Achiral amine additives in the enantioselective hydrogenation of aliphatic α,β-unsaturated acids over cinchonidine-modified Pd/Al 2O3 catalyst

Article abstract of DOI:10.1016/j.cattod.2011.07.034

The effect of the achiral amine additive structure was studied on the enantioselective hydrogenation of (E)-2-methyl-2-butenoic acid and (E)-2-methyl-2-hexenoic acid over Pd/Al₂O₃ catalyst modified by cinchonidine. It was found that

Full text of DOI:10.1016/j.cattod.2011.07.034

Catalysis Today 181 (2012) 56–61
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Achiral amine additives in the enantioselective hydrogenation of aliphatic
␣
,␤-unsaturated acids over cinchonidine-modified Pd/Al O catalyst
2 3
a
b
a,b,∗
Zsolt Makra , György Sz o˝ ll o˝ si , Mihály Bartók
a
Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary
Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The effect of the achiral amine additive structure was studied on the enantioselective hydrogenation
of (E)-2-methyl-2-butenoic acid and (E)-2-methyl-2-hexenoic acid over Pd/Al2O3 catalyst modified by
cinchonidine. It was found that secondary amines are similarly or even more efficient in increasing the
enantioselectivity as primary amines. The right basicity of the amine, which may vary in a rather wide
range, should be coupled with appropriate steric properties to be effective in increasing the enantioselec-
tivity. The best performing amines was the earlier widely used benzylamine and N-methylbenzylamine.
The influence of these amines on the effect of the catalyst amount, H2 pressure and reaction temperature
was studied. The effect of the amine amount on the hydrogenation of the two acids was also investigated.
Based on the results the involvement of the amine additive in the formation of surface intermediates
responsible for enantioselection is proposed.
Received 28 February 2011
Received in revised form 29 April 2011
Accepted 20 July 2011
Available online 26 August 2011
Keywords:
Aliphatic unsaturated acid
Amine additive
Cinchonidine
Enantioselective hydrogenation
Heterogeneous catalyst
Palladium
Decrease of the reaction temperature to 273 K increased the enantiomeric excess in the presence of
amines, resulting in the hydrogenation of (E)-2-methyl-2-hexenoic acid in up to 71% enantioselectivity
in favour of the S product enantiomer, the highest value obtained until now in the enantioselective
hydrogenation of aliphatic unsaturated carboxylic acids over chirally modified heterogeneous catalyst.
©
2011 Elsevier B.V. All rights reserved.
1
. Introduction
unsaturated acids [8,10]. The hydrogenation of unsaturated acids
in this catalytic system was sensitive to the structure of the acid
[11]. Excellent enantiomeric excesses (ee) were obtained in reac-
tions of (E)-2,3-diphenylpropenoic acids [12–17], whereas acids
having aliphatic substituents in both ␣ and ␤ positions provided
the saturated compounds in moderate, up to 67% ee [18–26]. Sev-
eral aspects of the reaction mechanism, including the structure of
the surface intermediate complex responsible for enantiodifferen-
tiation, are not yet clarified. Based on the effect of the reaction
conditions, it was ascertained that the active surface intermedi-
ates are different when the two types of acids, i.e. bearing aliphatic
or aromatic substituents, are hydrogenated. The enantioselective
hydrogenation of aliphatic unsaturated acids resulted in the best
ee when carried out in apolar solvents under high H2 pressure. It
was shown by spectroscopic and computational studies that under
these conditions the most stable cinchona alkaloid–acid adducts
contained two or three acid molecules interacting via hydrogen
bonds [27–29].
Catalytic asymmetric processes are convenient methods for the
synthesis of optically pure chiral pharmaceutical intermediates [1].
Following the development of a large variety of chiral metal com-
plexes able to assure enantiodifferentiation in the hydrogenation
of a wide range of prochiral unsaturated compounds, enantioselec-
tive hydrogenations are preferred options for inserting chirality in
fine chemicals [2,3]. Promotion of green and environmental benign
processes initiated the development of heterogeneous catalytic
systems as alternatives of chiral complexes [4]. A simple approach
to obtain catalytically active chiral materials for hydrogenation is
the modification of metal surfaces with adsorbed optically pure
organics. Among such catalysts the most successful are the tartaric
acid modified Ni and the cinchona alkaloid modified Pt and Pd [5–8].
Supported Pd catalysts modified by cinchona alkaloids were
found to provide high enantioselectivities in the hydrogenation
of prochiral olefins, such as 2-pyrone derivatives [8,9] and ␣,␤-
Despite the differences in reaction conditions necessary for
obtaining high ee and consequently in the composition and
structure of intermediate complexes, the use of an achiral base
additive increased the ee in the hydrogenation of both acid types
∗ Corresponding author at: Department of Organic Chemistry, University of
Szeged, Dóm tér 8, Szeged, H-6720, Hungary. Tel.: +36 62 544514;
fax: +36 62 544200.
E-mail addresses: szollosi@chem.u-szeged.hu (G. Sz o˝ ll o˝ si),
bartok@chem.u-szeged.hu (M. Bartók).
[
15,21,24,30]. However, the amine additive had different effect on
the rate of hydrogenations; rate increase was observed in reac-
tions of diphenylpropenoic acids [31], whereas hydrogenations of
0
920-5861/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.cattod.2011.07.034

Z. Makra et al. / Catalysis Today 181 (2012) 56–61
57
R
R
R
+
H2
N
OH
H
+
Pd/Al O + CD
8 9
S R
2
3
H
COOH
R: Me (1a)
R: Pr (1b)
solvent
S COOH
R COOH
major
minor
R: Me (2a)
R: Pr (2b)
N
(
CD)
Scheme 1. Hydrogenation of selected aliphatic ␣,␤-unsaturated acids over Pd/Al2O3 catalyst modified by cinchonidine.
aliphatic acids were decelerated by amines [26]. Up to now among
achiral amines benzylamine (3a) was found the most efficient in
increasing the ee. In a recent study Kim and Sugimura obtained
high ee values in the hydrogenation of diphenylpropenoic acids in
toluene without using amine additive [16]. Moreover, the addition
of 3a decreased the ee in the hydrogenation of several deriva-
tives in this solvent. The authors included the hydrogenation of an
aliphatic acid obtaining also decrease in the ee in the presence of
piperidine (3q) were purchased from Fluka or Aldrich. High purity
H2 gas (Linde AG, 99.999%) and Multisolvent grade toluene (Schar-
lau) were used.
2.2. Hydrogenation procedure and product analysis
Hydrogenations were carried out in stainless steel autoclaves
equipped with a pressure transmitter (P40, PMA GmbH) and with
3
a, in contrast with our report [26]. It should be noted that the two
studies were carried out over different catalysts, i.e. Pd/C STD-type
vs. Pd/Al O that could be the reason of the opposite tenden-
3
glass liner. Under typical conditions 15 mg 5% Pd/Al O , 10 cm
2
3
toluene, 0.05 mmol CD, 1 mmol acid and 1 mmol amine additive
2
3
were loaded into reactor, the autoclave was flushed with H , filled
2
cies. The former catalyst performed excellently in hydrogenations
of diphenylpropenoic acid derivatives in polar-aqueous solvents,
whereas apparently is far from being ideal for aliphatic unsaturated
acids, possibly as concerns the properties of the support, which
is crucial for reaching good enantioselection [32]. However, up to
now in the hydrogenation of aliphatic ␣,␤-unsaturated carboxylic
acids only primary amines were tested [26]. It is known that the
use of secondary and tertiary amine additives were less efficient in
increasing the ee in the hydrogenation of itaconic acid [23].
Our present study reports the examination of the effect of the
structure and amount of the achiral amine additive including pri-
mary, secondary and tertiary amines on the hydrogenation of two
aliphatic prochiral unsaturated acids, i.e. (E)-2-methyl-2-butenoic
to 5 MPa H and the reaction was commenced by stirring the slurry
using magnetic agitation (1000 rpm) at room temperature (295 K).
2
Initial H uptake rates (RHi) were calculated from the recorded pres-
2
sure drops up to 40 ± 5% conversions corrected with the uptake
registered in the absence of the acid. After the given time (t) the H2
was released, the slurry was filtered, the solution was treated with
1
0% HCl aq solution, dried over NaSO4 and analyzed.
Products were identified by GC–MS analysis using Agilent
Techn. 6890 N GC–5973 MSD equipped with 60 m HP-1MS capil-
lary column. Conversions (X (%)) and enantioselectivities (ee (%))
were calculated from gas chromatographic analysis using Agilent
Techn. 6890 N GC–FID equipped with HP-Chiral (30 m × 0.25 mm, J
&
W Sci. Inc.,) chiral capillary column with the formulae:
acid and (E)-2-methyl-2-hexenoic acid (Scheme 1) over Pd/Al O2
2
[
(S) − 2] + [(R) − 2]
modified by cinchonidine. We have also investigated the influence
of amines on the effect of some crucial reaction parameters such
as the H2 pressure and reaction temperature. The primary goal
of these investigations was to obtain further increase in the opti-
cal purities of the saturated acids in this heterogeneous catalytic
system in order to make the method more attractive for practi-
cal application. However, the results were also used to gain novel
mechanistic insights into this reaction, particularly as concerns the
composition of the surface intermediate responsible for enantios-
election in the presence of amine additives.
X(%) = 100 ×
and
[
1 ]
0
|[(S) − 2] − [(R) − 2]|
ee(%) = 100 ×
(
[(S) − 2] + [(R) − 2])
where [(S)-2] and [(R)-2] are the concentrations of the product
enantiomers and [1 ] is the initial concentration of the unsaturated
0
acid 1a or 1b. The analysis conditions were: head pressure 135 kPa
He; column temperature: 358 K (1a) or 388 K (1b), retention times
(min): (S)-2a 13.0, (R)-2a 13.9, 1a 21.2; (S)-2b 20.2, (R)-2b 21.8, 1b
2
6.8. The absolute configuration of excess enantiomers were deter-
mined by GC analysis using commercially available optically pure
products and based on published data [11]. Repeating some exper-
iments three times resulted in product compositions reproducible
within ± 1%.
2
. Experimental
2.1. Materials
Commercial 5% Pd/Al O (Engelhard, 40692) having BET sur-
face area 200 m g
3. Results and discussion
2
3
2
−1
and metal dispersion 0.21 [27] was used
as received. Cinchonidine (CD, Alfa Aesar, 99%), (E)-2-methyl-2-
butenoic acid (1a, 98%, Aldrich), (E)-2-methyl-2-hexenoic acid
The enantioselective hydrogenation of (E)-2,3-diphenylpro-
penoic acid over Pd catalyst modified by CD resulted in increased
ee in the presence of various achiral amine additives. The most
effective was found to be 3a, however, other additives includ-
ing secondary and tertiary amines also increased the ee [30,31].
Similarly, in the enantioselective hydrogenation of the aliphatic
dicarboxylic itaconic acid, the best ee was obtained in the pres-
ence of 3a and the efficiency of the additive decreased in the order:
primary > secondary > tertiary amines [23]. Our previous study on
the hydrogenation of 1a in the presence of a series of primary
(
1b, 98%, Alfa Aesar) were used without purification. The
amine additives: benzylamine (3a), (R)-␣-methylbenzylamine
(
(
3b), N-methylbenzylamine (3c), (R)-N,␣-dimethylbenzylamine
3d), N,N-dimethylbenzylamine (3e), dibenzylamine (3f), 2-
phenylethylamine (3g), methylamine, 33 wt% in ethanol (3h),
dimethylamine, 33 wt% in ethanol (3i), diethylamine (3j), tri-
ethylamine (3k), isopropylamine (3l), diisopropylamine (3m),
hexylamine (3n), dihexylamine (3o), dicyclohexylamine (3p) and

5
8
Z. Makra et al. / Catalysis Today 181 (2012) 56–61
Table 1
Effect of the achiral amine additive structure on the enantioselective hydrogenation of the aliphatic ␣,␤-unsaturated acids over Pd/Al2O3 modified by CD.
a
Entry
Additive, (pKa)b
Hydrogenation of 1a
t (min)/RHic
Hydrogenation of 1b
t (min)/RHic
ee (%)d
–
ee (%)d
1e
2
3
4
5
6
7
8
9
–
–
20/307
30/260
f
30/348
30/297
40/207
40/200
60/238
60/240
60/258
60 (99)/252
60 (93)/220
–
–
54
66
66
66
63
57
58
61
–
f
f
47
f
f
3a (9.49)
3b
3c (9.71)
3d
45/190
62
f
f
45/179
64
30/239
30/235
30/251
30/260
63
59
51
55
3e (9.03)
3f (7.70)
3g (10.08)
3h (10.63)
3i (10.94)
3j (11.02)
3k (10.68)
3l (10.63)
3m (11.50)
3n (10.85)
3o (11.01)
3p (10.80)
3q (11.30)
f
f
45/230
59
10
11
12
13
14
15
16
17
18
19
40/233
40/233
60/239
30/237
48
58
59
55
–
–
60 (98)/244
60 (99)/220
60/206
64
57
64
63
60
60
62
56
f
f
45/245
58
60/255
45 (99)/210
58
57
60/214
f
f
60 (86)/n.d.
60 (96)/208
60 (90)/229
60 (97)/258
60 (98)/n.d.
30 (99)/260
60/260
61
55
58
a
b
c
d
e
f
Reaction conditions: 15 mg 5% Pd/Al2O3, 10 cm3 toluene, 0.05 mmol CD, 1 mmol acid, 1 mmol additive, 5 MPa H2, 295 K.
For amines annotations see the experimental section, pKa values from [33–36].
Reaction time needed to reach complete transformation or the conversion (%) given in brackets/initial H2 uptake rate (mmol h
The (S)-2a or (S)-2b enantiomers were formed in excess.
Reactions over unmodified catalyst.
The results obtained with these primary amines were recently published [26].
−1 −1
g
); n.d. = not determined.
amines showed a combined effect of the basicity, the steric hin-
drances and the adsorption characteristics of additives, 3a having
optimal properties among achiral primary amines [26]. To test the
efficiency of other amines we have chosen to investigate the hydro-
genation of two aliphatic prochiral unsaturated acids (1a and 1b) in
the presence of a series of primary, secondary and tertiary amines
of different structures.
in the solution. Similar reason may explain the behaviour of the
cyclic 3q. On the contrary the insufficient steric hindrance of one
methyl group could be the reason of the lower ee obtained in the
presence of 3h. The steric effect of additives on the ee was also indi-
cated by comparing results obtained using amines having similar
basicities, such as 3h, 3k and 3l, respectively.
It must be noted that the slightly higher ee observed with 3c
when compared with 3a was valid for other primary–secondary
amine pairs of similar structure. Thus, secondary amines gave sim-
ilar or higher ee as primary ones when the 3h–3i, 3l–3m or 3n–3o
pairs are considered. A general tendency is that in the presence
of secondary amines the RHi is also higher when compared with
their primary amine pairs, though these values are lower than those
obtained in the absence of additive. The performance of secondary
amines confirmed the assumption that not solely the basicity of
the amine additive is responsible for its effect on the stereochem-
ical outcome of the reaction, steric effects are probable to play
also significant role. However, these results also confirmed that the
presence of one benzyl group favours high ees.
3.1. Effect of the amine additive structure
Selected results obtained in the hydrogenations of acids 1a and
1
b over CD-modified Pd/Al O3 using amine additives are collected
2
in Table 1.
All amines tested increased the ee and decreased the RHi in the
hydrogenation of both acids when compared with reactions in the
absence of additives. Interestingly, besides the optically pure pri-
mary amine 3b, the secondary amine 3c also gave higher or the
same ee as 3a. The basic strength of amines could not be corre-
lated directly with the increase in the ee; this increase was slightly
dependent also on the length of the ␤ alkyl chain of the acid. Thus,
when benzylamine derivatives are considered, one may reach to the
conclusion that amines having pKa = 9.5–10 have the ideal basicity.
However, only slightly lower ees were obtained by using 3o, 3 g or
The above observations on the effect of secondary amine addi-
tives urged us to examine the influence of the additive structure on
the effect of the reaction conditions.
3
j in the hydrogenation of 1a and 3j, 3l or 3 m in that of 1b when
3.2. Influence of amine additives on the catalyst amount
dependence
compared with 3a or 3c. Among these are primary and secondary
amines having the pKa in the range 10–11.5. Thus, the basicity of
the amine additive may vary in a relatively wide range (9.5–11.5)
and other factors also have role in determining the efficiency of the
additive. This is confirmed when one considers that the pKa of the
quinuclidine N in CD has a value in this range (∼10 [37]). Interest-
ingly, the optically pure amines 3b and 3d had opposite behaviour
when compared with 3a and 3c, i.e. 3d gave lower ee than 3c.
As a general rule we observed that tertiary amines (3e and 3k)
were the least efficient in increasing the optical purity of the prod-
ucts. Similarly low ees were obtained in the presence of 3f, 3q and
An important requirement of reactions over heterogeneous cat-
alysts is to fully exploit the activity of the catalyst. To ascertain
whether the reaction is not controlled by diffusion phenomena the
hydrogenation of 1a was studied using various amounts of catalyst
in the absence of additive and using two amines (3a and 3c). Results
obtained are illustrated in Fig. 1.
An important difference obtained in the absence of additive
when compared with the use of either of amines was the more sig-
nificant decrease in the ee by increasing the catalyst amount (over
∗
3
h. While the poor efficiency of 3f may be explained by the low
25 mg). The R deviated from the linearity over 25 mg catalyst,
Hi
basicity of this amine, the performance of other amines could be
traced back to steric reasons. Thus, tertiary amines may hinder the
adsorption on modified surface sites of the acid-amine salt formed
indicating that over higher amounts the reaction is not kinetically
controlled irrespective of the presence of amines. The slopes of the
∗
R
curves at low catalyst amounts were different due to changes
Hi

Z. Makra et al. / Catalysis Today 181 (2012) 56–61
59
7
0
14
R*Hi
a
70
300
RHi
ee (%)
ee (%)
1
1
8
6
4
2
0
2
6
6
5
5
4
4
5
6
6
5
5
5
0
0
5
0
5
0
0
5
0
250
200
45
4
0
150
300
0
10
20
30
40
50
0
0.5
1
1.5
2
Catalyst amount (mg)
Additive amount (eq)
∗
−1
Fig. 1. Effect of the catalyst amount on H2 uptake rate (R , mmol h , open symbols)
and ee (%, closed symbols) in the enantioselective hydrogenation of 1a in the absence
Hi
70
b
of amine additive (
,
), in the presence of 3a (
,
) and 3c (
,
). Reaction
ee (%)
6
RHi
conditions: see Table 1. Dashed lines are H2 uptake rates corresponding to lack of
mass transfer control.
5
either in the number of the active sites or in the activation energy in
the presence of the amines. When the diffusion became rate deter-
minant, the slopes of the three curves were similar, maintaining the
rate differences, which imply similar diffusion coefficients in the
three reactions (without amine, with 3a or with 3c). Over higher
amount of catalyst mass transfer control occurred at lower rates
60
250
200
150
5
5
50
∗
in the presence of amines and R remained lower in the presence
Hi
of amines when compared with reactions in absence of additives.
This indicated that the structure or composition of the migrating
chemical species is different, i.e. amines are incorporated in these
species.
4
5
40
In consequence, under conditions assuring surface reaction con-
trol in the presence of amine additives the number of surface active
sites decreased when compared with the amine free hydrogena-
tion. It must be also noted that the amount of CD used is sufficient
to maintain a complete modification of the active surface, thus
alterations in the CD/surface Pd ratio by increasing the catalyst
amount should not have significant effect on results obtained over
low amounts of catalyst. Accordingly, we consider the above obser-
vations as confirmation of the participation of amine additives in
the formation of the surface intermediate during the hydrogenation
of aliphatic unsaturated carboxylic acids over catalyst modified by
CD.
0
0.5
1
1.5
2
Additive amount (eq)
Fig. 2. Influence of 3a (
, open symbols) and ee (%, closed symbols) in the enantioselective
hydrogenation of 1a (a) and 1b (b). Reaction conditions: see Table 1.
,
) or 3c (
,
) amount on H2 uptake rate (RHi,
−
1
−1
mmol h
g
Accordingly, the effect of amines was proved to be slightly
dependent on the size of the ␤ substituent of the unsaturated acid,
and the influence of the amine amount was different when sec-
ondary amine was used instead of primary ones. The difference
obtained especially in RHi in the presence of these amines can be
accounted for alterations in the structure of the surface intermedi-
ate complex due to participation of the additive.
3.3. Effect of the achiral amine amount
The effect of the amine amount was studied in the hydrogena-
3.4. H2 pressure and temperature effect in presence of amines
tion of both 1a and 1b. The results using the selected amines (3a
and 3c) are presented in Fig. 2.
Significant differences were detected by using these amines.
Although, under 1 equivalent (eq., as compared with the acid)
of either amines the ee increased continuously by increasing the
amine amount, the maxima in the presence of 3a was obtained at
Increase in the H2 pressure or decrease in hydrogenation
temperature below room temperature increased the ee in the
hydrogenation of aliphatic ␣,␤-unsaturated carboxylic acids over
Pd catalyst modified by CD [18,26]. The effect of the H pressure on
2
the hydrogenation of 1a was studied in the presence of 3a and 3b
(see Fig. 3).
1
eq. of amine, whereas with 3c the ee increased up to 1.5 eq. in
the hydrogenation of both acids. Moreover, over 1 eq. of the lat-
ter amine ees surpassed those obtained with 3a. RHi decreased by
increasing the amine amount up to ∼0.7 eq. followed by practically
constant values at higher additive amounts. The amine amount
affected less the rate of the hydrogenation of 1a than that of 1b
especially when 3c was used, which implied a larger difference in
the effects of the two amines on the RHi of the former acid.
Decreasing the pressure from the typically applied 5 MPa
decreased both the RHi and ee independently on the absence or
presence of amine additives. However, the deceleration obtained
by decreasing the pressure was higher in the absence of additives
when compared with the use of either of selected amines. Less sig-
nificant differences were obtained in the slopes of the ee decrease
resulted in the absence or presence of amines. Nevertheless, in the

6
0
Z. Makra et al. / Catalysis Today 181 (2012) 56–61
Table 2
Effect of decreasing the reaction temperature on the enantioselective hydrogenation of aliphatic ␣,␤-unsaturated acids 1a and 1b.
a
Entry
Additiveb
Hydrogenation of 1a
X (%)/t (min)c
Hydrogenation of 1b
X (%)/t (min)c
ee (%)d
ee (%)d
1
2
3
–
100/90
100/90
100/90
100/90
47/48
62/67
63/67
65/66
100/90
95/90
96/90
54/56
66/68
66/71
67/71
3a
3b
3b
e
4
96/120
a
Reaction conditions: 15 mg 5% Pd/Al2O3, 10 cm3 toluene, 0.05 mmol CD, 1 mmol acid, 1 mmol additive, 5 MPa H2.
For amines annotations see the experimental section.
Conversion/hydrogenation time at 273 K.
Enantiomeric excesses obtained at 295 K/273 K; the S enantiomers formed in excess.
Using 1.5 eq. additive.
b
c
d
e
7
0
however, the effect of the slower hydrogenation of the modifier’s
anchoring quinoline moiety [38] or the effect of the temperature on
the conformational behaviour of the modifier on the surface [29]
cannot be excluded.
RHi
6
5
ee (%)
6
3
3
2
2
1
00
50
00
50
6
5
4
3
0
0
0
0
4. Conclusions
The effect of the achiral amine additive structure was studied
on the enantioselective hydrogenation of two aliphatic ␣,␤-
unsaturated carboxylic acids, i.e. (E)-2-methyl-2-butenoic acid and
(
E)-2-methyl-2-hexenoic acid, over Pd/Al O3 catalyst modified by
2
CD. We have found that secondary amines are similarly or even
more effective in increasing the enantioselectivity as primary ones.
It was shown that the basic strength of the additive may be varied in
relatively wide range (from pKa 9.5 to 11.5). However, the amines
beside the right basicity must also fulfil steric requirements in
order to provide high enantioselectivities. The most efficient were
found the earlier widely used benzylamine and the newly found
N-methylbenzylamine. Using these two amines the effect of the
catalyst and the amine amount was studied complemented by stud-
ies on the influence of the additive on the effect of the H2 pressure
and reaction temperature. The use of various catalyst amounts indi-
cated kinetically controlled reaction under the typical conditions.
Based on the decrease in the number of active sites in presence of
amines we assumed that these take part in the formation of the
surface intermediate. This assumption was confirmed by the effect
of the amine amount on the hydrogenation, also affected by the
alkyl chain length of the acid. Recently, it was demonstrated that
the most stable CD-acid complexes are formed by interacting three
unsaturated acid molecules with distorted open (3) CD conformer
100
0
1
2
3
4
5
H pressure (MPa)
2
Fig. 3. H2 pressure dependence of the hydrogenation of 1a in the absence of achiral
amine (
mmol h
,
g
), using 1 eq. of 3a (
,
) or 3c (
−1
, open symbols; ee, %, closed symbols). Reaction conditions: see Table 1.
,
) or 1.5 eq. 3c (
,
) (RHi,
−
1
presence of 1.5 eq. 3c under 3 MPa H2 the ee was only 2% smaller
when compared with that obtained in the reaction under 5 MPa.
Hence, the presence of amines had also effect on the RHi and ee
decrease resulted by decreasing the pressure. The effect of the H2
pressure was explained by decrease of the surface hydrogen con-
centration [18]. Thus, the presence of amines led to less significant
effect of this parameter on both the RHi and the ee. Decrease in the
number of the catalytically active sites in the presence of amine
additives may lead to such behaviour.
Decreasing the reaction temperature to 273 K increased the ee in
this catalytic system [18,20]. In the present study we attempted to
reach a better stereocontrol of the hydrogenation by combining the
beneficial effect of the presence of an achiral amine with decreasing
the hydrogenation temperature (see Table 2).
[
29]. We propose that the amines interfere in the H-bond network
on the surface, being incorporated in the intermediate complex.
This may justify the effect of the amine structure and amount on
the hydrogenation of these acids.
The above explanation can rationalize the influence of amines
on the effect of the H2 pressure, which showed less significant
effect of the surface hydrogen concentration on the rate and the
ee when additives are used. The decrease of the reaction temper-
ature to 273 K increased more the ee in the presence of amines
when compared with amine free hydrogenations. In consequence
Indeed decreasing the temperature to 273 K led to higher
increase in the ee in the hydrogenation of 1a in presence of either
a or 3c than in reactions carried out without additive. However, at
3
low reaction temperature there was no difference in ees obtained
with the two amines. On the contrary in the hydrogenation of 1b the
amine 3c was more efficient in increasing the ee at 273 K, obtaining
with 1 or 1.5 eq. of additive 71% ee. One explanation of the higher ee
obtained at 273 K compared to that at room temperature was given
in early studies of this catalytic system [18], i.e. the increase of the
H2 solubility and consequently the surface hydrogen concentra-
(
S)-2-methylhexanoic acid could be prepared in up to 71% opti-
cal purity, unprecedented in enantioselective hydrogenations of
aliphatic unsaturated carboxylic acids over chirally modified het-
erogeneous catalyst.
Acknowledgements
tion. However, the effect of the H pressure showed that variations
2
Financial support by the Hungarian National Science Foundation
OTKA Grant K 72065) is highly appreciated. The work was sup-
ported by the Bolyai János Research Scholarship of the Hungarian
Academy of Sciences (Gy. Sz o˝ ll o˝ si).
in the surface hydrogen concentration have less effect in the pres-
ence of the amines. Thus, the temperature effect on the ee should be
traced back to different reason(s). A possibility is the involvement
of the amine in the formation of the hydrogenation intermediate,
(

Z. Makra et al. / Catalysis Today 181 (2012) 56–61
61
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