than
that over 1.5%-Pd/MCM-41, whereas the SPd of 1.5%-Pd/MIL-101
was only 11% larger than that of 1.5%-Pd/MCM-41. Thus, we can
conclude that the larger SPd of 1.5%-Pd/MIL-101 was not the only
facter responsible for its higher activity. The accessible meso-
porous cages of MIL-101 may be another factor responsible for
the higher activity of 1.5%-Pd/MIL-101 relative to 1.5%-Pd/MCM-
41, which would favor the diffusion of the reactants into the pores
reaching the Pd active sites and effectively increasing the collision
frequency between reactants and Pd owing to the microreactor
effect. Meanwhile, the improved selectivity over 1.5%-Pd/MIL-101
relative to 1.5%-Pd/MCM-41 may be explained as arising from
the enhanced surface hydrophobicity of the MIL-101 host owing
to the organic linkers (bdc), which can impede the side reactions.
Moreover, side reactions are serious using commercially available
Pd/C as racemization catalyst, mainly because of the presence of
phenolic and carboxylic acid groups on the surface of charcoal.
Meanwhile, Pd/C is known as an efficient hydrogenolysis catalyst
for secondary amines at low hydrogen pressure [42]. This observa-
tion is in great agreement with Jacobs’ work where no obvious
improvement was found either using trimethylamine as solvent
or catalyst pretreatment with base [22].
(a)
(b)
(c)
(e)
(d)
(f)
Fig. 6. FESEM images of (a) MIL-101 and (b) ED-MIL-101. TEM images of (c) MIL-
101, (d) ED-MIL-101, (e) 1.5%-Pd/MIL-101, and (f) 1.5%-Pd/ED-MIL-101.
much fine Pd NPs in 1.5%-Pd/ED-MIL-101 (2.1 nm) than 1.5%-Pd/
MIL-101 (3.3 nm), as observed clearly from the TEM micrographs,
further demonstrates the superior influence of amine-grafting on
incorporation of Pd NPs in the cages.
3.2. Catalytic performances
Initially, the racemization activity of 1.5%-Pd/MIL-101 catalyst
was evaluated using (S)-1-phenylethylamine to determine the
optimal reaction conditions. The racemization rate was found to
be highly affected by temperature (Table S1, entries 1–4). At low
temperature, the dehydrogenation of (S)-1-phenylethylamine on
the surface of Pd was not activated completely, leading to a rela-
tively higher ee value, whereas high temperature caused a signifi-
cant decrease in the selectivity because of the increased side
reaction rate. Furthermore, the decrease in an appropriate hydro-
gen pressure is needed to favor the dehydrogenation and suppress
the formation of byproducts [23]; nevertheless, much lower hydro-

14
S. Xu et al. / Journal of Catalysis 363 (2018) 9–17
Table 2
DKR of racemic 1-phenylethylamine through Pd/lipase cocatalysis.a
Entry
Pd catalyst
T (oC)
PH2 (MPa)
Solvent
Conv. (%)
Sel.R-amide (%)
Sel.EB (%)
ee (%)
1
2
3
4
5
6
7
8
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
1.5%-Pd/MIL-101
0.5%-Pd/MIL-101
3%-Pd/MIL-101
1.5%-Pd/MCM-41
Pd/C
60
70
80
90
70
70
70
70
70
70
70
70
70
70
0.015
0.015
0.015
0.015
0.005
0.030
0.015
0.015
0.015
0.015
0.015
0.015
0.015
0.015
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Methanol
Ethanol
DMF
Hexane
Toluene
Toluene
Toluene
Toluene
73
98
97
98
84
75
79
91
79
90
90
95
82
85
83
77
71
66
68
83
80
76
79
79
67
78
70
40
14
23
29
34
10
17
19
22
19
21
20
22
30
38
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
9
10
11
12
13
14
a
Reaction conditions: a catalyst containing 0.75 mg of Pd, 37.5 mg of NovozymÒ 435, 0.13 mmol of rac-1-phenylethylamine, 0.13 mmol of ethyl methoxy acetate, 4 mL of
solvent, t = 18 h.
Table 3
The DKR of rac-1-phenylethylamine was performed in a one-pot
process by combining the Pd-catalyzed dehydrogenation-
hydrogenation sequence with the enzyme-aided resolution via
acetylation using commercially available immobilized lipase B
from Candida antarctica (NovozymÒ 435). Apparently, the yields
were far above the 50% limit and the product ee values exceeded
99% in all case when Pd-based catalysts were used for the one-
pot DKR process (Table 2), thus demonstrating the excellent com-
patibility of Pd catalysts with NovozymÒ 435. It was also observed
that the selectivity to the target products in the DKR process
became greater significantly (Table 2) in comparison with that in
the racemization reactions (Table S1) because the amines are gen-
erally well enzymatically acylated to the amides before it suffers
irreversibly lost through condensation and hydrogenalysis [23].
Upon screening various parameters, the 1.5%-Pd/MIL-101 proved
again to be the most efficient catalyst for DKR of rac-1-
phenylethylamine when combining with NovozymÒ 435 (Table 2).
Under optimal conditions, rac-1-phenylethylamine was converted
to enantiopure amide in an excellent conversion (98%) and a mod-
erate selectivity (77%) with a high ee value (>99%) within a shorter
reaction time (18 h) (Table 2, entry 2). In comparison with the
combination containing reference 1.5%-Pd/MCM-41 or commer-
cially available Pd/C (Table 2, entries 13, 14), the present chemoen-
zymatic catalyst combination gave much more superior
performances in the DKR of rac-1-phenylethylamine.
Despite this advance, efficient DKR protocols would be highly
desirable, particularly the selectivity to the target product. Jin
et al. have reported alkalic salt-modification of Pd catalysts to sup-
press side reactions during the racemization [25], which provided
an efficient tool for enhance the yield in the DKR of rac-1-
phenylethylamine. An attempt to addition Na2CO3 in the DKR of
rac-1-phenylethylamine was conducted and the influence of the
amount of Na2CO3 on the DKR performances of the combination
of 1.5%-Pd/MIL-101 and NovozymÒ 435 was investigated (Table 3).
Increasing the amount of Na2CO3 to 20 mg resulted in negligible
change in the conversion; nevertheless, excess Na2CO3 dramati-
cally decreased the catalytic activity because of the collapse of
the MIL-101 matrix originating from the attack of basic Na2CO3
and thus the agglomeration of Pd NPs. Meanwhile, similar change
in the ee value was observed, further confirming the collapse of the
Effect of the amount of Na2CO3 on DKR of racemic 1-phenylethylamine through 1.5%-
Pd/MIL-101/lipase cocatalysis.a
Na2CO3 amount (mg)
Conv. (%)
Sel.R-amide (%)
Sel.EB (%)
ee (%)
0
5
98
97
96
96
95
88
70
77
78
80
81
85
92
76
23
22
20
19
15
8
>99
>99
99
98
97
10
15
20
25
30
92
56
13
a
Reaction conditions: a catalyst containing 0.75 mg of Pd, 37.5 mg of NovozymÒ
435, 0.13 mmol of rac-1-phenylethylamine, 0.13 mmol of ethyl methoxy acetate,
T = 70 °C, PH2 = 0.015 MPa, 4 mL of toluene, t = 18 h.
MIL-101 matrix at higher Na2CO3 content which exposed Pd NPs to
lipase and thus causing unfavorable metal-enzyme interaction.
Significant improvement of selectivity could be also determined
with increasing the amount of Na2CO3 up to 25 mg, which can be
primarily ascribed to the suppress effect of the basic salt on the
condensation side reaction [22–25]. The distinct selectivity
decrease at excess Na2CO3 (30 mg) was merely in connection with
the agglomeration of the Pd NPs. In view of such results, 20 mg of
Na2CO3 was selected as an effective additive to the one-pot DKR of
rac-1-phenylethylamine catalyzed by the combination of 1.5%-Pd/
MIL-101 and NovozymÒ 435, giving an enhanced selectivity (85%)
in comparison with the Na2CO3-free system (77%). Industrial appli-
cation of heterogeneous catalysis greatly relies on its stability [43].
Next, we investigated the durability of the combination of 1.5%-Pd/
MIL-101 and NovozymÒ 435 during the one-pot DKR of rac-1-
phenylethylamine in the presence of Na2CO3 additive. Apart from
the slightly decreased ee value, the conversion during the recycling
test decreased greatly, as did the selectivity (Fig. 7). This

S. Xu et al. / Journal of Catalysis 363 (2018) 9–17
15
Conv.
ED-MIL-101 procedure on the DKR performances of rac-1-
phenylethylamine catalyzed by Pd/lipase cocatalyst. Apparently,
the selectivity to the enantiopure amide in the Na2CO3-free DKR
process using 1.5%-Pd/ED-MIL-101 is equal to, or even higher than,
that using 1.5%-Pd/MIL-101 accompanying with Na2CO3 additive
(Table 4). More importantly, 1.5%-Pd/ED-MIL-101 with appropriate
N content (1.9 mmol/gcat.) delivered the most efficiency, an excel-
lent conversion (99%) and a good selectivity (93%) with a high ee
value (>99%), regardless of nearly the same Pd loading. On the basis
of these observations, we could deduce that the ED-grafting on
MIL-101 would render it moderate basicity and, on the other hand,
favor the incorporation of Pd NPs with much small size in the
cages. The Pd loading was also investigated and the 1.5%-Pd/ED-
MIL-101 was screened as the most efficient catalyst for DKR of
rac-1-phenylethylamine combining with NovozymÒ 435
(Table S2). It should be noted that, to keep the same Pd content,
the amount of ED-MIL-101 used in the DKR process decreased with
the increase of Pd loading. As a result, gradual decrease in selectiv-
ity was observed at higher Pd loading (Table S2).
Fig. 9 shows the reaction profile during the one-pot DKR of
rac-1-phenylethylamine using the catalyst system containing both
the 1.5%-Pd/ED-MIL-101 and NovozymÒ 435. Along with the pro-
duction of amide, EB was identified as the only byproduct resulting
from the hydrogenolysis of formed secondary amine. Although the
content of EB was very low during the whole process of the test,
the selectivity to EB increased gradually with the reaction time.
Almost complete conversion of rac-1-phenylethylamine can be
achieved within 18 h. Further prolonging the reaction time
Sel.
Sel.
ee
R-amide
100
80
60
40
20
0
EB
1
2
3
4
Recycling number
Fig. 7. Recycling test of the enzyme and 1.5%-Pd/MIL-101 catalysts for one-pot DKR
of rac-1-phenylethylamine. Reaction conditions: a catalyst containing 0.75 mg of
Pd, 37.5 mg of NovozymÒ 435, 0.13 mmol of rac-1-phenylethylamine, 0.13 mmol of
ethyl methoxy acetate, 20 mg of Na2CO3, T = 70 °C, PH2 = 0.015 MPa, 4 mL of toluene,
t = 18 h.
undesirable stability is mainly due to the destruction of Na2CO3
additive on the structure of MIL-101, leading to a remarkable
agglomeration of Pd NPs, as revealed by the TEM image of
1.5%-Pd/MIL-101 catalyst after 4 consecutive cycle (Fig. 8).
In an effort to favor the stability of metal-enzyme combination
for the one-pot DKR of rac-1-phenylethylamine, MIL-101 was
grafted with ED groups to afford ED-MIL-101 and then, providing
1.5%-Pd/ED-MIL-101 racemization catalyst. We first investigated
the influence of the amount of ED during the preparation of
100
80
60
Conv.
Sel.
R-amide
40
20
0
Sel.
EB
ee
0
5
10
15
20
25
Time (h)
Fig. 9. Reaction profile in one-pot DKR of rac-1-phenylethylamine by lipase and
1.5%-Pd/ED-MIL-101. Reaction conditions: a catalyst containing 0.75 mg of Pd, 37.5
mg of NovozymÒ 435, 0.13 mmol of rac-1-phenylethylamine, 0.13 mmol of ethyl
methoxy acetate, T = 70 °C, PH2 = 0.015 MPa, 4 mL of toluene.
Fig. 8. TEM image of 1.5%-Pd/MIL-101 after 4 consecutive runs.
Table 4
Effect of the amount of ethylenediamine on DKR of racemic 1-phenylethylamine through Pd/lipase cocatalysis.a
b
Pd catalyst
ED amount (
lL)
N content (mmol/gcat.
)
Na2CO3 content (mg)
Conv. (%)
Sel.R-amide (%)
Sel.EB (%)
ee (%)
1.5%-Pd/MIL-101
–
–
20
0
0
95
98
99
82
85
86
93
89
15
14
7.0
9.0
97
1.5%-Pd/ED-MIL-101
1.5%-Pd/ED-MIL-101
1.5%-Pd/ED-MIL-101
100
150
200
0.7
1.9
3.6
>99
>99
>99
0
a
Reaction conditions: a catalyst containing 0.75 mg of Pd, 37.5 mg of NovozymÒ 435, 0.13 mmol of rac-1-phenylethylamine, 0.13 mmol of ethyl methoxy acetate, T = 70 °C,
PH2 = 0.015 MPa, 4 mL of toluene, t = 18 h.
b
Determined by elemental analysis.

16
S. Xu et al. / Journal of Catalysis 363 (2018) 9–17
resulted in the decrease of selectivity to target product owing to
the side reactions. Besides the high efficiency, the 1.5%-Pd/ED-
MIL-101 and NovozymÒ 435 combination could be easily sepa-
rated from the reaction solution via centrifugation and could be
used repetitively eight times without appreciable loss of
conversion, selectivity, and ee value during the one-pot DKR of
rac-1-phenylethylamine (Fig. 10). This result demonstrates the
robustness of this chemoenzymatic catalyst combination under
the present DKR conditions. As shown in Fig. 10, at the end of
the ninth cycle, the conversion decreased by 19%. ICP-OES analysis
revealed that no leaching of Pd could be detected in the reaction
mixtures during the repetitive runs, implying that the metallic
Pd was stable against the chelating effect of the substrates. The
TEM image of the used 1.5%-Pd/ED-MIL-101 (Fig. 11) revealed that
the Pd NPs aggregated to 5 nm after 9 cycles, which might be the
main factor responsible for the decrease in catalytic activity.
Further investigations of the generality of the present strategy
revealed that one-pot DKR of other several structurally different
racemic benzylic amines can be also achieved by using the
chemoenzymatic catalyst combination of the 1.5%-Pd/ED-MIL-
101 and NovozymÒ 435 with good conversion (86–91%) and selec-
tivity (86–91%), as well as excellent enatioselectivity (>99%)
(Table 5).
Conv.
Sel.
R-amide
Sel.
EB
100
ee
80
60
40
20
0
1
2
3
4
5
6
7
8
9
Recycling number
Fig. 10. Recycling test of the enzyme and 1.5%-Pd/ED-MIL-101 catalysts for one-pot
DKR of rac-1-phenylethylamine. Reaction conditions: a catalyst containing 0.75 mg
of Pd, 37.5 mg of NovozymÒ 435, 0.13 mmol of rac-1-phenylethylamine, 0.13 mmol
of ethyl methoxy acetate, T = 70 °C, PH2 = 0.015 MPa, 4 mL of toluene, t = 18 h.
25
20
15
10
5
0
1
2
3
4
5
6
7
8
9 10
Diameter (nm)
Fig. 11. TEM image (left) and its corresponding size distribution histogram (right) of 1.5%-Pd/ED-MIL-101 after 9 consecutive runs.
Table 5
DKR of racemic benzylic amine through 1.5%-Pd/ED-MIL-101/lipase cocatalysis.a
Entry
1
Amine
Product
Conv. (%)
90
Sel.R-amide (%)
90
Sel.EB (%)
10
ee (%)
>99
2
3
86
91
91
86
9.0
14
>99
>99
a
Reaction conditions: a catalyst containing 0.75 mg of Pd, 37.5 mg of NovozymÒ 435, 0.13 mmol of rac-benzylic amine, 0.13 mmol of ethyl methoxy acetate, T = 70 °C, PH2
= 0.015 MPa, 4 mL of toluene, t = 18 h.

S. Xu et al. / Journal of Catalysis 363 (2018) 9–17
17
Appendix A. Supplementary material
100
80
60
40
20
0
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.jcat.2018.04.006.
Conv.
Sel.
R-amide
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4. Conclusions
In summary, Pd NPs confined in the cages of ethylenediamine-
grafted MIL-101 could be employed as an efficient racemization
catalyst, and exhibited excellent matchability with immobilized
lipase B for one-pot DKR of rac-1-phenylethylamines. Meanwhile,
the present chemoenzymatic catalyst combination possessed bet-
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showing great promise for practical application. Our findings
highlight the advantages of amine modification of the surface of
the cages in MIL-101 in terms of conferring basic property to the
material and locating Pd NPs inside its cages. Additionally, micro-
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the Pd-catalyzed racemization with the enzyme-aided resolution.
This recyclable chemoenzymatic catalyst combination also might
provide a preferable method for the one-pot cascade reactions.
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Acknowledgement
This work is supported by the Ministry of Education of China
(PCSIRT_IRT_16R49).