Is amine addition vital for highly enantioselective hydrogenation of α,β-unsaturated carboxylic acid over cinchonidine-modified palladium?

Article abstract of DOI:10.1016/j.molcata.2010.05.013

Benzylamine (BA) is a commonly employed additive for the hydrogenation of α,β-unsaturated acids over the cinchonidine-modified palladium catalyst, but the BA addition effects largely depend on the reaction solvent. In toluene, BA is not required to obtain the high enantioselectivity. Quicker desorption of the product due to weaker acidity in toluene than in a commonly used wet dioxane reasonably explains both the kinetic properties and the product selectivities.

Full text of DOI:10.1016/j.molcata.2010.05.013

Journal of Molecular Catalysis A: Chemical 327 (2010) 58–62
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Is amine addition vital for highly enantioselective hydrogenation of
␣,␤-unsaturated carboxylic acid over cinchonidine-modified palladium?
Tae Yeon Kim, Takashi Sugimura∗
Graduate School of Material Science, University of Hyogo, 3-2-1 Kohto, Kamigori, Ako-gun, Hyogo 678-1297, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2010
Received in revised form 19 May 2010
Accepted 19 May 2010
Available online 27 May 2010
Benzylamine (BA) is a commonly employed additive for the hydrogenation of ␣,␤-unsaturated acids over
the cinchonidine-modified palladium catalyst, but the BA addition effects largely depend on the reaction
solvent. In toluene, BA is not required to obtain the high enantioselectivity. Quicker desorption of the
product due to weaker acidity in toluene than in a commonly used wet dioxane reasonably explains both
the kinetic properties and the product selectivities.
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Pd/C
Enantioselectivity
Hydrogenation
Unsaturated acid
Additive
1. Introduction
includes formation of a complex containing the three components,
CD, BA and the substrate, on the basis of the rate comparison under
For the enantioselective hydrogenation over heterogeneous pal-
ladium catalysts, olefins are representative substrates [1]. The most
studied reaction is conversion of ␣,␤-unsaturated acids into satu-
rated ones carrying a chiral ␣-carbon, the stereochemistry of which
can be controlled satisfactorily with cinchonidine (CD) as a chi-
ral surface modifier [2,3]. A possible mechanism for differentiating
enantioface of the substrate originates in an acid–base interaction
with CD at the quinuclidine (1-azabicyclo[2.2.2]octane) part. The
enantiomeric excess (ee) of the product largely depends on the
preparation method of the palladium catalyst as well as the hydro-
genation conditions, but so far in all the cases, addition of amine,
usually benzylamine (BA) in a stoichiometric amount (0.6–1.0
molar equivalent to the substrate), was indispensable to obtain
the high product ee. The BA effects were first reported by Nitta;
the presence of BA increased the product ee with accompanying
increase in the reaction rate of the hydrogenation of phenylcin-
namic acid (1) (Scheme 1), and the amine effects were attributed
to promotion of the product desorption from the modified cata-
lyst surface [4]. The BA effects were observed in all the solvents
examined, though they were limited to protic or water-containing
solvents. Szöllösi et al. reported the same effects for the hydro-
genation of different ␣,␤-unsaturated acids, but they suggested
a different mechanism for hydrogenation of itaconic acid, which
moderate enantioselectivity (ee < 50%) [5]. Now, we assume that
addition of BA is not essential for the enantioselective hydrogena-
tion if the role played by BA is only in the product desorption from
the CD-modified site as suggested by Nitta, and that the high prod-
uct ee could be obtained without BA by performing the catalysis
under proper conditions. In this report, we will summarize details
of the results of reinvestigation aiming at an atom-economically
more preferable process to minimize use of the BA additive.
2. Experimental
The CD-modified Pd catalyst was prepared from STD-type
5%Pd/C supplied by N.E. Chemcat in a wet form (51%, w/w). The
metal surface area of the catalyst is 339 m2 g−1 (metal base),
corresponding to metal dispersion of 76%. Substrates 1 and 9
were obtained from commercial source, and other substrates were
prepared as reported [6]. BA was used from a freshly opened
bottle since an old one contained a considerable amount of N-
benzylidene(phenyl)methanamine. Solvents were reagent grade
and used as obtained. The hydrogenation procedure including the
pretreatment method of Pd/C was the same as that reported [7,8].
The procedure for the hydrogenation of 1 in toluene in the absence
of BA is as follows. In a 50 ml flat-bottomed glass flask with a
small septum port, Pd/C (43 mg as the wet form) and a stirring
bar were placed. The flask was evacuated to 13 kPa (10 Torr) for
10 min to remove the water and then was charged with hydro-
gen at the atmospheric pressure. Toluene (5 ml) was added to the
∗
Corresponding author. Tel.: +81 791 58 0168; fax: +81 791 58 0115.
E-mail address: sugimura@sci.u-hyogo.ac.jp (T. Sugimura).
1381-1169/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2010.05.013

T.Y. Kim, T. Sugimura / Journal of Molecular Catalysis A: Chemical 327 (2010) 58–62
59
Scheme 1. Enantioselective hydrogenation of phenylcinnamic acid (PCA) over CD-modified Pd/C.
the hydrogen uptake. IR spectra were obtained by a JASCO Ubest-50
with a solution cell having CaF2 windows.
3. Results
The effects of BA on the product ee were first investigated for the
hydrogenation of 1 using different solvents. Table 1 summarizes ee
values obtained in the presence and absence of BA, the differences
of which are given as ꢀee. The initial hydrogenation rates are in
parentheses. Dielectric constants and hydrogen solubilities of the
solvents studied are also given [9]. In the presence of BA, high ee
values in a range of 78–83% were obtained in all the solvents so
far studied. In contrast, the ee in the absence of BA depends on the
solvent used. The ee values are low in wet dioxane and wet DMF
as reported [4], but the ee is high in toluene and xylene to make
the effect of BA unclear. Another distinctiveness of the reactions
in toluene and xylene is lack of acceleration by the BA addition as
seen in rBA/rnoBA values, though the values become larger than unity
under different conditions (vide infra). The polarity or hydrogen
solubility of the solvent does not seem to be related with the BA
effects.
Fig. 1. Structures of the employed substrates.
flask, and the mixture was heated at 353 K for 30 min under stirring
(1200 rpm). The suspension was cooled to 296 K in a temperature-
controlled water bath, and a solution of CD (6 mg, 0.02 mmol) in
toluene (1 ml) was added. After stirring for 30 min, a solution of
1 (112 mg, 0.5 mmol) in toluene (4 ml) was added. The catalytic
activity was evaluated from the rate of hydrogen consumption at
20–25% conversion. The reaction was continued until hydrogena-
tion was complete. To the hydrogenation mixture, 2 M HCl (1 ml)
was added and the mixture was filtered to remove the catalyst.
Here, it was confirmed that the product was completely dissolved
in the solution, and no detectable product remained in the filtered
solid. The filtrate was extracted with ethyl acetate (5 ml) and then
washed with water (5 ml 2×). The extract was analyzed by 1H NMR
(600 MHz, CDCl3) to confirm completion of the hydrogenation, and
by HPLC with a chiral column (Chiracel OJ-H: Daicel), eluted with
a mixture of 2-propanol/hexane/trifluoroacetic acid = 5/95/0.1 at
a flow rate of 1 ml/min to determine the enantiomer ratio of the
product from 1. The standard retention times were 15.4 min for the
R-product and 24.4 min for the S-product. See Ref. [6] for HPLC anal-
ysis conditions for the other products. Kinetic study was performed
under the conditions similar to those used for ee determination
except for use of twice more substrate (1 mmol) and at a higher
temperature (323 K) to reduce experimental errors in measuring
Table 2 summarizes the results with substrates 1–9, the struc-
tures of which are shown in Fig. 1. Under the optimized conditions
with BA, 4,4ꢀ-dimethoxy substrate (2) shows higher enantioselec-
tivity than 1. Substrates 3–5 are analogues of 1 having different
steric hindrance at the ␤-p-phenyl that should play a major role in
the adsorption of the substrate [6]. Substrates 6–8 are analogues of
2 having different affinity to the solvent and the catalyst surface.
Substrate 9 is an aliphatic one that is known to give higher enantios-
electivity at 5 MPa than at the atmospheric pressure of hydrogen
by suppressing an isomerization/hydrogenation ratio [10]. For each
substrate, difference (ꢀee) in the effects of BA was compared
between the two solvents, wet dioxane and toluene. With all the
substrates, the effects of BA are clear on the reactions in wet diox-
ane, while the effects are not obvious in toluene; ꢀee’s are small
or even better ee was obtained in the absence of BA with several
substrates. The BA effects on the rate do not change systemat-
ically according to the properties of the substrates, presumably
due to the product precipitation unexpectedly occurring during the
hydrogenation to deteriorate the catalyst performance.
The kinetic effect of the BA addition could not be determined
precisely under the conditions of the reactions given in Table 2.
Reliable values were obtained from the hydrogen uptake monitored
with twice more substrate (1 mmol) and at a higher temperature
Table 1
Enantiomer excess (initial rate r/mmol g−1 h−1) of the product of hydrogenation of 1 in different solvents in the presence or absence of benzylamine (BA).
a
b
Solvent
εr
104x2
With BA
Without BA
ꢀeec (rBA/rnoBA
)
Wet dioxane
Ethyl acetate
MeOH
DMF
Toluene
2.5
6.1
33.6
37.1
2.4
–
83 (72)
78 (26)
83 (36)
83 (14)
78 (36)
80 (33)
57 (12)
59 (14)
61 (14)
58 (8)
75 (72)
72 (72)
26 (6)
3.46
1.61
–
3.15
4.15
19 (1.9)
12 (1.7)
25 (1.8)
3 (0.5)
8 (0.5)
p-Xylene
2.2
a
Dielectric constant.
H2 gas solubility in mol fraction.
ꢀee = (ee with BA) − (ee without BA).
b
c

60
T.Y. Kim, T. Sugimura / Journal of Molecular Catalysis A: Chemical 327 (2010) 58–62
Table 2
Enantiomeric excess (initial rate r/mmol g−1 h−1) of the product of hydrogenation of various substrates in the presence or absence of benzylamine in wet dioxane or toluene.
Substrate
In wet dioxane
BA
In toluene
BA
Without BA
57 (12)
ꢀeea
Without BA
75 (72)
ꢀeea
1
2
3
4
5
6
7
8
83 (72)
26
25
16
35
26
30
32
19
6
78 (36)
3
4
92 (43)
86 (40)
85 (34)
81 (16)
79 (21)
92 (34)
91 (42)
22 (<2)
38
67 (3)
70 (15)
50 (9)
55 (4)
49 (10)
60 (14)
72 (35)
16 (16)
21
88 (36)
75 (57)
63 (27)
62 (8)
82 (19)
89 (5)
85 (15)
16 (34)
28
84 (11)
83 (75)
63 (51)
65 (48)
73 (7)
91 (17)
86 (5)
21 (36)
33
−8
0
−3
9
−2
−1
−5
−5
9
9 (5 MPa)
17
a
Difference in the ee between those obtained in the presence and absence of BA.
Table 3
Initial hydrogenation rates (mmol g−1 h−1) of 1 and 2 at 323 K: comparison of the results obtained in the presence/absence of BA and in wet dioxane/toluene over the modified
and unmodified Pd catalyst.
Substrate
Catalyst
In wet dioxane
BA
In toluene
BA
None
BA/noBA
None
BA/noBA
1
1
2
2
Unmodified Pd
CD–Pd
Unmodified Pd
CD–Pd
432
344
180
179
522
120
223
12
0.83
2.9
0.81
15
402
199
138
180
499
172
165
45
0.81
1.2
0.84
4.0
(323 K), where the precipitation formation was still observed at the
later stage of the reaction. The uptake profiles of hydrogen are given
in Fig. 2. The reaction of 1 was performed over unmodified and CD-
modified catalysts in the absence and presence of BA in wet dioxane
(a). The same sets of the experiments were performed in toluene
(b), and with 2 in wet dioxane (c) and in toluene (d). The hydrogena-
tion rates given in Table 3 were determined from the initial linear
part consisting of 5–7 data points (r2 > 0.995). In all the experiments
with the CD-modified Pd, the BA addition accelerates the reaction
(BA/noBA > 1), while BA decelerates the reaction with the unmodi-
fied catalyst (BA/noBA = 0.81–0.84). The kinetic effect of BA on the
hydrogenation of 1 in wet dioxane is negative with unmodified Pd/C
to result in deceleration of 0.83 time, but it becomes positive with
CD-modified Pd/C to result in acceleration of 2.9 times, and thus
the ratio of the modified/unmodified catalysts (=m/u) is 3.5. This
m/u value is much larger with 2 to be 19 (=15/0.81). In toluene, the
Fig. 2. Hydrogenation uptake properties of (a) 1 in wet dioxane, (b) 1 in toluene, (c) 2 in wet dioxane, and (d) 2 in toluene. Each plot indicates following conditions. Open
circles: unmodified Pd/C in the absence of BA. Closed circles: unmodified Pd/C in the presence of BA. Open squares: CD-modified Pd/C in the absence of BA. Closed squares:
CD-modified Pd/C in the presence of BA.

T.Y. Kim, T. Sugimura / Journal of Molecular Catalysis A: Chemical 327 (2010) 58–62
61
Fig. 3. Expected difference between the solvents in the turn-over mechanism.
kinetic BA effect is also positive with CD-modified Pd/C to result
in acceleration, but it is much smaller than that observed in wet
dioxane. As a result, the m/u values in toluene, 1.5 (=1.2/0.81) for 1
and 4.8 (=4.0/0.84) for 2, are smaller than those in wet dioxane.
ative contribution from the background reaction to increase the
total product ee. The polarity of 2.5% water-containing dioxane
is not high (εr = ca. 2.5), but carboxylic acid should have certain
acidity due to the specific solvation. However, the degree of ion-
ization seems to be still low as deduced from the IR spectrum of
the PCA·CD salt dissolved in wet dioxane, where a sharp absorp-
tion peak corresponding to the hydrogen-bonding neutral carboxyl
group was observed at 1710 cm−1, while no obvious absorption for
4. Discussion
During the reinvestigation of solvent effects on the hydrogena-
tion of 1, it was found that the ee values obtained without BA are
sufficiently high in toluene but the BA effects are poor. In xylene,
the ee was somewhat lower than in toluene, but the BA effects
were similar. The poor BA effects at the high ee in toluene were
also observed with other substrates having different properties.
The value of 91% ee with 7 obtained without BA is on the same
level of the highest ee obtained by using CD-modified Pd catalyst
under the conditions optimized with BA. Since toluene has diffi-
culty in the product solubility under the present conditions, some
of the ee values obtained in toluene may be improved by tuning the
reaction conditions to solubilize the product. In fact, the reaction
of 1 without BA in toluene gave higher 78% ee (r = 70) when the
substrate concentration was reduced to half that of the standard
conditions.
carboxylate was observed in a range of 1550–1650 cm−1
.
In an aprotic solvent, acidity of the carboxylic acid becomes
weak as pKA = 11–12 even in very polar DMSO (12–14 in DMF), and
should be much weaker in less polar toluene. In contrast, basicity of
amine is not much affected; pKBH = 11.0 for quinuclidine in water
and 9.8 in DMSO [11]. Thus, interaction between carboxylic acid
and tertiary amine in toluene should not be a polar acid–base salt
formation, but weaker hydrogen-bonding. Hence, as illustrated in
Fig. 3b, the interaction between the product and CD on Pd surface
should be less ionic in toluene, and the unionized product on CD
can be exchanged quickly with the neutral substrate.
5. Conclusion
Another notable feature observed with the toluene solvent is the
kinetic effect of BA. Acceleration effect by the BA addition is evident
in wet dioxane with the CD-modified Pd, while it was not observed
without CD modification. This observation is in good agreement
with the reported results, which gives the following explanation
on the ee improvement by the BA addition [4]. The substrate is
adsorbed on the CD-modified metal surface by the assistance of an
acid–base interaction with CD, which makes the substrate adsorp-
tion stronger. Just after the hydrogenation step, the product is still
adsorbed similarly, and the strong adsorption makes the desorp-
tion step rate-determining of the overall hydrogenation reaction.
The slow catalytic cycle due to the desorption problem at the CD-
modified catalyst surface will allow the background reaction to
show up, which occurs at the CD-unmodified surface to produce
the racemic product [6]. The observed ee values suggest that the
reaction in toluene does not have a desorption problem in giving
high product ee independent of the BA addition. Kinetic effects of
BA in toluene are dependent on the reaction conditions, but they
are much smaller than those in wet dioxane in conformity with the
above explanation.
By the present study, it was found that the BA addition is
effective, but is not always required to obtain the high enantios-
electivity in the hydrogenation of ␣,␤-unsaturated acids over the
CD-modified Pd/C. As a result, the atom-economically preferable
process avoiding the use of BA could be established. From a differ-
ent viewpoint, the solvent effect on the enantioselectivity is large
in the absence of BA due to the background reaction.
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