Enhanced enantioselectivity achieved at low hydrogen pressure for the asymmetric hydrogenation of methyl acetoacetate over a tartaric acid NABR-modified Raney nickel catalyst: A kinetic study

Article abstract of DOI:10.1246/bcsj.20190070

To ensure high enantiopurity of the product, enantio-differentiating hydrogenation of methyl acetoacetate over a (R,R)-tartaric acid-modified Raney nickel catalyst is normally performed under elevated H₂-pressure (³10 MPa). In this study, higher enantioselectivity than previously reported for methyl acetoacetate was achieved (92% ee) under low H₂pressure of 0.42 MPa. Effects of reaction conditions on the enantioselectivity and hydrogenation rate were investigated using a low-pressure reaction system (<0.5 MPa of H₂). It was found that impurities in the solvent greatly reduce the enantioselectivity of MAA. The low-pressure reaction system enabled a satisfactory kinetic approach. The reaction rate was well described by Langmuir-Hinshelwood formalism, verifying the previous assumption that the addition of adsorbed hydrogen to the substrate interacting with surface tartrate is a rate-determining step.

Full text of DOI:10.1246/bcsj.20190070

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Document type: Article
Enhanced Enantioselectivity Achieved at Low Hydrogen Pressure
for the Asymmetric Hydrogenation of Methyl Acetoacetate over a
Tartaric Acid NaBr-Modified Raney Nickel Catalyst: A Kinetic Study
Azka Azkiya Choliq, Rio Nakae, Mariko Watanabe, Tomonori Misaki, Morifumi Fujita,
Yasuaki Okamoto, and Takashi Sugimura*
Graduate School of Material Science, University of Hyogo, Kohto, Kamigori, Hyogo 678-1297, Japan
E-mail: sugimura@sci.u-hyogo.ac.jp
Received: March 12, 2019; Accepted: April 11, 2019; Web Released: May 31, 2019
Takashi Sugimura
Dr. Takashi Sugimura, Professor at the University of Hyogo, graduated from Osaka University in 1979 and
received his PhD in 1984. After working as a postdoctoral fellow at Ohio State University, USA for two years,
he got a job at Himeji Institute of Technology in 1986. He has been a full professor at University of Hyogo,
Graduate School of Material Science, since 2006. He has been studying in the fields of both organic
synthesis and asymmetric hydrogenation catalysis. He received an award in 1995 for Excellent Young
Scientists from The Society of Organic Synthetic Chemistry, Japan.
O
O
OH O
Abstract
To ensure high enantiopurity of the product, enantio-
H2
O
O
(R,R)-TA-NaBr-MRNi
differentiating hydrogenation of methyl acetoacetate over a
(R,R)-tartaric acid-modified Raney nickel catalyst is normally
performed under elevated H2-pressure (³10 MPa). In this
study, higher enantioselectivity than previously reported for
methyl acetoacetate was achieved (92% ee) under low H2-
pressure of 0.42 MPa. Effects of reaction conditions on the
enantioselectivity and hydrogenation rate were investigated
using a low-pressure reaction system (<0.5 MPa of H2). It
was found that impurities in the solvent greatly reduce the
enantioselectivity of MAA. The low-pressure reaction system
enabled a satisfactory kinetic approach. The reaction rate was
well described by Langmuir-Hinshelwood formalism, verifying
the previous assumption that the addition of adsorbed hydrogen
to the substrate interacting with surface tartrate is a rate-
determining step.
Scheme 1. Enantio-differentiating hydrogenation of methyl
acetoacetate (MAA) under low pressure over a (R,R)-
tartaric acid-NaBr-modified Raney nickel catalyst.
achieved was 98% ee (enantiomeric excess) when methyl 3-
cyclopropyl-3-oxopropanoate was used as a substrate.4 The
hydrogenation of methyl acetoacetate (MAA), the simplest β-
ketoester, resulted in methyl 3-hydroxybutyrate (MHB) with
enantiopurity of 86% ee (Scheme 1) over tartaric acid-NaBr-
modified Raney nickel.5 Recently Osawa and co-workers
reported higher ee values of 88% and 91% with tartaric acid-
NaBr-modified reduced Ni14 and commercial Ni powder16,17
catalysts, respectively, at 9 MPa of H2. Severe reaction condi-
tions (10 MPa, 333 K) are mostly used to study this system to
ensure high reactivity and enantioselectivity.1,2,5,18
Keywords: Low-pressure enantioselective hydrogenation
Modified Ni catalyst Reaction kinetics
j
However, it would be much more favorable for industrial
applications, particularly in terms of safety and atom economy
of hydrogen, if the reaction could be conducted under low
hydrogen pressure, preferably atmospheric pressure of hydro-
gen, while maintaining high enantioselectivity of the reaction.
The dependency of enantioselectivity of the asymmetric
hydrogenation over tartaric acid-modified Ni catalysts on
hydrogen pressure has been investigated previously by several
groups (Figure 1). Lipgart et al.12 reported that the enantiose-
lectivity hardly changed under hydrogen pressure of 2.5-10
MPa for the hydrogenation of ethyl acetoacetate over a
modified Raney nickel catalyst. The maximum enantioselec-
tivity achieved was 17% ee. Ozaki and co-workers6 reported
j
1. Introduction
(R,R)-Tartaric acid and NaBr-modified Raney nickel is
known as an excellent catalyst for the asymmetric hydro-
genation of β-ketoesters and ketones. This catalyst system has
been intensively studied by various groups for a long time to
enhance the enantiopurity of the hydrogenation products. Many
aspects have been thoroughly investigated, including cata-
lyst preparations, reaction conditions, substrate generality and
reaction mechanism.1-15 The highest enantioselectivity ever
Bull. Chem. Soc. Jpn. 2019, 92, 1175–1180 | doi:10.1246/bcsj.20190070
© 2019 The Chemical Society of Japan | 1175

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shown that the reaction rate can be expressed by a Langmuir-
Hinshelwood formalism assuming the first hydrogen addition
to the substrate as a rate-determining step.
2. Experimental
2.1 Materials. Methyl acetoacetate (MAA) and acetic acid
were purchased from Kishida Chemical Co., Ltd. and used as
received. Ion exchanged water for the catalyst preparation was
supplied from Kishida Chemical Co., Ltd. (R,R)-tartaric acid
sodium salt was supplied from Nacalai Tesque, Inc. and used as
received. Commercially available THF was distilled vigorously
using sodium-potassium alloy and benzophenone prior to use
as a solvent.
Figure 1. Previous reports by several groups regarding the
dependency of enantioselectivity on hydrogen pressure;
Nitta et al.18 (filled circles), Kukula and Cerveny11 (filled
triangles), and Osawa et al.8 (filled and empty squares).
2.2 Catalyst Preparation.
Raney nickel (RNi) was
prepared from a Ni/Al alloy (42/58, Kawaken Fine Chemicals,
Ltd., Japan) by the W-2 type development method, followed by
washing with water under ultrasonic irradiation. An aliquot of
the alloy (1.0 g) was treated in an alkaline solution of NaOH
(4.5 g) in deionized water (20 mL) at 373 K for 1 h. The modi-
fication was performed to prepare tartaric acid and NaBr-
modified Raney nickel (TA-NaBr-MRNi) by heating RNi at
373 K for 1 h in a 50 mL aqueous solution of (R,R)-tartaric acid
mono sodium salt as a chiral modifier (6.6 mmol) and NaBr
(5 g) as an auxiliary. After the modification, the solution was
removed by decantation, followed by washing with water
(50 mL © 2), then with methyl alcohol (50 mL © 2), and finally
with tetrahydrofuran (distilled THF) (50 mL © 2) to prepare TA
NaBr MRNi (400 mg).
2.3 Hydrogenation. To a 250 mL glass autoclave (Parr,
Hydrogenation Apparatus, Model 3916) equipped with a ther-
mocouple, heating mantle, temperature controller, pressure
gauge, gas cylinder and reciprocal shaker, MAA was placed
with THF (50 mL), acetic acid (0.2 mL) and TA-NaBr-MRNi
(400 mg). The residual air in the reactor was replaced with
hydrogen by performing a cycle of refill of H2 at 0.5 MPa/
release at 0.1 MPa five times and then hydrogen was injected
into the reactor for the reaction (total pressure, 0.13-0.50 MPa).
Hydrogen pressure was kept constant during the hydrogenation
reactions by use of a hydrogen reservoir. The partial hydrogen
pressure was calculated assuming a Raoult’s law for the solvent
THF (ca. 0.08 MPa at 333 K). The autoclave was heated to
333 K and then reciprocating shaking was applied to initiate the
catalytic reaction. The reciprocating cycle was 175 cycles per
minute. The reaction was conducted for 16 h, 24 h, 32 h, 48 h or
96 h with TA-NaBr-MRNi. The reaction mixture was separated
from the catalyst by decantation. NMR was used to determine
the conversion of the substrate. Prior to determining enantio-
selectivity, the reaction products were acetylated with acetic
anhydride and pyridine. Enantiomeric excess of the products
was determined with gas chromatography (Shimadzu GC 17A
equipped with a CP-Chirasil DEX-CB capillary column, 0.25
mm © 25 m with a helium flow in 32 cm/s) at 100 °C; Rt =
5.18 min for (S)- and 5.32 min for (R)-product. Analytical
condition at different temperature has been reported elsewhere.4
Enantiomeric excess (%ee) is defined as,
the maximum enantioselectivity of 39% ee for the hydrogena-
tion of MAA under atmospheric pressure of hydrogen using a
tartaric acid-modified Raney nickel catalyst. Nitta and co-
workers18 studied the dependency of optical yields on hydro-
gen pressure for the hydrogenation of MAA over a tartaric acid
NaBr-modified Ni/SiO2 catalyst. It was shown that under
vigorous stirring, by which diffusion limitation was assumed to
be negligible, the enantioselectivity was slightly decreased and
then remained constant as the hydrogen pressure increased
from 0.5-13 MPa (333 K, 15% conversion). The maximum
enantiopurity of the product achieved was 80% ee. According
to Kukula and Červený,11 the optical yield of the hydrogenation
of MAA in THF at 333 K over a tartaric acid-NaBr-modified
Raney nickel catalyst increased as the hydrogen pressure
increased from 1 to 12 MPa. The maximum enantiopurity of the
product was 83% ee at 12 MPa. More recently, Osawa and co-
workers8 reported the hydrogen pressure-dependency of the
optical yield over a tartaric acid-NaBr-modified Raney nickel
catalyst for the hydrogenation of MAA in THF at 373 K using
an autoclave equipped with a magnetic stirrer (1220 rpm). It
was shown that the optical yield of the product remained
almost constant under hydrogen pressure of 2-9 MPa, but
decreased significantly as the pressure decreased below 1 MPa.
At the low hydrogen pressure, a higher stirring rate was neces-
sary to ensure sufficient hydrogen supply onto the catalyst sur-
face to attain higher enantiopurity of the product. A maximum
enantioselectivity of 82% was achieved under 0.2 MPa at 333 K
at a high stirring rate (1630 rpm). Low-pressure asymmetric
hydrogenation of MAA assisted by hydrogen atom transfer has
also been reported using tartaric acid-NaBr-modified supported
Ni.13 2-Propanol, as a hydrogen transfer agent, was used as the
solvent. A maximum enantioselectivity of 64% was attained
when the hydrogenation reaction was conducted at 323 K under
atmospheric pressure of H2 using tartaric acid-NaBr-modified
Ni/CeO2.
In this study, we report the enhanced enantioselectivity for
the hydrogenation of MAA over tartaric acid and NaBr-
modified Raney nickel under low hydrogen pressure (0.05-0.42
MPa) using a reciprocating reactor, with the maximum enan-
tiopurity, 92% ee, being achieved under 0.42 MPa, the highest
ee value ever reported. A kinetic study was satisfactorily per-
formed under the present low-pressure reaction system. It is
%ee ¼ 100 ꢀ ð½Rꢁ ꢂ ½SꢁÞ=ð½Rꢁ þ ½SꢁÞ
ð1Þ
where [R] and [S] denote the amounts of the (R)- and (S)-
products.
1176 | Bull. Chem. Soc. Jpn. 2019, 92, 1175–1180 | doi:10.1246/bcsj.20190070
© 2019 The Chemical Society of Japan

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selectivity and a lower reaction rate acceleration (a smaller
ligand-acceleration effect). Based on this preliminary study,
distilled THF was used as the solvent for further study on
reaction kinetics.
3. Results and Discussion
3.1 Effect of Solvent Impurities. Tetrahydrofuran has been
known as the best solvent for asymmetric hydrogenation of β-
ketoesters over TA-NaBr-MRNi resulting in the highest enan-
tiopurity of the product.5,6 Thus, in the present study, THF was
used as the solvent. However, commercially available THF
contains impurities, such as 2,6-di-tert-butyl-4-methylphenol
(250 ppm) and water (<0.05%), which may affect the hydro-
genation reaction. Therefore, preliminary experiments were
conducted to investigate the effect of impurities contained in
THF on the asymmetric hydrogenation of MAA.
Table 1 summarizes the effect of impurities in THF on the
hydrogenation reaction of MAA. When untreated commercially
available THF was used as the solvent, the asymmetric hydro-
genation of MAA resulted in 57% conversion after 24 h of
reaction time, producing MHB in 78% ee (Entry 1). However,
when commercially available THF was distilled prior to use
(Entry 2), the conversion of MAA slightly increased to 61%.
Moreover, surprisingly, the enantiopurity of the product sig-
nificantly increased to 90% ee.
The addition of 1 mL H2O into the distilled THF (50 mL)
considerably decreased the total hydrogenation rate to almost
one-third compared to that using distilled THF, accompanying
a significant decrease in enantioselectivity to 60% ee (Entry 3).
The production rate of (R)-MHB was decreased to almost one-
fourth by the addition of H2O, while that of (S)-MHB slightly
increased. This result is in agreement with the findings reported
by Izumi1 that water could act as an additive in the hydrogena-
tion of MAA over amino acid-modified RNi catalysts to reduce
the enantiopurity or, at a higher doping, even to reverse the
configuration of MHB. It is probable that the deteriorating
effect of H2O in Table 1 is due to the formation of hydrogen
bonding between water and, possibly, one hydroxy group of
surface tartrate, leaving only one hydroxy group available for
the interaction with MAA. In the presence of water-modifier
interaction, it is considered that a part of MAA interacts with
the surface modifier in the reversed position, in which the
relatively bulky alkoxy group of MAA is positioned opposite
from water due to steric hindrance, resulting in reversed enan-
tioface prior to the hydrogenation reaction. The decrease in the
hydrogenation rate of MAA in the presence of water might
be explained by competitive adsorption between MAA and
water on the active sites of the catalyst, which in consequence
decelerate the hydrogenation of MAA. We have observed
similar phenomenon in our previous studies where malic acid,
having only one hydroxy group, was used as a modifier instead
of tartaric acid.19 Malic acid-modified RNi resulted in a lower
3.2 Enantioselectivity of MAA-Hydrogenation under
Low Hydrogen Pressure.
With the current low-pressure
reciprocating reactor, sampling was not possible during the
reaction. Therefore, each reaction was conducted separately for
different length of time in order to understand the reaction rate
profile. Figure 2 shows the conversion of MAA against reac-
tion time under two representative hydrogen pressures: 0.42
MPa and 0.05 MPa. These results indicate that the reproduci-
bility of the catalyst preparation and reaction procedures is high
enough for a kinetic study. The initial reaction rate was
evaluated from the slope of the conversion-reaction time curve
below 20% conversion.
The effect of MAA conversion on the enantioselectivity of
MAA hydrogenation was also investigated under various
hydrogen pressures. Figure 3 shows the enantioselectivity of
MAA hydrogenation as a function of MAA conversion and
hydrogen pressure ranging from 0.05 to 0.42 MPa. As shown
in Figure 3, the enantioselectivity of the MAA hydrogenation
slightly increases as the conversion increases; the degree of the
increase being marginally enhanced as the hydrogen pressure
increases from 0.12 to 0.42 MPa. The selectivity remains
almost constant for the reaction under 0.05 MPa of H2.
Ozaki et al.6 reported a more extensive increase in the enan-
tioselectivity of MAA hydrogenation over a tartaric acid-
modified Raney nickel catalyst with increasing reaction time at
10 MPa (<40% ee). Kukula and Červený11 also observed that
Figure 2. Methyl acetoacetate (MAA) conversion against
reaction time at two representative hydrogen pressures:
0.42 MPa (red square) and 0.05 MPa (cross). (MAA 18.5
mmol, THF 50 mL, acetic acid 0.2 mL, TA-NaBr-MRNi
0.4 g, 333 K)
Table 1. Effect of impurities in THF on the hydrogenation rate of methyl acetoacetate (MAA) and enantiopurity of
methyl 3-hydroxybutyrate (MHB)a
r
rR
rS
Entry
Solvent
Additive
ee (%)
¹1
¹1
¹1
(mol h¹1 g-cat
)
(mol h¹1 g-cat
)
(mol h¹1 g-cat
)
1
2
3
THFb
78
90
60
1.09
1.18
0.41
0.97
1.12
0.32
0.12
0.06
0.08
Distilled THF
Distilled THF
H2O 1 mL
aMAA 18.5 mmol, THF 50 mL, acetic acid 0.2 mL, TA-NaBr-MRNi 0.4 g, 333 K, 0.42 MPa of H2, 24 h-reaction time.
bCommercially available THF was directly used without any pre-treatment.
Bull. Chem. Soc. Jpn. 2019, 92, 1175–1180 | doi:10.1246/bcsj.20190070
© 2019 The Chemical Society of Japan | 1177

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the selectivity on the MAA hydrogenation increased as the
reaction proceeded over a tartaric acid-NaBr-modified Raney
nickel catalyst at 12 MPa (<83% ee). In contrast, Nitta and
coworkers18 found with a tartaric acid-modified Ni-SiO2 cata-
lyst that the optical yield of MHB showed the maximum
around 50% conversion of MAA at 1 MPa of H2 (<60% ee).
The reasons of the selectivity increase with increasing conver-
sion are not clear enough at present. Ozaki et al.6 assumed that
non-selective sites of the modified Raney nickel catalysts
suffered from the loss of the hydrogenation activity caused by
contamination by residual Al-compounds during the reaction,
thereby causing the selectivity increase. In addition to the activ-
ity loss of the non-selective sites, it may be also possible to
evoke a small contribution of pre-adsorbed hydrogen, which
evolves during the catalyst preparation and remains on the
resultant catalyst surface, in particular, on the unmodified or
non-selective sites even after the chiral modification, to be
responsible for the initial formation of racemic products and,
probably, for the relatively lower selectivity at 0.05 MPa of H2.
We investigated the enantioselectivity of the hydrogenation
of MAA over TA-NaBr-MRNi using distilled THF as the sol-
vent at 333 K under low H2-pressures, ranging from (0.05-0.42
MPa). Table 2 summarizes the enantioselectivity of the MAA-
hydrogenation as a function of the H2-pressure.
It is shown in Table 2 that, regardless of the reaction time,
the enantioselectivity of MAA gradually increases as the
hydrogen pressure increases from 0.05 to 0.42 MPa, with the
maximum enantioselectivity (92% ee, the highest ee value ever
reported for MAA) being achieved at 0.42 MPa. However,
it decreases significantly to 82% ee for the reaction at sub-
atmospheric pressure (0.05 MPa). The highest enantioselectiv-
ity, 86% ee, reported previously5 for the hydrogenation of
MAA has been achieved at elevated pressure of H2 by optimiz-
ing the catalyst preparation of TA-NaBr-MRNi and reaction
conditions. The present research group greatly improved in
1994 the enantio-differentiating ability of the catalyst system
from 80 to 86% ee for MAA hydrogenation at 10 MPa by
applying ultrasonic irradiation during washing procedures after
leaching.3 Since then, the selectivity of 86% ee has long been
the highest and, then, the target selectivity for the asymmetric
hydrogenation of MAA, a kind of a standard compound in
the asymmetric hydrogenation of β-ketoesters over modified
Raney nickel catalysts, although a higher selectivity of 91% ee
was recently reported over a modified commercial Ni powder
catalyst at 9 MPa of H2.16,17 In addition, as noted in Introduc-
tion and Figure 1, the selectivity remains almost constant at
a relatively high hydrogen pressure (2-10 MPa) but signifi-
cantly decreases as the hydrogen pressure decreases, in partic-
ular, below 0.5 MPa. However, as summarized in Table 2, it is
very noteworthy here that the selectivity of 92% ee is attained
at as low as 0.42 MPa of H2. This extraordinary enantio-
differentiating ability of TA-NaBr-MRNi resulted from the
purification of the solvent used, as suggested above. A slight
increase in the selectivity with increasing hydrogen pressure
may be due to the increase in the ratio of the reaction rates over
modified sites to unmodified sites. The fraction of the
unmodified sites was estimated to be below 5%.2 The present
findings that the highest ever enantioselectivity is achieved
even under a low hydrogen pressure will expand the industrial
applications of modified Raney nickel catalyst systems for the
asymmetric hydrogenation of β-ketoesters.
3.3 Reaction Kinetics of MAA Hydrogenation over TA-
NaBr-MRNi. The initial hydrogenation rate was evaluated
from Figure 1 below 20% conversion of MAA. Figure 4 shows
the effect of hydrogen pressure on the hydrogenation rate
of MAA at two representative MAA concentrations: (a) 0.71
mol/L and (b) 1.42 mol/L. It is apparent that the reaction rate
increases with the hydrogen pressure, following a convex
Figure 3. Dependence of the enantioselectivity of the MAA
hydrogenation on the MAA conversion under various H2-
pressures: 0.42 MPa (red square), 0.32 MPa (yellow
triangle), 0.22 MPa (blue circle), 0.12 MPa (green dia-
mond) and 0.05 MPa (cross). (18.5 mmol of MAA and
0.2 mL of acetic acid in 50 mL of THF at 333 K)
Table 2. Enantioselectivity of asymmetric hydrogenation of MAA over TA-NaBr-MRNi at 333 Ka
Hydrogen pressure/MPa
Reaction time/h
Conversion/%
Enantioselectivity/%ee
0.05
24
16
24
16
48
16
24
24
48
25
28
45
42
91
33
63
59
93
82
87
87
89
89
88
90
91
92
0.12
0.22
0.32
0.42
aReaction Conditions: 18.5 mmol of MAA and 0.2 mL of acetic acid in 50 mL of THF with 0.4 g of the catalyst.
1178 | Bull. Chem. Soc. Jpn. 2019, 92, 1175–1180 | doi:10.1246/bcsj.20190070
© 2019 The Chemical Society of Japan