Reactions of chlorine substituted (E)-2,3-diphenylpropenoic acids over cinchonidine-modified Pd: Enantioselective hydrogenation versus hydrodechlorination

Article abstract of DOI:10.1016/j.molcata.2010.09.013

The effect of the chlorine position on the C-Cl bond hydrogenolysis and the enantioselective hydrogenation of Cl substituted (E)-2,3-diphenylpropenoic acid derivatives has been studied over cinchonidine-modified Pd/Al₂O ₃. In contrast to the fast hydrodechlorination of the β-phenyl-para-Cl substituted acids the Cl on the α-phenyl ring was barely hydrogenolized. These observations were interpreted by the different arrangements of the two phenyl rings on the surface, with the α- and β-phenyl rings adsorbed tilted and parallel, respectively. The results confirmed the beneficial effect of the α-phenyl-ortho-substituents on the chiral discrimination, thus the 2,3-diphenylpropionic acids substituted by Cl on the α-phenyl ring could be prepared in good yields and optical purities. The conclusions were used for the rational design of an acid, i.e. (E)-2-(2-methoxyphenyl)-3-(3,4-difluorophenyl)propenoic acid, which afforded the best optical purity (ee up to 95% at 295 K) described until now in this heterogeneous system.

Full text of DOI:10.1016/j.molcata.2010.09.013

Journal of Molecular Catalysis A: Chemical 333 (2010) 28–36
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Reactions of chlorine substituted (E)-2,3-diphenylpropenoic acids over
cinchonidine-modified Pd: Enantioselective hydrogenation versus
hydrodechlorination
György Szo˝ llo˝ sia,∗, Beáta Hermánb, Erika Szabadosc, Ferenc Fülöpa,b, Mihály Bartóka,c
a Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, Dóm tér 8, Szeged H-6720, Hungary
b Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös utca 6, Szeged H-6720, Hungary
c Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged H-6720, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2010
Received in revised form 2 September 2010
Accepted 10 September 2010
Available online 18 September 2010
The effect of the chlorine position on the C–Cl bond hydrogenolysis and the enantioselective
hydrogenation of Cl substituted (E)-2,3-diphenylpropenoic acid derivatives has been studied over
cinchonidine-modified Pd/Al2O3. In contrast to the fast hydrodechlorination of the ␤-phenyl-para-Cl
substituted acids the Cl on the ␣-phenyl ring was barely hydrogenolized. These observations were inter-
preted by the different arrangements of the two phenyl rings on the surface, with the ␣- and ␤-phenyl
rings adsorbed tilted and parallel, respectively. The results confirmed the beneficial effect of the ␣-phenyl-
ortho-substituents on the chiral discrimination, thus the 2,3-diphenylpropionic acids substituted by Cl
on the ␣-phenyl ring could be prepared in good yields and optical purities. The conclusions were used for
the rational design of an acid, i.e. (E)-2-(2-methoxyphenyl)-3-(3,4-difluorophenyl)propenoic acid, which
afforded the best optical purity (ee up to 95% at 295 K) described until now in this heterogeneous system.
Keywords:
Enantioselective hydrogenation
Cinchonidine
Chlorine-substituent
(E)-2,3-Diphenylpropenoic acids
Palladium
© 2010 Elsevier B.V. All rights reserved.
1. Introduction
good enantiomeric excesses (ee) [14–21], while in the reaction
of (E)-2,3-diphenylpropenoic acid and its ring substituted deriva-
Optically pure carboxylic acids are often used chiral building
blocks in the fine chemicals industry [1,2]. Asymmetric catalytic
hydrogenations of the corresponding unsaturated acids are widely
used synthetic methods for the preparation of these compounds
[3,4]. The increased interest in environmental benign processes
motivated the efforts on developing heterogeneous asymmet-
ric catalytic systems to replace the widely used soluble metal
complexes [5,6]. A simple method to obtain enantioselective het-
erogeneous hydrogenation catalysts is the surface modification of
an active metal by chiral compounds. However, only a few efficient
heterogeneous catalytic systems developed using this approach
were reported up to now [7–12]. Among these Pd catalysts mod-
ified by cinchona alkaloids were found the most appropriate
for the enantioselective hydrogenation of prochiral unsaturated
carboxylic acids and other activated olefins [12,13]. The enan-
tioselectivities obtained in the hydrogenation of ␣,␤-unsaturated
carboxylic acids over cinchonidine (CD) modified Pd catalysts were
found highly dependent on the structure of the acid. The hydro-
genation of aliphatic or cycloaliphatic acids afforded moderate or
tives good to excellent, over 90% enantioselectivities were reached
[22–29].
For predicting the enantioselectivities obtainable with certain
carboxylic acids and thus, to further extend the scope of this cat-
alytic system it is necessary to know the interactions of the acid
with the modifier and the metal surface, i.e. the adsorption mode
of the acids on chirally modified surface sites. However, in this
complex three-phase catalytic system, collecting in situ data for evi-
dencing these interactions is difficult even with the fast developing
physico-chemical tools available today. Thus, in situ methodologies
still rely on information gathered under real reaction conditions by
controlled alteration of the structure and properties of one of the
reaction components, i.e. modifier, substrate, solvent or catalyst.
Although, such alterations may influence the reaction rate and ee by
multiple effects, the collected data may provide valuable mechanis-
tic details for understanding the surface processes and the structure
of the intermediates involved.
In the hydrogenation of (E)-2,3-diphenylpropenoic acid the
importance of the interaction strength of the substrate with the
chiral modifier was illustrated by the effect of the methoxy sub-
stituents on the phenyl rings [24–28]. The interaction of the
substrate with the metal surface was also addressed by using het-
eroaromatic analogs of (E)-2,3-diphenylpropenoic acid [30,31]. The
∗
Corresponding author. Tel.: +36 62 544514; fax: +36 62 544200.
E-mail address: szollosi@chem.u-szeged.hu (G. Szo˝ llo˝ si).
1381-1169/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2010.09.013

G. Szo˝llo˝si et al. / Journal of Molecular Catalysis A: Chemical 333 (2010) 28–36
29
present study besides widening the scope of the enantioselective
X1
hydrogenation of (E)-2,3-diphenylpropenoic acid derivatives over
CD modified Pd, was aimed to collect further experimental data
to ascertain the adsorption mode of the acid on the metal sur-
face. Due to the well-known hydrogenolysis of the C–Cl bond of
chloro-aromatics over Pd catalysts [32–34], we anticipated, that Cl
substituted acids are appropriate to indicate the sites of the acid in
contact with the surface. Thus, we prepared twelve derivatives of
(E)-2,3-diphenylpropenoic acid substituted at least with one Cl and
examined their hydrogenation on unmodified and CD-modified
Pd/Al2O3. The position of the Cl in the acid molecule was chosen
based on the effect of other substituents (F, CH3O and CH3 groups)
on the rate and ee and taking into account the possible arrange-
ments of the phenyl rings derived from theoretical calculations
[35].
Y
X2
COOH
(1a) X1 = H, X2 = Cl, Y = H
(1b) X1 = H, X2 = Cl, Y = MeO
(1c) X1 = H, X2 = Cl, Y = F
(1d) X1 = Cl, X2 = H, Y = H
(1e) X1 = Cl, X2 = H, Y = MeO
(1f) X1 = Cl, X2 = H, Y = F
(1g) X1 = MeO, X2 = H, Y = Cl
(1h) X1 = H, X2 = MeO, Y = Cl
(1i) X1 = H, X2 = F, Y = Cl
(1j) X1 = Cl, X2 = H, Y = Cl
(1k) X1 = H, X2 = Cl, Y = Cl
(1l) X1 = Cl, X2 = Cl, Y = H
2. Materials and methods
2.1. Materials
Fig. 1. The structure of the Cl substituted (E)-2,3-diphenylpropenoic acids.
The catalyst used was a known commercial 5% Pd/Al2O3
(Engelhard, 40692) which was pretreated before use as described
earlier [26,27]. Cinchonidine (CD, Alfa Aesar, 99%), the ben-
zaldehyde and phenylacetic acid derivatives (Aldrich) were used
without purification. Benzylamine additive (BA, Fluka, ≥99.5%),
N,N-dimethylformamide (DMF, Scharlau, Multisolvent grade) and
H2 gas (Linde AG, 99.999%) were used as received. The substituted
(E)-2,3-diphenylpropenoic acid derivatives were prepared by the
Perkin condensation [26,27] and were purified by several crystal-
lizations in ethanol–water to over 98% purities. The acids were
identified and their purity was determined by 1H and 13C NMR
spectroscopy (Bruker Avance DRX 400 spectrometer at 400 MHz
(1H) and 100 MHz (13C) in d6-DMSO) and by GC–MS (Agilent Techn.
6890N GC–5973 MSD, 60 m HP-1MS capillary column) analysis of
the methyl esters formed by using CH2N2 ethereal solution (for
analytical data see the Supplementary material).
formed in excess were assumed to be S based on the rotation sign
[21–30] of the samples obtained after removal of CD and BA (Pola-
mat A polarimeter, the dextrorotatory enantiomers were formed in
excess) and based on the similar chromatographic behaviour of the
Cl substituted saturated products with the CH3O and F derivatives
obtained in previous studies [26,27].
3. Results and discussions
The hydrogenation of (E)-2,3-diphenylpropenoic acid over CD
modified Pd catalyst results in the excess formation of the (S)-
2,3-diphenylpropanoic acid in increased ee in the presence of
BA [22,23]. In the hydrogenation of CH3O and/or F substituted
derivatives the ee further increased except with ␤-phenyl-ortho-
substituents [24–27]. Beside the effect of the substituents on the
interaction strength of the acid with the modifier, the adsorp-
tion strengths of the acids were also affected by the substituents,
influencing the stereochemical out-come of the reactions [27,30].
Chlorine substituted derivatives may suffer parallel or consec-
utive C–Cl bond hydrogenolysis (hydrodechlorination) of the
unsaturated or/and saturated acids resulting in the correspond-
ing dechlorinated acids (Scheme 1, 3 and 4). The ratio of the
hydrogenation/hydrodechlorination rates is determined by the
adsorption mode of the substrate, i.e. the position of the Cl sub-
stituent. Thus, to obtain evidence on the adsorption mode of the
acids on the Pd surface we investigated the hydrogenation of
Cl substituted acids (Fig. 1). To be able to directly compare the
reactivity of the differently positioned Cl in the hydrogenolysis
reaction these derivatives included dichlorine substituted acids as
well.
2.2. Hydrogenation procedure and product analysis
The hydrogenations were carried out in a glass hydrogenation
apparatus under atmospheric H2 pressure and room tempera-
ture using magnetic agitation (1000 rpm). The H2 consumptions
between 0.15 and 0.25 equivalents (compared to the acid amount)
were used for calculating the initial H2-uptake rates (RiH). In a typ-
ical run 0.025 g catalyst was suspended in 3 cm3 DMF containing
2.5 vol% H2O, the apparatus was flushed with H2 and the catalyst
was pretreated for 0.5 h by stirring the slurry. After the pretreat-
ment 0.025 mmol CD, 0.5 mmol unsaturated acid and 0.5 mmol BA
(when used) in 2 cm3 solvent were added, the system was flushed
again with H2 and the reaction commenced by stirring the mixture.
After the given time 5 cm3 methanol was added, the catalyst was
filtered and washed with 5 cm3 methanol.
Portions (∼0.2–0.3 cm3) of the resulted solutions were concen-
trated in vacuum and used for the preparations of the methyl esters
(using CH2N2 ethereal solution). The resulted compounds were
identified by GC–MS analysis (see Supplementary material). Con-
versions (X (%)), chemoselectivities (Sel (%)) and enantioselectivities
(ee (%)) were calculated from the results of the gas chromato-
graphic analysis of these samples (YL6100 GC–FID) using chiral
capillary columns: Cyclosil-B (30 m × 0.25 mm, J&W Sci. Inc.,) and
ChiraldexTM G-TA (Astec, 40 m × 0.25 mm, Supelco). The ee was cal-
culated with the formulae: ee (%) = 100 × |[S] − [R]|/([S] + [R]); where
[S] and [R] are the concentrations of the product enantiomers.
Experiments carried out several times resulted in product compo-
sitions within 1%. The absolute configurations of the enantiomers
3.1. Effect of the ortho-chlorine substituent on the ˛-phenyl ring
The results obtained in the hydrogenation of the acids 1a, 1b and
1c which contained Cl substituent in ortho position on the ␣-phenyl
ring are presented in Table 1 and Fig. 2.
The initial H2-uptake rates (RiH) in the hydrogenation of these
compounds showed similar trends as observed in the reactions
of other (E)-2,3-diphenylpropenoic acid derivatives [22–28], i.e.
decreased as effect of modification by CD and the presence of BA
increased the RiH over modified catalyst. We point on the following
observations:

30
G. Szo˝llo˝si et al. / Journal of Molecular Catalysis A: Chemical 333 (2010) 28–36
Cl
Cl
+H2
Pd/Al2O3 + CD
COOH
S
COOH
(2)
(1)
+H2, Pd/Al2O3
-HCl
+H2, Pd/Al2O3
-HCl
N
OH
H
8
9
H
S
R
+H2
Pd/Al2O3 + CD
COOH
N
(CD)
COOH
S
(3)
(4)
Scheme 1. Example of the possible reaction pathways in the enantioselective hydrogenation of Cl substituted (E)-2,3-diphenylpropenoic acid derivatives over CD-modified
Pd catalyst.
(i) In none of these reactions unsaturated dechlorinated acids
(3a–3c) were formed.
(ii) The initial high hydrogenation selectivities (Sel (%)) decreased
and at extended reaction times significant amounts of dechlo-
rinated saturated acids (4a–4c) were obtained.
(iii) The hydrogenations of these acids slowed down over modified
catalyst at relatively low conversions (the values depended on
the substituent on the ␤-phenyl ring).
(iv) The ee of the saturated product (2a–2c) decreased in time over
modified catalyst in the absence of BA, while in the presence of
the additive slightly increased.
cally enriched 2a–2c) or a shift of their preferential formation from
unmodified to chirally modified sites during the reaction. How-
ever, the similar shapes of the conversion and ee (4a–4c) curves
supported the latter assumption (see Fig. 1a). The decrease in the
ee of 2a–2c by time may be attributed to the transformation of CD
in hydrochloride salt changing the enantiodifferentiating ability of
the modified sites by possible alterations in the conformation of the
modifier [36]. The ee decrease could also be due to the hydrodechlo-
rination of the readsorbed 2a–2c; the preferential readsorption of
the excess enantiomer may lead to kinetic resolution, as over Ni
modified by tartaric acid or cinchona alkaloid modified Pt [37–43].
In the presence ofBAthe formedHCl is neutralizedby this amine.
Thus, in these reactions besides increasing the desorption rate of
the saturated acids from modified sites [22–28], BA has the addi-
tional effect of preventing the alteration of the chiral sites. The time
dependence of the ee of 2a–2c in the presence of BA was influenced
by the ␤-phenyl substituent. The differences may be explained by
the influence of the para-substituents on both the substrates acidi-
ties and consequently on the strength of the acid–CD interactions
and the acids adsorption strength, also having effect on the read-
sorption rate of the saturated acids.
(v) The ee of the side products 4a–4c were initially low and
increased by time.
The decrease in the RiH over modified catalyst before reach-
ing complete conversions may be attributed to poisoning of the
Pd by the HCl formed during hydrodechlorination. The absence
of the unsaturated dechlorinated acids in the product indicated
that the hydrodechlorination was slower than the hydrogena-
tion. The low initial ee of 4a–4c were indication of coupled
hydrogenation–hydrodechlorination over unmodified surface sites
even in the presence of CD. The significant increase in these val-
ues parallel with the increase in their selectivities showed either
a change in the reaction pathway (by readsorption of the opti-
Altogether, the results indicated that on chiral surface sites the
adsorption of these acids does not lead to hydrodechlorination, this
process may occur by readsorption of the saturated acids when
Table 1
Hydrogenation of (E)-2-(2-chlorophenyl)-3-phenylpropenoic acid (1a) and (E)-2-(2-chlorophenyl)-3-(4-methoxyphenyl)propenoic acid (1b).a
c
Acid
Catalyst conditionb
RiH
t (h)d
X (%)d
Sel (%)e
2; 3; 4
ee (%)
2
4
1a
Unmodified
CD
21
5
0.7
1
2
8
1
2
6
1.5
6
3
81
100
70
77
70
81
94
44
65
25
32
35
62
84
96; 0; 4
89; 0; 11
99; 0; 1
91; 0; 9
97; 0; 3
94; 0; 6
86; 0; 14
76; 0; 24
69; 0; 31
94; 0; 6
87; 0; 13
94; 0; 6
86; 0; 14
76; 0; 24
–
–
–
–
5
30
15
19
33
–
70
64
69
70
71
–
CDBA
7
1b
Unmodified
CD
12
3
–
–
90
88
92
91
89
23
50
56
68
78
6
3
8
20
CDBA
11
a
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 cm3 N,N-dimethylformamide (DMF) + 2.5 vol% H2O, 0.5 mmol acid, 0.1 MPa H2, 295 K, 0.025 mmol CD (if used), 0.5 mmol BA (if
used).
b
Reactions carried out over unmodified or modified catalyst (CD) in the absence or in the presence of benzylamine (CDBA).
RiH: initial H2-uptake rate (mmol h−1 g−1).
c
d
e
t: reaction time needed to obtain the given X conversions.
Sel: product selectivities (for annotations see Scheme 1 and Fig. 1).

G. Szo˝llo˝si et al. / Journal of Molecular Catalysis A: Chemical 333 (2010) 28–36
31
Fig. 2. Hydrogenation of 1c over unmodified and CD-modified catalyst in the
absence (a) and presence of BA (b). Reaction conditions: see Table 1. Xrac and XCD
are the conversions (in parentheses the corresponding RiH values (mmol h−1 g−1));
Sel(2c)rac and Sel(2c)CD (%) are the selectivities of 2c over unmodified and CD-
modified catalysts (formation of 3c was not detected in these reactions, thus,
Sel(4c) ≈ 100 – Sel(2c)); ee(2c) and ee(4c) (%) are the enantioselectivities of 2c and
4c.
Fig. 3. Hydrogenation of 1e over unmodified and CD-modified catalyst in the
absence (a) and presence of BA (b). Reaction conditions: see Table 2. For abbrevia-
tions see Figs. 1 and 2 (the formation of 3e was detected only over modified catalysts,
Sel(3e) = 4–5% and 2–4% in the absence and presence of BA, respectively).
(ii) The formation of small amounts of unsaturated dechlorinated
acids (3d–3f) was detected especially over modified catalyst.
(iii) The initially high hydrogenation selectivities decreased by
time, longer hydrogenations led to significant amounts of
4d–4f formed by the hydrodechlorinations of 2d–2f and in a
smaller part by the hydrogenations of 3d–3f.
(iv) The transformation of these compounds was also decelerated
over modified catalyst before reaching full conversions.
(v) The ee of the saturated products 2d–2f decreased in time over
modified catalyst in the absence of BA, while in its presence
increased (except 2d, which was constant).
increased saturated product concentrations are reached. These
observations may be interpreted by the tilted arrangement of the
␣-phenyl ring of the acid on the modified Pd surface. We note
that the ees obtained in the hydrogenation of 1b and 1c in the
presence of BA equalled those reached in the reactions of the com-
pounds bearing F (ee 92% and 91%) or CH3O group (ee 90% and 93%)
instead of Cl [27], while provided higher ees as the correspond-
ing ortho-unsubstituted (ee 84%) or CH3-substituted compounds
(ee 84% [27]). This led us to suggest that the beneficial effect of the
substituents in this position on the ee is due to the partial charge of
the substituents (due to their electrostatic or dipole–dipole inter-
action with the modifier [44]) and their steric effect plays a less
significant role.
(vi) The ees of 4d–4f were constant or increased during these reac-
tions.
According to these results the behaviour of the ortho- and para-Cl
substituted acids (1a–1c and 1d–1f) were essentially similar, which
may be regarded as an indication of the similar reaction pathways
occurring during the hydrogenations of these types of chlorinated
acids. Thus, it may be assumed that initially the hydrodechlorina-
tion did not occur over chiral surface sites. The formation of HCl
had similar effect as previously, i.e. inhibited the hydrogenations
over modified catalyst in the absence of BA (see Fig. 3a). The low
ees obtained in the hydrogenations of 1d–1f may be ascribed to the
absence of electrostatic interaction with CD and in some part to
the lack of steric influence of the para-Cl on this interaction. The
above differences may originate mostly from these alterations of
the acid-CD interactions. Furthermore, the adsorption on unmodi-
fied surface sites of the para-Cl compounds through the ␣-phenyl
3.2. Effect of the para-chlorine substituent on the ˛-phenyl ring
The results obtained in the hydrogenations of acids bearing the
Cl substituent in para position on the ␣-phenyl ring (1d, 1e and 1f)
are summarized in Table 2 and Fig. 3.
The most important differences and similarities obtained in the
hydrogenations of these compounds and the previous acids are the
following:
(i) The RiH were much higher as those obtained in the hydro-
genation of the corresponding ortho-Cl substituted compounds
under identical conditions.

32
G. Szo˝llo˝si et al. / Journal of Molecular Catalysis A: Chemical 333 (2010) 28–36
Table 2
Hydrogenation of (E)-2-(4-chlorophenyl)-3-phenylpropenoic acid (1d) and (E)-2-(4-chlorophenyl)-3-(4-fluorophenyl)propenoic acid (1f).a
b
Acid
Catalyst conditionb
RiH
t (h)b
X (%)b
Sel (%)b
2; 3; 4
ee (%)
2
4
1d
Unmodified
CD
27
12
1
2
1
2
4
1
2
4
1
3
1
6
16
1
2
3
69
97
47
74
95
64
88
99
44
70
43
74
76
73
96
100
91; 0; 9
87; 0; 13
98; 0; 2
95; 1; 4
92; 1; 7
92; 3; 5
89; 2; 9
85; 0; 15
85; 4; 11
73; 0; 27
93; 2; 5
87; 2; 11
77; 1; 22
88; 2; 10
83; 2; 15
78; 0; 22
–
–
–
–
48
48
47
49
49
48
–
33
33
33
3
29
34
–
CDBA
16
1f
Unmodified
CD
34
9
–
–
63
54
47
53
73
73
22
29
38
28
59
61
CDBA
21
a
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 cm3 DMF + 2.5 vol% H2O, 0.5 mmol acid, 0.1 MPa H2, 295 K, 0.025 mmol CD (if used), 0.5 mmol BA (if used).
For abbreviations see Table 1, Scheme 1 and Fig. 1.
b
ring is not as much hindered as that of the ortho-substituted acids,
bond over unmodified Pd, leading to the formation of 4g–4i as the
major product. The extensive hydrodechlorination of the substrates
implies the formation of higher amounts of HCl and faster trans-
formation of CD in hydrochloride as compared with the previous
reactions. This is accompanied by lower ee of 2g–2i and also by
decrease in these values during the reactions. However, the low ees
are also due to the unfavourable effect on the CD–acid interaction of
the electron withdrawing Cl. The low ee of 4g–4i and the decrease of
due to the distance of the substituent from the ␣-C. Consequently,
the results obtained with these acids confirmed the tilted adsorp-
tion of the ␣-phenyl ring on the modified Pd.
3.3. Effect of the para-chlorine substituent on the ˇ-phenyl ring
For probing the arrangement of the ␤-phenyl ring on the Pd
surface we studied the hydrogenations of three compounds bearing
the Cl substituent in para position on this ring (1g, 1h and 1i). The
results are presented in Table 3 and Fig. 4.
These results showed a completely different behaviour of the
␤-phenyl-para-Cl substituted acids, as compared with those sub-
stituted on the ␣-phenyl. The most significant differences are the
followings:
(i) The
hydrogenated
product
selectivities
are
low
(Sel(2g–2i) = 13–40% depending on the acid and reaction
conditions), and small alteration in these values were
observed by time.
(ii) Over unmodified catalyst the major products are the dechlo-
rinated saturated acids 4g–4i and the unsaturated 3g–3i were
not formed.
(iii) In contrast, over modified catalyst the initial main products
are the dechlorinated acids 3g–3i, which were consecutively
hydrogenated to 4g–4i after extended reaction times.
(iv) The RiH values decreased drastically due to chiral modifica-
tion of the catalyst and increased 6–9 times when BA was also
used. The transformation of these compounds were the most
severely inhibited over modified catalyst in the absence of BA
(X 14–15% after 6 h).
(v) The ee of the saturated products 2g–2i strongly decreased in
time over modified catalyst in the absence of BA. In the pres-
ence of BA only small modifications were obtained, dependent
on the position and nature of the ␣-phenyl substituent.
(vi) The ee of 4g–4i were low and further decreased in the absence
of BA. In the presence of BA the alterations in the ees of 4g–4i
followed a similar trend as those of 2g–2i.
The results indicated an adsorption mode of the (E)-
2,3-diphenylpropenoic acids, which makes possible the fast
hydrogenolysis of the C–Cl bond on the ␤-phenyl ring, i.e. the flat
adsorption of this moiety. The rate of hydrogenolysis became the
Fig. 4. Hydrogenation of 1g (a) and 1h (b) over CD-modified catalyst in the presence
of BA. Reaction conditions: see Table 3. For abbreviations see Scheme 1, Figs. 1 and 2.
same order of magnitude as that of the hydrogenation of the C
C

G. Szo˝llo˝si et al. / Journal of Molecular Catalysis A: Chemical 333 (2010) 28–36
33
Table 3
Hydrogenation of (E)-2-(4-methoxyphenyl)-3-(4-chlorophenyl)propenoic acid (1g), (E)-2-(2-methoxyphenyl)-3-(4-chlorophenyl)propenoic acid (1h) and (E)-2-(2-
fluorophenyl)-3-(4-chlorophenyl)propenoic acid (1i).a
b
Acid
Catalyst conditionb
RiH
t (h)b
X (%)b
Sel (%)b
2; 3; 4
ee (%)
2
4
1g
Unmodified
CD
50
5
1
4
6
20
2
5
6
20
1
3
6
20
1
3
6
60
72
15
35
36
56
14
30
34
54
15
40
70
95
100
24; 0; 76
23; 0; 77
22; 63; 15
20; 2; 78
33; 0; 67
30; 0; 70
14; 77; 9
16; 9; 75
25; 2; 73
23; 0; 77
16; 73; 11
13; 10; 77
28; 51; 21
23; 32; 45
21; 7; 72
–
–
43
20
–
–
–
2
0
–
–
13
6
–
1h
1i
Unmodified
CD
19
2
–
64
26
–
Unmodified
CD
24
3
–
–
47
20
74
78
80
50
n.d.
78
81
n.d.
CDBA
22
a
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 cm3 DMF + 2.5 vol% H2O, 0.5 mmol acid, 0.1 MPa H2, 295 K, 0.025 mmol CD (if used), 0.5 mmol BA (if used).
For abbreviations see Table 1, Scheme 1 and Fig. 1; n.d.: not determined.
b
these values by time were indicative of the preferential successive
equal (∼60%). The ␣-phenyl-dichlorine-substituted compound (1l)
had an intermediate behaviour as compared with the correspond-
ing mono-Cl-substituted 1a and 1d as regards the ee, being closer
to that obtained in the reaction of 1a, indicating the dominating
effect of the ␣-phenyl-ortho-substituent on the ee.
hydrogenation of the dechlorinated unsaturated acids over racemic
surface sites (except 1i). The presence of BA had favourable effect
on both the selectivities and the ees of 2g–2i and 4g–4i, thus, the
poor results obtained in the absence of BA may be attributed mostly
to the effect of HCl on both the surface and the modifier. However,
even in the presence of BA the selectivities of 2g–2i were low and
the ees were smaller than those obtained in the hydrogenations of
the acids bearing F or CH3O group instead of Cl in the same position
or even in that of the corresponding ␤-phenyl-para-unsubstituted
acids [26,27], confirming the contribution of the electronic effects
of the ␤-phenyl-para-Cl substituent in determining the ee of 2g–2i.
Accordingly, the main reaction pathways in the hydrogenations
of the (E)-2,3-diphenylpropenoic acids substituted by Cl in different
positions may be summarized as sketched in Scheme 2. The differ-
ences in the reactivities of the Cl on the two phenyl groups indicated
without doubt that these moieties are differently arranged on the
surface when the acid is interacting with CD, i.e. the ␣-phenyl is
anchored in a tilted orientation, while the ␤-phenyl is adsorbed
parallel with the surface. The suggested arrangement of the (E)-2,3-
diphenylpropenoic acids interacting with CD on the metal surface is
illustrated on Fig. 5. The degree of tilt of the ␣-phenyl ring should be
dependent on the nature and steric effect of the substituents, which
will influence the rate and the ee of the hydrogenation. Experi-
ments aimed at determining more accurately the arrangement of
this moiety on the surface are in progress. Finally, these experi-
ments evidenced, that the CD-modified Pd catalyst, is not suitable
3.4. Hydrogenation of dichlorine-substituted derivatives
For the direct comparison of the effect of differently positioned
Cl next we studied the hydrogenation of three dichlorine substi-
tuted acids (1j–1l). The hydrodechlorination of these compounds
may result in the formation of two pairs of mono-Cl substituted
unsaturated and saturated acids, respectively, and a completely
dechlorinated unsaturated and saturated acid pair. Fortunately,
with each acid the hydrodechlorination occurred predominantly
in a specific position. The results obtained were summarized in
Table 4.
All these compounds showed preferential hydrodechlorination
pathways, which were in accordance with those indicated by the
hydrogenolysis selectivities of the mono-Cl derivatives. Thus, the
compounds bearing para-Cl on the ␤-phenyl ring suffered fast C–Cl
hydrogenolysis, resulting in low saturated product selectivities (2j,
2k) and predominant formation of the acids dechlorinated on the
␤-phenyl ring. In contrast, when both Cl substituents were situated
on the ␣-phenyl ring (in ortho and para position, 1l) high saturated
acid (2l) selectivities were obtained, with increasing amount of
dechlorinated product (4l) only after reaching complete conversion
of 1l. The ees also confirmed the interpretations of the hydrogena-
tions of the mono-Cl derivatives. Thus, the alterations in the ees
of both 2j and 4j obtained in the hydrogenations of 1j resembled
the behaviour observed in the hydrogenation of 1g (see Table 3
and Fig. 4), with somewhat lower values of the former, ascribed
to the effect of the ␣-phenyl-para-substituent (CH3O vs. Cl). Simi-
larly, small differences were observed when the ␣-phenyl ring was
substituted in ortho position with Cl or CH3O group (compare the
behaviour of 1k and 1h). In the hydrogenations in the presence of
BA the ees of the saturated dechlorinated 4k and 4h were almost
X'
X'
+ H2
Cl
Cl
X
X
Pd/Al2O3 - CD
COOH
X'
COOH
S
low selectivity,
+ H2
low to moderate ee
X'
- HCl
Pd/Al2O3
+ H2
X
X
Pd/Al2O3 - CD
COOH
S
COOH
the major products
(X and X' = H, F, MeO)
Cl
low ee
Cl
+ H2
Y
Y
Pd/Al2O3 - CD
COOH
COOH
S
high selectivity,
(Y = H, F, MeO)
moderate to good ee
(up to over 90 %)
Scheme 2. Reaction pathways observed in the enantioselective hydrogenation of
Cl substituted (E)-2,3-diphenylpropenoic acids over CD-modified Pd catalyst.

34
G. Szo˝llo˝si et al. / Journal of Molecular Catalysis A: Chemical 333 (2010) 28–36
Table 4
Hydrogenation of (E)-2,3-di(4-chlorophenyl)propenoic acid (1j), (E)-2-(2-chlorophenyl)-3-(4-chlorophenyl)propenoic acid (1k) and (E)-2-(2,4-dichlorophenyl)-3-
phenylpropenoic acid (1l).a
b
Acid
Catalyst conditionb
RiH
t (h)b
X (%)b
Sel (%)b
ee (%)
2; 3c; 4c
2
4d
1j
Unmodified
CD
28
3
1
4
6
20
1
2
2
4
6
20
2
6
1
3
6
2
3
6
50
81
17
62
84
99
47
65
13
38
98
99
100
59
81
64
87
100
32; 1e; 63e
32; 0; 62
27; 51; 20
29; 1; 67
43; 25; 29
37; 0; 49
14; 0f; 81f
12; 0; 72
6; 84; 10
10; 4; 80
38; 56; 4
12; 38; 41
90; 0g; 5g
95; 0; 3
–
–
–
–
28
12
50
55
–
1e
1
CDBA
34
22
2
40
43
–
1k
1l
Unmodified
CD
–
–
57
26
76
82
–
62
68
65
64
48
4f
4
CDBA
19
60
60
–
Unmodified
CD
21
7
n.d.g
n.d.
n.d.
83
62
90; 1; 6
96; 0; 3
92; 0; 5
62; 0;35
CDBA
8
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 cm3 DMF + 2.5 vol% H2O, 0.5 mmol acid, 0.1 MPa H2, 295 K, 0.025 mmol CD (if used), 0.5 mmol BA (if used).
For abbreviations see Table 1, Scheme 1 and Fig. 2; n.d.: not determined.
The selectivities of the major dechlorinated unsaturated and saturated products.
The ees of the major dechlorinated saturated acids.
3j: (E)-2-(4-chlorophenyl)-3-phenylpropenoic acid; 4j: 2-(4-chlorophenyl)-3-phenylpropionic acid.
3k: (E)-2-(2-chlorophenyl)-3-phenylpropenoic acid; 4k: 2-(2-chlorophenyl)-3-phenylpropionic acid.
3l = 3k; 4l = 4k.
a
b
c
d
e
f
g
for the preparation of 2,3-diphenylpropionic acids substituted by
However, in the presence of BA this inhibition was not observed and
the ee was only slightly lower than that obtained in the absence of
HCl. These results confirmed the assumption, that the HCl formed
during the hydrogenation of the chlorinated acids in the absence
of BA alters the enantiodifferentiating ability of the CD and inhibits
the reaction by poisoning the catalyst. The added BA neutralized
the HCl; the slightly lower ee may be attributed to decrease in the
amount of free BA available during the reaction.
Cl on the ␤-phenyl ring, however, may be an appropriate choice for
the preparation in good yields and optical purities of acids bearing
Cl substituent on the ␣-phenyl ring.
3.5. Hydrogenation in the presence of HCl and the scope of the
catalytic system
The low hydrogenolysis rate of both ␣-phenyl-ortho- and
para-Cl substituted acids was interpreted by the tilted arrange-
ment of this moiety on the surface. To further ascertain on the
above assumption the hydrogenation of a derivative bearing F
substituents in both ortho-positions on the ␣-phenyl ring was
attempted (1n, Fig. 6). It is known that the Ar–F bond is several
orders of magnitudes more resistant to hydrogenolysis than the
Ar–Cl [32,45], thus, the chosen substitution pattern should hinder
the adsorption and the hydrogenation of 1n. Indeed, low conver-
sions were achieved even over unmodified catalyst and beside the
saturated acid 2n, formation of a hydrodefluorinated product was
also detected. Over modified catalyst both in the absence and pres-
ence of BA decrease by one order of magnitude in the RiH led to
low conversions even after 20 h. The presence of BA decreased the
rate, the conversion and also the ee. Thus, these results showed
that substitution on both sides of the ␣-phenyl ring in ortho posi-
tion dramatically decelerates the hydrogenation as effect of their
steric hindrance, confirming the tilted arrangement of this moiety
on the surface.
The results of the hydrogenations of the chlorinated acids
were interpreted by assuming that the HCl formed during the
hydrogenolysis of the C–Cl bond poisoned the metal surface in
the absence of BA and also changed the intrinsic enantiodif-
ferentiation ability of the chiral sites by transformation of CD
in hydrochloride [36]. This assumption was verified by using
CD × HCl as modifier and hydrogenation in the presence of added
HCl. As a test compound we used (E)-2-(2-methoxyphenyl)-3-(4-
fluorophenyl)propenoic acid (1m, Fig. 6), which provided high ee
in previous studies (Table 5) [27].
The use of CD × HCl as modifier in the absence of BA resulted
in slightly decreased RiH and conversion as well, while the ee was
much lower as compared with CD. However, when BA was added
both the RiH and the ee were similar with the hydrogenation using
the free base (CD). Addition to the reaction mixture of 0.1 mmol HCl
had a striking effect on both the rate and ee, the hydrogenation was
severely inhibited and the product formed had very low optical
purity. We mention that this amount of HCl corresponds to the
amount formed by 20% hydrodechlorination of a Cl substituted acid.
The above conclusions and the results reported up to now
[24–28] delimited the scope of this catalytic system. Acids highly
substituted on the ␤-phenyl ring may be hydrogenated in excellent
ees depending on the electronic effect of the substituent [24,25],
except when this is in ortho position [26,27]. The substituents in
the latter position exert a strong steric inhibition on the CD-acid
interaction resulting in low rate and ee. The substituents on the
␣-phenyl ring have more limited effect, except those in the ortho
position [26,27]. These were found to increase the ee for reasons
not fully clarified yet (by their effect on the interaction with CD).
The ␣-phenyl moiety tolerates substitution in para, both meta [28]
Fig. 5. Schematic illustration of the arrangement on the Pd surface of (E)-2,3-
diphenylpropenoic acids interacting with the modifier.

G. Szo˝llo˝si et al. / Journal of Molecular Catalysis A: Chemical 333 (2010) 28–36
35
F
F
F
F
F
OMe
COOH
X
F
COOH
COOH
(1o) X = F
(1p) X = MeO
(1m)
(1n)
Fig. 6. Methoxy and fluorine substituted (E)-2,3-diphenylpropenoic acids examined.
Table 5
Hydrogenation of fluorine- and methoxy-substituted (E)-2,3-diphenylpropenoic acids.a
BA,b
Substrate
Modifier
RiH; RiH
X/t; XBA/tc
ee; eeBA (%)d
e
1m
–
9
99/6; –
94/6; 99/6
74/6; 99/6
5/6; 98/6
0; –
CDe
3; 7
2; 7
0.1; 7
4
0.4; 0.2
13
86; 93
67; 94
16; 89
0; –
75; 70
0; –
CD × HCl
CD + HClf
1n
1o
1p
–
50(86g)/6; –
50(95g)/20; 35(90g)/20
100/3; –
100/6; 100/6
100/4; –
CD
–
CD
–
6; 9
10
78; 87
0; –
CD
5; 9
100/8; 100/8
88; 95
a
Reaction conditions: 25 mg 5% Pd/Al2O3, 5 mL DMF + 2.5 vol% H2O, 0.5 mmol acid, 0.1 MPa H2, 295 K, 0.025 mmol CD (if used), 0.5 mmol BA (if used).
Initial H2-uptake rates (mmol h−1 g−1) in the absence and presence of BA.
Conversions (%) obtained after hydrogenation times t (h) in the absence and the presence of BA.
The ees (%) obtained in the absence and presence of BA.
Results published previously [27] and repeated during this work.
Addition of 0.1 mmol HCl (as 5 M aqueous solution) following CD and before adding the acid and BA (if used).
Selectivity of the saturated product 2n.
b
c
d
e
f
g
and one of the ortho positions. However, one of the ortho C must
remain unsubstituted to avoid impeding the adsorption of the acid
by the tilted ␣-phenyl ring.
The interpretation of the results was supported by hydrogenations
in presence of HCl and by the reaction of an ␣-phenyl-ortho,ortho-
difluorine substituted acid. Moreover, the conclusions of this study
were used for the design of an acid, which by hydrogenation in this
catalytic system under mild reaction conditions (room tempera-
ture) provided the saturated product in the best optical purity (ee
95%) reached up to now.
With these observations and conclusions in mind we attempted
to design two fluorinated acids (1o and 1p, Fig. 6), which could be
hydrogenated in higher ee as the (E)-2,3-diphenylpropenoic acid
derivatives studied up now (the highest ee value obtained in reac-
tions carried out at room temperature was 93% [27]). Although,
good ee was obtained in the hydrogenation of 1o, the best value
remained below 90% (Table 5). To our delight the replacement of
the ortho-F on the ␣-phenyl ring by CH3O group (1p) fulfilled our
expectations. Both in the absence and presence of BA the ee was
higher as obtained in the reactions of 1m under the same conditions
(room temperature), reaching up to 95% ee at full conversion.
Acknowledgements
Financial support by the Hungarian National Science Foundation
(OTKA Grant K 72065) is highly appreciated. The work was sup-
ported by the János Bolyai Research Scholarship of the Hungarian
Academy of Sciences (Gy. Szo˝ llo˝ si).
4. Conclusions
Appendix A. Supplementary data
A series of Cl substituted (E)-2,3-diphenylpropenoic acids were
prepared and their enantioselective hydrogenations over CD-
modified Pd/Al2O3 was studied in order to obtain in situ evidence
on the adsorption mode of this type of acids on the chirally modified
surface. The low C–Cl hydrogenolysis rates of the acids substituted
on the ␣-phenyl ring by Cl in either ortho or para position was in
contrast with the fast hydrodechlorination of the ␤-phenyl para-
Cl substituted acids. This behaviour was attributed to the different
arrangement of the two phenyl rings of the adsorbed acids, the
␤-phenyl parallel, while the ␣ tilted to the surface during the enan-
tioselective hydrogenation. The results obtained also confirmed the
beneficial effect of the ␣-phenyl-ortho-substituents on the chiral
discrimination, while in ␤-phenyl-para position the substituents
should have electron donating effect in order to reach good optical
purities. The differences in the effect of the Cl in different positions
were also evidenced by the hydrogenations of three dichlorine-
substituted acids.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molcata.2010.09.013.
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