Preparation, characterization and catalytic activity of palladium catalyst supported on MgCO3 for dynamic kinetic resolution of amines

Article abstract of DOI:10.21577/0103-5053.20180089

Pd nanoparticle catalyst loading 4.7 wt.percent was prepared by the deposition-precipitation method and characterized by X-ray diffraction and transmission electron microscopy (TEM). The crystallite size estimated from the integral width of the highest intensity line using the Scherrer equation was 2.3 nm. Images obtained from TEM showed an equal distribution of the particles size between 0-2 and 2-4 nm, and also a good dispersion of the nanoparticles on the catalyst support. The catalytic activity of this nanocatalyst was studied for racemization reactions of (S)-(-)-1-phenylethylamine. After that, the catalyst was used in the chemoenzymatic dynamic kinetic resolution (DKR) of some primary amines. Expressive yields and optical purities were obtained.

Full text of DOI:10.21577/0103-5053.20180089

http://dx.doi.org/10.21577/0103-5053.20180089
J. Braz. Chem. Soc., Vol. 29, No. 10, 2144-2149, 2018
Printed in Brazil - ©2018 Sociedade Brasileira de Química
Article
Preparation, Characterization and Catalytic Activity of Palladium Catalyst
Supported on MgCO3 for Dynamic Kinetic Resolution of Amines
Marina M. M. Ferreira,a Camila R. Cabreira,a Pedro H. K. Chaves,a
Gabriela M. Labussiére,a Renata C. Zimpeck,a Sania M. de Lima*,b and
Fernanda A. de Siqueira*,a
aLaboratório de Síntese Orgânica e Catálise, Instituto de Ciências Ambientais, Químicas e Farmacêuticas,
Departamento de Química, Universidade Federal de São Paulo (UNIFESP), Campus Diadema,
Rua Prof. Arthur Riedel, 275, Bairro Jardim Eldorado, 09972-270 Diadema-SP, Brazil
bLaboratório de Processos Ambientais, Bioquímicos e Químicos (LABQ),
Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Departamento de Engenharia Química,
Universidade Federal de São Paulo (UNIFESP), Campus Diadema, Rua São Nicolau, 210,
Centro, 09913-030 Diadema-SP, Brazil
Pd nanoparticle catalyst loading 4.7 wt.% was prepared by the deposition-precipitation method
and characterized by X-ray diffraction and transmission electron microscopy (TEM). The crystallite
size estimated from the integral width of the highest intensity line using the Scherrer equation was
2.3 nm. Images obtained from TEM showed an equal distribution of the particles size between 0-2
and 2-4 nm, and also a good dispersion of the nanoparticles on the catalyst support. The catalytic
activity of this nanocatalyst was studied for racemization reactions of (S)-(–)-1-phenylethylamine.
After that, the catalyst was used in the chemoenzymatic dynamic kinetic resolution (DKR) of some
primary amines. Expressive yields and optical purities were obtained.
Keywords: palladium catalysts, chiral amines, racemization, dynamic kinetic resolution
Introduction
enantiomerically pure compounds in theoretical yields up
to 100%.24-28
The development and use of metal nanocatalysts has
attracted attention of the scientific community in recent
years because of their physical and chemical properties.1,2
Palladium is a metal catalyst very useful for several organic
transformations. Its chemical property as catalysts for
several reactions such as Mizoroki-Heck, Suzuki-cross
coupling, Stille and Sonogashira coupling reactions, can
illustrate its versatility in organic synthesis.3-10
Enantiomerically pure amines are useful intermediates
for the synthesis of biologically active compounds.11-19
They are also largely used as chiral auxiliary and resolving
agents.20-23 Kinetic resolution mediated by enzymes is a
versatile strategy to prepare chiral amines starting from
racemic reagents. However, the maximum of 50% yield
is a relevant limitation. Chemoenzymatic dynamic kinetic
resolution (DKR) is a protocol which combines the kinetic
resolution with in situ racemization of the undesired
enantiomer and converts racemic starting materials into
The racemization step in DKR of amines is difficult
because it requires harsh conditions. This is the reason for
the reduced number of reports concerning selective DKR
of amines. Most of the catalysts used for racemization of
chiral amines are ruthenium complexes, more specifically
Shvo’s catalyst.26,29 More recently, heterogeneous palladium
nanoparticles supported on alkaline earth metals such
as BaSO4, CaCO3 and BaCO3, displayed selectivity in
racemization of chiral amines, inhibiting the formation of
the side products. The higher selectivity was assigned to
the nature of the support.30-34
Herein, wedescribethepreparationandcharacterization
of Pd supported on MgCO3 containing 4.7 wt.% in
metallic form. Next, the catalytic activities of all
catalysts were evaluated in the racemization reaction of
(S)-(–)-1-phenylthylamine. The use of the catalyst
Pd/MgCO3 with 4.7% Pd led to a more satisfactory
racemization than with the others. Therefore, it was
selected for the dynamic kinetic resolution of some
primary amines because of its reactivity.
*e-mail: smlima@unifesp.br; fasiqueira@unifesp.br

Vol. 29, No. 10, 2018
Ferreira et al.
2145
Experimental
was purified by flash column chromatography using an
isocratic elution of MeOH:CH2Cl2 (1:1).
General methods
General procedure for the dynamic kinetic resolution
The X-ray powder diffraction (XRD) pattern of
the catalysts were obtained with nickel-filtered CuKα
radiation (λ = 1.5418 Å) using a Siemens D5005
diffractometer. The XRD data were collected between
2θ = 5 and 80° (in steps of 2° min-1). Transmission
electron microscopy (TEM) images were obtained using
a Tecnai FEI G20 operated at 200 kV. Samples were
prepared by drop casting an alcoholic suspension of
In a glass tube it was added alpha-methylbenzylamine
(0.0610 g, 0.500 mmol), 4.7% Pd/MgCO3 catalyst
(0.0730 g), toluene (3.5 mL), Na2CO3 (0.0530 g), CaLB
(lipase B from Candida antarctica) (0.060 g) and acyl
donor (isopropyl acetate, ethyl acetate, isoamyl acetate)
(0.3 mL). The tube was sealed with a rubber septum and
parafilm, followed by hydrogen introduction at 1 atm
pressure. The reactions were heated (60 or 80 °C) and
stirred for 24 h. The mixture was filtered, washed with
ethyl acetate and then with methanol. The solvent was
removed under reduced pressure. The crude was purified by
flash column chromatography (isocratic elution with ethyl
ether). The product was isolated as a yellowish white solid.
1
nanomaterial in carbon coated copper grid. H nuclear
magnetic resonance (NMR) spectra were recorded at
300 MHz instrument with chemical shifts (ppm) reported
relative to tetramethylsilane (TMS), using CDCl3 as
solvent. Enantiomeric excesses (ee) were determined by
gas chromatography (GC) analysis using a TRACETM
1310 Thermo ScientificTM chromatograph with a beta
cyclodextrin capillary column. The low-resolution mass
spectra (LRMS) were recorded on a Shimadzu GCMS-
QP2010 Plus mass-spectrometer. Optical rotations were
performed on A.Krüss Optronic automatic polarimeter
P3000 (λ 589 nm) using a cell with a path length of 50 mm.
20
[α]D +118.4 (c 1.51, EtOH); mp 98-102 °C; LRMS
(m/z, %): 163 ([M]+, 40), 106 ([M – 57]+, 100); 1H NMR
(300 MHz, CDCl3) d 7.33-7.23 (m, 5H, Ph–H), 5.95
(br s, 1H, NH), 5.11 (quint, 1H, J 6.9 Hz, CH), 1.96
(s, 3H, CH3), 1.47 (d, 3H, J 6.9 Hz, CH3); 13C NMR
(75 MHz, CDCl3) d 169.1, 143.1, 128.6, 127.3, 126.1,
48.7, 23.4, 21.7. GC analysis: β-cyclodextrin column,
(S)-enantiomer = 16.08 min, (R)-enantiomer = 17.18 min.
Preparation of Pd/MgCO3 containing 4.7% Pd
Basic magnesium carbonate (0.100 g, 12.0 mmol)
was dispersed in a solution of palladium acetate (0.010 g,
0.040 mmol) in H2O (2.0 mL), and was stirred at 80 °C
for 1 h. The mixture was cooled to room temperature. A
previously prepared reduction solution of formaldehyde
(0.5 mL, 37%) and sodium hydroxide (0.5 mL, 30%) was
added. The heating was continued for 30 min at 80 °C. The
catalyst was filtered, washed with distilled water and dried
under vacuum at 60 °C for 8 h.
Results and Discussion
The catalyst Pd/MgCO3 containing 4.7 wt.% of
palladium in metal form was prepared following the
deposition-precipitation method. Pd(OAc)2 and basic
MgCO3 were used as catalyst precursor and were converted
to Pd0 and MgC2O4, respectively. The reduction process
was performed by the addition of an alkaline solution of
formaldehyde in a ratio of 10:1 (formaldehyde:Pd), as
described in the literature.24 Initially, basic MgCO3 was
dispersed as a support in a mixture of Pd(OAc)2 in H2O,
which was heated at 80 °C for 1 h. In the beginning, the
mixture was brown and became black when the reduction
was completed. The X-ray diffraction pattern of the catalyst
is shown in Figure 1.
The X-ray diffraction patterns reflected peaks related
to the presence of Pd0. The diffraction lines at 2θ = 40.1
and 46.7° are characteristic of the Pd in metallic phase.
Together with the lines of Pd0, the XRD exhibited other
diffraction lines at 2θ = 17.1, 22.4, 37.2, 47.9 and 49.9°,
which correspond to magnesium oxalate phase. Crystallite
size was estimated from the integral width of the highest
intensity line of Pd0 (40.1°) using the Scherrer equation. The
value calculated was 2.3 nm. Magnesium oxalate was formed
General procedure for the racemization of (S)-(–)-1-phenyl-
ethylamine
To a solution of (S)-(–)-1-phenylethylamine (0.061 g,
0.50 mmol) in toluene, dimethyl sulfoxide (DMSO) or
acetonitrile (5.0 mL), it was added Pd/MgCO3 loading
4.7% Pd (0.061 g) and Na2CO3 (0.053 g). The reaction
was sealed with a rubber septum and parafilm, followed
by hydrogen introduction at 1 atm pressure. The mixture
was stirred and warmed (80 or 60 °C) for 24 h. After that,
the solution was filtered and the residue was washed with
ethyl acetate. The organic phase was washed with distilled
water, with brine and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure. The crude

2146
Preparation, Characterization and Catalytic Activity of Palladium Catalyst Supported on MgCO3
J. Braz. Chem. Soc.
A preliminary reaction condition chosen for initial studies
was using toluene as solvent, at 80 °C, under hydrogen
atmosphere for 24 h. Without the use of hydrogen, the
racemization reaction was not observed, indicating that
the hydrogen pressure is crucial. The reaction furnished
the desired product in 1% ee only and 76% yield. The ideal
racemization reaction should provide the conversion of 50%
of the (S)-substrate to the corresponding (R)-enantiomer,
affording the racemate (0% ee).
The next step was to find proper reactional conditions
for the catalytic racemization of (S)-(–)-1-phenylethylamine
(Table 1). The racemization was affected by the solvent,
temperature and additive. The best rate was obtained in
toluene, at 80 °C and without the use of Na2CO3 (Table 1,
entry 1). The presence of Na2CO3 affected the reaction
leading to lower yields. For the reactions performed in
DMSO, the racemization was not observed (entries 5-7).
On the other hand, when performing the reaction in
acetonitrile, the enantiomeric excesses were great, but
the racemized amine was isolated in moderate yields only
(entries 8-10), that could be explained by the formation of
side products, which was observed more significantly in
acetonitrile. Thin layer chromatography (TLC) analysis of
all reactions presented only one compound. However, the
GC analysis revealed the presence of secondary products
which could not be characterized due to the difficulty of
viewing and isolation.
The mechanism for racemization step, depicted in
Scheme 1, was adapted from the literature.24,30 The reaction
shown is a metal-catalyzed process of dehydrogenation-
hydrogenation and it produces the prochiral imine 3
as intermediate. After the hydrogenation of 3, both
enantiomers (1 and 4) are formed because of the syn
addition of hydrogen on the two faces of 3. The formation
of side products can be explained by the reaction of
Figure 1. X-ray diffractogram of Pd/MgCO3 catalyst.
during the reduction process, by the reaction of magnesium
carbonate with formaldehyde in a basic medium.
Representative image of the palladium catalyst with
4.7% Pd0 content was obtained by TEM, as well as the
corresponding particle size distribution in the catalyst
(Figure 2).
By the TEM analysis, the presence of palladium
nanoparticles, which generally present sizes ranging from
2 to 10 nm,24 was characterized by the most shaded spots
dispersed on the used support. A distribution in equal
proportions of diameters between 0-2 and 2-4 nm has been
noted. In addition, a good dispersion of the nanoparticles
was observed on the support of the catalyst, discarding the
possibility of agglomeration that could harm the catalytic
activity.
The catalytic activity of this catalyst was evaluated by the
reaction of racemization of the (S)-(–)-1-phenylethylamine.
Figure 2. (Left) Image of 4.7% Pd on MgCO3 and (right) its size distribution of nanoparticles (NPs) obtained by TEM analysis.

Vol. 29, No. 10, 2018
Ferreira et al.
2147
Table 1. Racemization of (S)-(–)-1-phenylethylamine using 4.7% Pd/
optimized for the racemization reactions, with addition of
isopropyl acetate as acyl donor (Table 2, entry 1).After that,
we decided to investigate the temperature and the acyl donor
influences for the DKR. Performing the reaction at milder
temperature of 60 °C and using isopropyl acetate as acyl
donor, the compound 2 was converted to the corresponding
acetamide (11) in excellent yield (98%) with high optical
purity (> 99%) (Table 2, entry 2). Isopropyl acetate was
the best among three acylating agents tested for DKR of 2.
While the use of Na2CO3 in the racemization reaction has
not contributed positively, for the DKR this reagent had an
important role. The use of Na2CO3 at milder temperature
may have been responsible for the suppression of the side
products formation.
Next, the reaction scope of the DKR protocol was
extended to a compound bearing electron withdrawing
group (8) and electron donor group (9) at the aromatic
position. In both studied cases, the substituents contributed
for less reactivity, compared to that obtained for amine 2.
A longer reaction time of 36 h was necessary to complete
the conversion of the fluorinated substrate 8 to the
corresponding chiral acetamide (entries 6 and 7). For the
methyl substituted compound 9, a higher temperature
of 100 °C and isoamyl acetate as acylating agent were
required to improve the reaction yield to 66% (entry 12).
The reactions of the cyclic benzylic amine 10 required less
hindered acyl donor ethyl acetate, a milder temperature
of 80 °C and a longer reaction time of 36 h to furnish
the corresponding asymmetric acetamide 14, which
was isolated in excellent yield with high optical purity
(entry 14).
MgCO3 catalysta
entry Solvent
Additive Temperature / °C Yieldb / % eec / %
1
2
3
4
5
6
7
8
9
10
toluene
toluene
toluene
toluene
DMSO
DMSO
DMSO
CH3CN
CH3CN
CH3CN
–
Na2CO3
–
80
80
60
60
80
80
60
80
60
60
76
51
43
46
29
30
41
18
34
30
1
16
60
46
99
99
98
5
Na2CO3
–
Na2CO3
–
Na2CO3
–
3
Na2CO3
8
aThe reactions were performed on a 0.5 mmol scale with Pd/MgCO3
loading 4.7% Pd (0.061 g), Na2CO3 (1.0 equiv.), in toluene, DMSO or
acetonitrile (5 mL); bisolated yields; cenantiomeric excess by chiral GC
(β-cyclodextrin).
amine 2 with imine 3, which is acid-catalyzed and provides
the secondary amine 6 after the hydrogenation of the
intermediate 5. The hydrogenolysis of 6 is metal-catalyzed
and produces an equimolar mixture of 2 and ethylbenzene.
Conclusions
This paper describes the preparation and characterization
of Pd supported on MgCO3 containing 4.7 wt.% in metallic
form. The catalyst was characterized by X-ray diffraction
and transmission electron microscopy. After analyzing
the diffractogram, it was possible to identify the phases
corresponding to metallic palladium and estimate its
particles size. The catalyst support phases were attributed
to magnesium oxalate, which does not take precedence
as a component of heterogeneous palladium catalyst.
Transmission electron microscopy image showed an
equal distribution of the particles size between 0-2 and
2-4 nm, and also a good dispersion of the nanoparticles
on the support. The catalytic activity was evaluated by the
racemization reactions of (S)-(–)-1-phenylethylamine and
also by the DKR of racemic primary amines. In optimized
conditions, expressive yields and optical purities were
obtained.
Scheme 1.
The chemoenzymatic DKR of ( )-1-phenylethylamine
(2), which was used as a model compound, catalyzed by
CaLB and 4.7 wt.% Pd/MgCO3 afforded the asymmetric
N-acetylated product in 63% yield and 90% ee, when
the reaction was performed in a similar condition to that

2148
Preparation, Characterization and Catalytic Activity of Palladium Catalyst Supported on MgCO3
J. Braz. Chem. Soc.
Table 2. Dynamic kinetic resolution of amines mediated by 4.7 wt.% Pd/MgCO3 catalysta
entry
Substrate
Product
Temperature / °C
Acyl donor
time / h
24
Yieldb / %
eec / %
1
80
isopropyl acetate
63
90
2
3
4
2
2
2
11
11
11
60
60
60
isopropyl acetate
isoamyl acetate
ethyl acetate
24
24
24
98
82
75
> 99
98
> 99
5
60
isopropyl acetate
24
43
99
6
7
8
8
12
12
60
60
isopropyl acetate
ethyl acetate
36
36
95
90
99
98
8
60
isopropyl acetate
24
29
95
9
9
9
9
9
13
13
13
13
60
60
ethyl acetate
isoamyl acetate
isoamyl acetate
isoamyl acetate
48
24
24
24
47
47
59
66
95
99
99
99
10
11
12
80
100
13
60
isopropyl acetate
36
45
90
14
10
14
80
ethyl acetate
36
90
> 99
aThe reactions were performed on a 0.5 mmol scale with CaLB, Na2CO3 in toluene; bisolated yields; cenantiomeric excess by chiral GC (β-cyclodextrin).
Supplementary Information
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Published online: May 7, 2018
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