Catal Lett (2014) 144:478486

DOI 10.1007/s10562-013-1177-1

Reversal of Enantioselectivity in Aldol Reaction: New Data

on Proline/c-Alumina OrganicInorganic Hybrid Catalysts
Gyorgy Sz}
oll}
osi Monika Fekete
Andras A. Gurka Mihaly Bartok

Received: 30 September 2013 / Accepted: 26 November 2013 / Published online: 12 December 2013
Springer Science+Business Media New York 2013

Abstract We report new results on the aldol reactions

between aldehydes of three different types (aromatic, aliphatic and cycloaliphatic) and acetone/cycloalkanones as
reaction partners, driven by organicinorganic hybrid catalyst Pro/c-Al2O3. In contrast to the homogeneous liquidphase reaction, over Pro/c-Al2O3 reversal of the enantioselection in up to 2040 % ee depending on the structure of
the aldehyde was observed in reactions of acetone.
Reversal of the ee in the presence of c-Al2O3 cannot be
generalized, as it has only been observed for acetone
among the ketones studied by us. It was proven using
methods of a great variety such as ultrasonic irradiation,
reuse measurements on used catalyst and the filtrate of
the first reaction, measurements on the L-Pro-L-Pro(OH)
dipeptide, studies using mixtures of L-Pro and D-Pro that
the organicinorganic hybrid catalyst Pro/c-Al2O3 formed
in situ is responsible for reversal of the ee. In the reactions
of cycloalkanones there is presumably competition
between the liquid-phase and the surface reaction over Pro/
c-Al2O3 with preference for the former. Based on these
results a surface reaction pathway was proposed. Although,
the ees obtained under heterogeneous catalytic conditions
are low, further studies may lead to application of this
unusual phenomenon for obtaining chiral heterogeneous
catalysts suitable for the preparation of the desired enantiomer of a chiral compound using the same chiral source.

G. Sz}oll}osi
M. Bartok
MTA-SZTE Stereochemistry Research Group, Dom ter 8,
Szeged 6720, Hungary
M. Fekete
A. A. Gurka
M. Bartok (&)
Department of Organic Chemistry, University of Szeged, Dom
ter 8, Szeged 6720, Hungary
e-mail: bartok@chem.u-szeged.hu

123

Keywords Asymmetric catalysis
Aldol reaction

L-Pro/c-Al2O3 catalyst
Inversion of enantioselectivity

1 Introduction
Asymmetric heterogeneous catalysis has become widely
studied for the production of chiral compounds [16].
Easily available, optically active compounds of natural
origin (alkaloids, aminoacids, peptides, carbohydrates) are
advantageously used as chiral catalysts or catalyst modifiers in these synthetic procedures. A widely used group of
chiral catalystsespecially in the aldol reaction studied in
this manuscriptis supported-proline and its synthetic
derivatives [7, 8]. In our studies on heterogeneous catalytic
asymmetric syntheses, in addition to enantioselective
hydrogenations [3], studies on organocatalytic reactions
[911], among which certain aldol reactions over polystyrene resin supported-proline catalysts were also initiated
[12]. In the meantime, considerable progress has been
made in the research of peptide-type immobilized organocatalysts [1316].
In the course of investigating the mechanism of enantioselective heterogeneous catalytic hydrogenations, an
unexpected inversion observed [17, 18] turned our attention to studying the role of this phenomenon, earlier recognized by Kagan et al. [19], in the origin of chiral
induction. As a first step, the pertinent literature was
reviewed [20], and it was found that at the present stage of
research it was not possible to draw general conclusions so
far. Among publications on heterogeneous chiral catalysts
causing unexpected inversion, our attention was also
attracted by the publication by Li and coworkers [21]
reporting the application of L-proline (and other L-amino
acids) as well as an organicinorganic hybrid catalyst

Reversal of Enantioselectivity in Aldol Reaction on Proline/c-Alumina

containing alumina in the aldol reaction. In the course of

their work these authors established that in the case of
amino acids adsorbed on c-alumina, unexpected inversion occurred as compared to dissolved amino acids, i.e.
non-heterogenized catalysts. They demonstrated by UVRaman spectroscopy that adsorption on alumina brought
about the formation of a new type of catalyst designated
organicinorganic hybrid catalyst.
This manuscript present the results of our recent investigations aiming at the extension of the applicability of the
new heterogenized catalyst in the aldol reaction, the
accumulation of further data on the reaction mechanism,
increasing the optical yield, and collecting further information regarding this practically important reaction.

2 Experimental
2.1 Materials
L-proline

(L-Pro) and D-proline (D-Pro), and analytical

grade solvents were purchased from Sigma-Aldrich and
used as received. Aldehydes: 2-nitrobenzaldehyde (1), isobutyraldehyde (2), butyraldehyde (3), cyclohexanecarboxaldehyde (4) and ketones: acetone (5), cyclohexanone (6),
cyclopentanone (7) were purchased from Sigma-Aldrich
and purified either by crystallization or by distillation.
L-Pro-L-Pro(OH) was prepared according to known procedure using L-Pro-OtBu and Fmoc-L-Pro-OH derivatives
purchased from Bachem GmbH and Sigma-Aldrich,
respectively [22]. Aluminum oxides were purchased from
Alfa Aesar (AA, 42576, c-Al2O3, 110 lm powder, BET
surface area 60 m2 g-1) and Sigma-Aldrich (SA, 544833,
nanopowder, c phase, particle size \50 nm, BET surface
area [40 m2 g-1) and were used as received, without any
pretreatment.
2.2 General Procedure for the Aldol Additions
The reactions were carried out in closed glass reactors. The
given amount of chiral amino acid catalyst (typically 0.075
or 0.15 mmol L-Pro or D-Pro) was suspended/dissolved in
2 mL acetone or the given amount of solvent followed by
addition of c-Al2O3, the corresponding aldehyde, ketone
(except reaction using acetone both as aldol donor and
solvent) and 5 lL n-tetradecane (as internal standard). The
reaction mixture was stirred magnetically at 25 C for the
given time. After the specified reaction time the catalyst
was removed either by washing with sat. NH4Cl and
extracting the products in ethyl acetate (reactions without
the use of c-Al2O3) or by centrifugation of the solid catalyst (the Pro/c-Al2O3) and washing the remaining solid
with ethyl acetate. The unified organic phases were

479

analysed by gas chromatography (GC). After some reactions the Pro/c-Al2O3 materials were dried and recycled
using identical reaction conditions (solvent, aldehyde,
ketone amounts) as in the first reaction. Reactions using
mixtures of L-Pro and D-Pro were carried by using the
appropriate amounts of the enantiomerically pure amino
acids. Reactions under sonication were carried out using
identical experimental setup, except instead of magnetic
agitation the reactors were immersed in a sonication bath
(Branson 1510, frequency 40 kHz) for 1 h.
2.3 Analysis Methods
Products were identified by their mass spectra using Agilent Techn. 6890 N GC-5973 inert MSD and HP-1MS
60 m 9 0.25 mm i.d. capillary column. Quantitative analysis including enantiomeric separation was performed
using GC equipped with flame ionization detector (FID):
Agilent Techn. 6890N GC-FID and Cyclosil-B 30 m 9
0.25 mm i.d. chiral capillary column. Enantiomeric
excesses (ee) were calculated using the formula ee [%] =
|conc R - conc S|/(conc R ? conc S) 9 100, where conc R
and conc S are the concentrations of the aldol product
enantiomers. Chromatographic conditions and retention
times are shown in Table 1. The absolute configurations of
the aldol products were assigned by analogy with previously reported results using L-Pro as catalyst. The reproducibility of the reactions was 3 %.
IR spectra of the Pro/c-Al2O3 materials recovered after
reactions were recorded on a Bio-Rad Digilab Division
FTS-65A/896 FT-IR spectrometer operated in diffuse
reflectance mode (DRIFT) between 4,000 and 400 cm-1 at
2 cm-1 resolution by averaging 256 scans.

3 Results and Discussion

In the present study several oxides were used as additives
in the aldol reaction of 1 with acetone, e.g. a-Al2O3, two cAl2O3-s, silica, mesoporous Al-silicates, zeolites, ThO2,
ZrO2, Y2O3 and ZnO. From these only c-Al2O3-s showed
inverted enantioselectivities, S enantiomer formed in
excess with L-Pro/c-Al2O3 instead of R obtained with L-Pro
in the absence of oxide additive. Other oxide additives did
not exhibit any activity to invert the sense of enantioselection in this reaction, i.e. using L-Pro an excess of
R product was formed in an ee close to 75 %, as if the
oxides were not present at all. According to these preliminary experiments the two c-aluminas:c-Al2O3AA and
c-Al2O3AS were selected for further studies. Pro/c-Al2O3
catalysts were obtained under in situ conditions and characterized by FT-IR spectrometry (Fig. 1). The spectra of
the used c-aluminas were compared with the spectra of the

123

480

G. Sz}
oll}
osi et al.

Table 1 Chromatographic conditions used for analysing the aldol products over Cyclosil-B capillary column
Column temperature (C); hp (psi)a

Substrates

Retention times (min)

Aldehyde

S or S,Sb

R or R,Rb

Other stereoisomers

Aldehyde

Ketone

115 C 10 min, 1 min-1 165 C 50 min; 22

34.5

94.6

96.5

40 C 5 min, 2 min-1 120 C 30 min; 20

2.5

36.6

36.1

55 C 5 min, 2 min-1 155 C 15 min; 20

21.5

55.3

55.8

-1

40 C 5 min, 2 min

160 C 15 min; 20

2.5

53.8

54.4

55.5; 55.9

40 C 5 min, 2 min-1 160 C 15 min; 20

2.5

52.8

53.5

58.1; 58.3

40 C 5 min, 2 min-1 160 C 15 min; 20

3.0

57.3

58.4

58.8; 59.2

100 C 50 min, 1 min-1 115 C 125 min; 25

4.5

167.5

169.5

181.0; 183.3

He head pressure

Absolute configurations of the corresponding aldol addition product enantiomers

as received materials and crystalline L-Pro, which confirmed the immobilization of L-Pro on the surface of the
c-Al2O3.
Characteristic experimental data obtained in aldol
reactions using several aldehydes and ketones of different
types are summarized in Tables 2, 3 and Figs. 2, 3. Table 2
presents results obtained in studies on aldol reactions
between acetone and an aromatic, an aliphatic or a cycloaliphatic aldehyde. Namely, aldol reactions using 1 (R:2NO2C6H4), 2 (R:(CH3)2CH) or 4 (R:C6H11) as reaction
partners of acetone were studied. In addition to the catalysts described in Ref. [21] (i.e. L-Pro/c-Al2O3), their
variants containing D-Pro were also included in these
studies, mainly for the purpose of studying the dependence
of the product ee on the catalyst ee. As regards the actual
results, in the case of all three aldehydes the catalysts
containing D-Pro exhibited similar activities, but promoted
the formation of products of the opposite configuration as
compared to those containing L-Pro, just as expected. In the
reaction using D-Pro the S enantiomer formed in excess
(entries 2, 8, 12), in contrast with the R enantiomer
obtained in excess over D-Pro/c-Al2O3 (entries 4, 10, 14).
The rate of the reactions conducted under identical
experimental conditions can be evaluated on the basis of
comparing conversions and reaction times. For example,
Fig. 2 represents changes in conversion and ee in the aldol
reaction of 1 with acetone catalyzed by L-Pro and L-Pro/
c-Al2O3AA catalysts. According to the relationship regarding conversions of the three aldehydes we observed:
1  2 [ 4. This relationship holds for both homogeneous
and heterogeneous phase reactions (i.e. in the presence of
c-Al2O3). Remarkably, there is no significant difference
between conversions in homogeneous and heterogeneous
phase reactions except at low reaction times.
The relationship regarding selectivities is different from
that regarding conversions, i.e.: 2 [ 1 [ 4. In the case of 4
the selectivity is especially low on heterogenized catalysts,
most probably due to secondary reactions occurring as a

123

Fig. 1 FT-IR spectra of crystalline L-Pro, c-aluminas and L-Pro/cAl2O3 catalysts after use in aldol reaction of 2-nitrobenzaldehyde with
acetone, for reaction conditions see Table 1 entry 3

consequence of the long reaction times needed. In accordance with experimental data published earlier for
4-nitrobenzaldehyde [21], the change in configuration
brought about by heterogenization, i.e. the so-called
unexpected inversion was observable in the reactions of
all three aldehydes. This reversal of the enantioselectivity
is usually only about 1620 % in case of 1 (entries 36),
but can reach values up to 3739 % in aldol reactions of 2
or 4 (entries 9, 10, 13, 14). In the course of the experiments
the dependence of conversion and ee on the amount of

Reversal of Enantioselectivity in Aldol Reaction on Proline/c-Alumina

481

Table 2 Aldol reaction between aldehydes and acetone catalyzed by L-Pro or D-Pro in the absence and presence of c-Al2O3

rt, stirring

OH

catalyst

R: 2-NO2C6H4 (1)
R: (CH3)2CH (2)
R: C6H11 (4)

OH

R R

R S

R: 2-NO2C6H4 (R-8)
R: (CH3)2CH (R-9)
R: C6H11
(R-10)

O
R

(S-8)
(S-9)
(S-10)

Entry

Catalyst; (mmol)

Aldehyde; (mmol)

c-Al2O3; (mg)

Time (h)

Conversion (%)

Selectivity (%)a

ee (%); (conf.)a
74; (R)

L-Pro;

0.15

1; 0.5

90.5

80

D-Pro;

0.15

1; 0.5

90

85

73; (S)

L-Pro;

0.15

1; 0.5

AA; 150

93

75

20; (S)

D-Pro;

0.15

1; 0.5

AA; 150

93

70

16; (R)

L-Pro;

0.15

1; 0.5

AA; 150

1; )))b

91

75

18; (S)

D-Pro;

0.15

1; 0.5

AA; 150

1; )))b

94

79

17; (R)

L-Pro;

0.15

2; 0.25

22

77

99

90; (R)

D-Pro;

0.15

2; 0.25

22

70

99

89; (S)

9
10

L-Pro;
D-Pro;

0.15
0.15

2; 0.25
2; 0.25

SA; 250
SA; 250

22
22

65
52

99
98

39; (S)
34; (R)
83; (R)

11

L-Pro;

0.15

4; 0.25

22

61

67

12

D-Pro;

0.15

4; 0.25

22

51

75

82; (S)

13

L-Pro;

0.15

4; 0.25

SA; 250

22

76

19

37; (S)

14

D-Pro;

0.15

4; 0.25

SA; 250

22

80

16

37; (R)

Reaction conditions: 2 mL acetone

a

Selectivity and ee of the aldol product, the absolute configuration of the excess enantiomer in brackets

Reactions carried out by ultrasonication of the mixture

c-Al2O3 was also determined, as shown in Fig. 3 for 1. The

change in ee is especially conspicuous, which proves the
surface formation of a new enantioselective catalyst.
Although experimentally not determined, the amount of the
adsorbed L-Pro can be estimated from these results.
According to these results 0.15 mmol L-Pro is adsorbed on
150 mg c-Al2O3AA and about 200 mg c-Al2O3SA, as
further increase in the oxides amount didnt result in
change in the ee, whereas lower oxide amounts gave
smaller or opposite ees. Accordingly, the coverage of the
oxides with L-Pro will be 60 mmol m-2 corresponding to
10 wt% L-Pro (AA) and 53 mmol m-2 corresponding to
8 wt% L-Pro (AS). The formation of a solid enantioselective catalyst is also suggested by the effect of sonication
[23, 24] on the reaction using L-Pro with added c-Al2O3
(compare Table 2, entries 36), since in the reaction under
ultrasonication a 1 h reaction was sufficient for the
achievement of over 90 % conversion.
In Table 3 experimental data obtained in the aldol
reaction of 2, 3 or 4 with 6 and 7 under similar conditions
as in Table 2, were summarized. Due to the slower reaction
rates, longer reaction times (2248 h) were needed to
achieve high conversions. The relationship describing the

order of conversions is 2 ? 7 [ 2 ? 6 * 3 ? 6 [ 4 ? 6.
The order of selectivities is: 2 ? 6 [ 4 ? 6 [ 2 ? 7 *
3 ? 6; as regards diastereoselectivities (anti/syn), in all
four reactions the formation of the anti diastereomer is
convincingly dominant. Unlike in the aldol reactions with
acetone (Table 2), enantioselectivities exceed 90 %, and
there is no characteristic difference between homogeneous
phase and heterogeneous phase reactions.
The most conspicuous new observation as compared to
the data summarized in Table 2, however, is the absence of
unexpected inversion: when using acetone, reversal of
enantioselectivity occurs, but when cycloalkanones are
used, it doesnt. The probable reason for the absence of
reversal of the enantioselectivity lies in the inhibition of the
formation of the intermediate adduct (assumedly an
enamine) on the surface of c-alumina, as a consequence of
which the reaction proceeds in the solution rather than on
the surface. These experimental observations and especially the measurements on reuse (Table 4) allow concluding that aldol reactions in these cases are indeed driven
by proline in the liquid phase. Reuse studies were carried
out for some of the reactions in order to substantiate this
assumption (Table 4).

123

482

G. Sz}
oll}
osi et al.

Table 3 Aldol reaction between isobutyraldehyde, butyraldehyde, cyclohexanecarboxaldehyde and cyclohexanone or cyclopentanone
O

OH
catalyst
rt, stirring

n=1 (6);
n=0 (7);

+ R

R S

( C )n
H2
R: (CH3)2CH (2)
R: CH3CH2CH2 (3)
R: C6H11 (4)

OH

+ R

( C )n
H2

( C )n
H2
R: (CH3)2CH, n=1
R: (CH3)2CH, n=0
R: CH3CH2CH2, n=1
6H11, n=1

(S,S-11)
(S,S-12)
(S,S-13)
(S,S-14)

( C )n
H2

(R,R-11)
(R,R-12)
(R,R-13)
(R,R-14)

Entry

Catalyst; (mmol)

Aldehyde; (mmol)

Ketone

c-Al2O3; (mg)

Time (h)

Conversion (%)

Selectivity (%)a

Anti/syna

ee (%); (conf.)a

L-Pro;

0.15

2; 0.5

44

75

97

98/2

85; (S,S)

L-Pro;

0.15

2; 0.5

AA; 150

44

73

98

94/6

94; (S,S)

L-Pro;

0.08

2; 0.25

SA; 125

44

80

97

97/3

96; (S,S)

L-Pro;

0.08

2; 0.25

22

99

73

96/4

96; (S,S)b

D-Pro;

0.08

2; 0.25

22

99

74

96/4

96; (R,R)b

L-Pro;

0.08

2; 0.25

AA; 150

22

98

57

99/1

87; (S,S)b

L-Pro;

0.08

2; 0.25

SA; 125

22

98

60

99/1

96; (S,S)b

L-Pro;

0.08

3; 0.25

44

82

80

92/8

94; (S,S)b

D-Pro;

0.08

3; 0.25

44

87

86

96/4

95; (R,R)b

10

L-Pro;

0.08

3; 0.25

AA; 75

44

84

55

91/9

95; (S,S)b

11

D-Pro;

0.08

3; 0.25

AA; 75

44

65

77

92/8

94; (R,R)b

12

L-Pro;

0.08

3; 0.25

SA; 125

44

83

59

91/9

96; (S,S)b

13

D-Pro;

0.08

3; 0.25

SA; 125

44

75

78

92/8

95; (R,R)b

14

L-Pro;

0.15

4; 0.5

44

46

94

97/3

90; (S,S)

15

L-Pro;

0.15

4; 0.5

AA; 150

44

28

89

92/8

94; (S,S)

Reaction conditions: solvent 0.5 mL dimethyl sulfoxide (DMSO), 2 mmol ketone

a

Selectivity, diastereomer ratio and ee of the aldol products, the absolute configuration of the excess enantiomer in brackets

Assumed configuration based on similarity with known reactions

The data listed in Table 4 clearly demonstrate that in

case of acetone reversed enantioselection is brought about
by the reaction taking place on the L-Pro/c-Al2O3 catalyst
surface (entries 13). The aldol reaction of cyclohexanone,
however, is mainly driven by L-Pro in solution, thus a
homogeneous liquid phase reaction takes place (entries
1217). Increase of the pretreatment temperature (c-Al2O3
with L-Pro) did not have a favorable effect on the interaction between c-Al2O3 and L-Pro (see ees obtained in
entries 13 vs entries 911). On the in situ formed L-Pro/cAl2O3 catalyst the ee was higher as compared to the previously prepared L-Pro/c-Al2O3 obtained in DMSO before
addition of the reactants (entry 4 vs 1; entry 15 vs 12).
After both aldol reactions, the solid catalyst obtained following centrifugation of the reaction mixture produced
products in slightly higher ee upon reuse (entries 2, 7; 14,
17); however, addition of fresh reactants to the liquid phase
products (supernatant) resulted in no further reaction when
acetone is used (entry 5). By addition of 0.15 mmol L-Pro

123

Fig. 2 Aldol reaction between 2-nitrobenzaldehyde and acetone:

effect of time on conversion (open symbols) and ee (closed symbols)
in absence (circles) and presence (triangles) of c-Al2O3AA; for
reaction condition see Table 2

Reversal of Enantioselectivity in Aldol Reaction on Proline/c-Alumina

Fig. 3 Aldol reaction between 2-nitrobenzaldehyde and acetone:

effect of c-Al2O3 quantity on conversion (open symbols) and on
ee (closed symbols); c-Al2O3AA triangles, c-Al2O3SA diamonds,
a-Al2O3square. For reaction condition see Table 2

483

and fresh aldehyde to this solution the reaction continued,

however, the R enantiomer, characteristic to homogeneously catalyzed reaction formed in excess (entry 6). In
contrast in the reaction of cyclohexanone the reaction
continued by addition of fresh aldehyde to the liquid phase
mixture (supernatant) resulted over catalyst prepared in situ
L-Pro/c-Al2O3 (see entries 15 and 16). Both c-Al2O3-s
performed similarly in the latter reaction; however in
presence of c-Al2O3SA the stereoselectivities obtained
were higher.
In addition to the above techniques, other methods were
also employed in order to investigate the origin of catalytic
centers responsible for the sense of the chiral induction. On
the one hand, the effect on enantioselection of the dipeptide
L-Pro-L-Pro(OH) potentially formed from L-Pro by Al2O3
in the course of the aldol reaction was studied. On the other
hand, studies on the effect of the composition of L-Pro and
D-Pro catalyst mixtures, i.e. nonlinear effect studies, typically used in investigations of reaction mechanism [2528]
were also carried out. The L-Pro-L-Pro(OH) dipeptide catalyst is known to catalyze the formation of the R product in

Table 4 Reuse of L-Pro/c-Al2O3 catalysts in aldol reactions of 2-nitrobenzaldehyde (1) and isobutyraldehyde (2) with acetone (5) or cyclohexanone (6) and others studies
Entry

Catalyst; (mmol)

Reaction of 1 with 5b
c
1
L-Pro/c-Al2O3AA; 0.15
d
2
L-Pro/c-Al2O3; rc
d
3
L-Pro/c-Al2O3; rc
e
4
L-Pro/c-Al2O3AA; 0.15, is
f
5
Liquid product
6
Liquid productf ? L-Pro; 0.15
d
7
L-Pro/c-Al2O3; rc
d
8
L-Pro/c-Al2O3; rc
c
9
L-Pro/c-Al2O3AA; 0.15, 50C
d
10
L-Pro/c-Al2O3; rc
d
11
L-Pro/c-Al2O3; rc
Reaction of 2 with 6g
c
12
L-Pro/c-Al2O3AA; 0.075
f
13
Liquid product
d
14
L-Pro/c-Al2O3; rc
e
15
L-Pro/c-Al2O3AA; 0.075, is
f
16
Liquid product
d
17
L-Pro/c-Al2O3; rc
e
18
L-Pro/c-Al2O3SA; 0.075, is
f
19
Liquid product
d
20
L-Pro/c-Al2O3; rc
a
b
c
d
e
f
g

Solvent; (mL)

Time (h)

Reuse nr.

Conversion (%)

Selectivity (%)a

Anti/syna

ee (%); (conf.)a

DMSO; 0.5

DMSO; 0.5

5
5
5
5
5
5
5
5
5
5
5

1st
2nd

1st
2nd

1st
2nd

82
92
62
90
45
80
70
34
91
62
38

86
91
76
82
82
91
82
69
92
87
88

3; (S)
10; (S)
12; (S)
13; (S)
12; (S)
40; (R)
15; (S)
14; (S)
7; (S)
10; (S)
9; (S)

DMSO;

DMSO;
DMSO;

DMSO;
DMSO;

DMSO;

44
88
88
44
88
88
44
88
88

1st

1st

1st

91
46
78
92
99
88
96
89
99

87
88
94
91
95
95
96
97
98

83/17
85/15
89/11
92/8
95/5
94/6
97/3
97/3
97/3

76;
90;
88;
85;
93;
92;
98;
96;
97;

0.5
0.5
0.5
0.5
0.5
0.5

(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)

Selectivity, diastereomer ratio and ee of the aldol products, the absolute configuration of the excess enantiomer in brackets
Reaction conditions: reactions carried out in 2 mL acetone with 0.5 mmol 1 using 150 mg c-Al2O3AA
Catalyst prepared in solvent and used by addition of 1 and 5
Catalyst from previous entry recycled following centrifugation
Catalyst formed in situ
Use of the separated liquid phase from the previous entry
Reaction conditions: 0.25 mmol 2, 2 mmol 6 using either 150 mg c-Al2O3AA or 125 mg c-Al2O3SA

123

484

G. Sz}
oll}
osi et al.

Table 5 Comparison of the use of L-Pro and L-Pro-L-Pro(OH) catalysts in the absence and presence of c-Al2O3
Entry

Catalyst; amount
(mmol)

Aldehyde;
(mmol)

Ketonea

Solvent;
(mL)

c-Al2O3;
(mg)

Time
(h)

Conv.
(%)b

Sel.
(%)b

Anti/
synb

ee (%);
(conf.)b

L-Pro;

0.15

1; 0.5

91

80

74; (R)

L-Pro;

0.15

1; 0.5

AA; 150

93

75

20; (S)

L-Pro-L-Pro(OH)
TFA;
c

1; 0.5

82

88

16; (S)

0.15
L-Pro-L-Pro(OH)
TFA;
0.15c

1; 0.5

AA; 150

91

94

11; (S)

L-Pro;

0.075

2; 0.25

22

77

99

90; (R)

L-Pro;

0.075

2; 0.25

SA; 250

22

65

99

39; (S)

L-Pro-L-Pro(OH)
TFA;
c

2; 0.25

22

64

90

23; (S)

L-Pro-L-Pro(OH)
TFA;
c

2; 0.25

AA; 150

22

79

70

L-Pro-L-Pro(OH)
TFA;
c

2; 0.25

SA; 250

22

77

85

6; (R)

10

L-Pro;

0.075

2; 0.25

DMSO;
0.5

48

94

96

98/2

91; (S,S)

11

L-Pro;

0.075

2; 0.25

DMSO;
0.5

AA; 100

48

77

97

95/5

95; (S,S)

12

L-Pro-L-Pro(OH)
TFA;
c

2; 0.25

DMSO;
0.5

44

96

95

87/13

16; (R,R)

L-Pro-L-Pro(OH)
TFA;
c

2; 0.25

DMSO;
0.5

SA; 125

44

90

93

83/17

35; (R,R)

0.075

0.075

0.075

0.075

13

0.075

Reaction in 2 mL 5 or using 2 mmol 6

Conversion of the aldehyde, selectivity, diastereomer ratio and ee of the aldol products, the absolute configuration of the excess enantiomer in
brackets

1 equivalent triethylamine (as compared with the dipeptide salt) was added

Fig. 4 Effect of L-Pro- and D-Pro mixture composition on the ee

obtained in the aldol reaction of 2-nitrobenzaldehyde with acetone in
the absence (circles) and presence of c-Al2O3AA (triangles); closed
symbols 0.15 mmol, open symbols 0.075 mmol mixture of proline.
For reaction condition see Table 2

123

the aldol reaction of 4-nitrobenzaldehyde and acetone in

13 % ee [29]. Results of our experiments using this
dipeptide in the absence and presence of c-Al2O3 in
comparison with the amino acid L-Pro are summarized in
Table 5.
Three aldol reactions were used in this study, namely
those between 1 and 5, 2 and 5 or 6. Comparison of the data
regarding L-Pro and L-Pro-L-Pro(OH) allows the following
conclusions to be drawn: (i) Under the conditions of
homogeneous catalysis, catalysts L-Pro and L-Pro-LPro(OH) catalyze the formation of products of opposite
configuration in all three reactions (entries 1 vs 3, 5 vs 7, 10
vs 12); (ii) Under the conditions of heterogeneous catalysis,
on catalyst L-Pro/c-Al2O3 reversal of the enantioselection
takes place in the first two reactions (entries 1 vs 2, 5 vs 6),
whereas on catalyst L-Pro-L-Pro(OH)/c-Al2O3 inversion is
observed only in the second one (entries 7 vs 9); (iii)
Accordingly, the reversal of the enantioselection recognized by Li and coworkers [21] on L-Pro/c-Al2O3 hybrid
catalysts is most probably not caused by the L-Pro-LPro(OH) dipeptide formed in situ on the alumina surface
but, indeed, by the L-Pro/c-Al2O3 catalyst of as yet
unknown surface structure.

Reversal of Enantioselectivity in Aldol Reaction on Proline/c-Alumina

Scheme 1 Schematic enamine
mechanism of the L-Procatalysed asymmetric aldol
reactions

485

HN
O

+
- H2O

HO

HO
O
O

L-Pro

- L-Pro

HO

H
O
_

+
O

Al

O
O

O
Al

Al

O H H
O
O
O
Al
Al
Al
O
O

O
+

N H

OH

O H
O

Al

O
O

N
O

H
Al

O H

-H2O

O
O

Al

Al

O
O

H
O
Al

+ O

N H

O H
O

Al

O
O

O
Al

+H2O

Al

OH

N
OH

+ H2O
R HO

HO

+ RCHO

O H
O

Al

O
O

R
H O

N
O

O
Al

O H
O

Al

O
O

Al

H
O
Al

Scheme 2 Suggested structure of the L-Pro/c-Al2O3 catalyst and the mechanism of the asymmetric aldol reaction occurring on this catalyst
surface

In order to obtain new information on the mechanism of

the asymmetric aldol reaction taking place on the organic
inorganic hybrid catalyst L-Pro/c-Al2O3, experiments similar to those described in Ref. [25] were also carried out.
Namely, we studied how the absolute configuration of the
product formed changed depending on the composition of
L-Pro and D-Pro mixtures as well as on in situ formed L-Pro/
c-Al2O3 and D-Pro/c-Al2O3 catalysts mixtures under
identical experimental conditions. The data obtained in
these experiments on the linear or nonlinear behavior are
summarized in Fig. 4.
Reversed enantioselection catalyzed by L-Pro in the
presence of c-Al2O3 as compared to the reaction without
c-Al2O3 is again clearly shown in Fig. 4. Data shown in
this figure proved the assumption that, as suggested by Li
and coworkers [21], the reaction associated with reversal of
the ee observed in the presence of L-Pro/c-Al2O3 catalyst is
driven by L-Pro chemisorbed on the surface of c-Al2O3. At
the same time, the linear effect obtained in presence of
c-Al2O3 confirms the validity of heterogeneous catalytic
nature of the reaction mechanism. In solution it is accepted

that the L-Pro catalyzed asymmetric aldol reaction proceeds

according to enamine mechanism as illustrated in
Scheme 1 [25]. Li and co-workers suggested the strong
chemisorption of L-Pro over the c-Al2O3, accordingly, the
proposed mechanism of the heterogeneous catalytic reaction may be envisaged as shown in Scheme 2.
The unusual shape of the product ee versus catalyst ee
function in the absence of c-Al2O3 can be explained by the
results of Blackmond published in 2006 [26]. According to
these, at relatively low L-Pro concentrations, where L-Pro is
fully dissolved, a linear relationship can be observed in the
entire composition range of L-Pro ? D-Pro mixtures. At
higher proline concentrations, however, the catalyst is no
longer fully dissolved (the solution is visibly opaque), there
is asymmetric amplification based on the equilibrium
solidliquid phase behavior of amino acids in solution. In
this case the shape of the curve (see Fig. 1 in [26]) is
identical with that of the curve in Fig. 4 obtained by us in the
absence of alumina. The data in Fig. 4 also corroborate the
proposed mechanism of the aldol reaction involving an
enamine intermediate. At the same time, however, they also

123

486

indicate that in one case the reaction is of the homogeneous

liquid phase type, whereas in the presence of Al2O3 the
reaction proceeds on the Pro/c-Al2O3 catalyst formed on the
surface of c-Al2O3 rather than in the solution phase.

4 Conclusions
Li and coworkers [21] observed unexpected inversion in
the well-known, L-proline-catalyzed aldol reaction between
aromatic aldehydes and acetone in the presence of c-Al2O3
additive. Namely, R product was formed instead of the
expected S product. The unexpected stereochemistry was
attributed to the effect of the organicinorganic hybrid
catalyst L-Pro/c-Al2O3 formed in the course of the reaction.
The present work reports the following, so far unpublished
experiments and their conclusions: (i) studies on aldol
reactions catalyzed by L-Pro and D-Pro between acetone,
cyclohexanone and cyclopentanone on the one hand and
2-nitrobenzaldehyde, isobutyraldehyde, butyraldehyde and
cyclohexanecarboxaldehyde on the other hand; (ii) studies
on the effect of ultrasonic irradiation on the reaction rate
and on the enantioselection; (iii) experiments using L-ProL-Pro(OH) dipeptide catalyst; (iv) the effect of the composition of L-Pro and D-Pro mixtures on the ee (linear/
nonlinear behavior); (v) reuse measurements on used catalyst and its collected supernatant.
The experiments allowed the following new conclusions
to be drawn: (i) in the aldol reaction between 2-nitrobenzaldehyde and acetone, in the presence of c-Al2O3,
under identical experimental conditions both L-Pro and
D-Pro produced unexpected inversion in ee of *20 %, as
opposed to the ee of *75 % of the reaction without
c-Al2O3; (ii) in the case of the aliphatic and cycloaliphatic
aldehydes, the ee of the reaction with c-Al2O3 was *40 %
and of that without Al2O3 was *90 %; (iii) reversal of the
ee cannot be generalized for aldol reactions in the presence
of c-Al2O3, because it has only been observed for acetone
among the ketones studied by us; (iv) our various experiments supply further evidence to support the hypothesis of
Li et al., namely that the reaction takes place on the surface
of the L-Pro/c-Al2O3 catalyst generated in the course of the
reaction; (v) in the case of cycloalkanones there is presumably competition between the liquid-phase and the
surface reaction with preference for the former, as a consequence of which reversal of the ee fails to take place; (vi)
further research is needed to resolve the synthesis of chiral
organicinorganic hybrid catalysts enabling higher ee values. Our current research is focused on using this heterogeneous catalytic system in a continuously operated high
pressure flow system to exploit the advantage of the heterogeneous nature of this hybrid catalyst. Other non-conventional oxide supports will also be used for immobilizing

123

G. Sz}
oll}
osi et al.

organocatalysts; in our preliminary experiments using

graphite oxide as inorganic support [30] for L-Pro we have
reached up to 50 % ee.
Acknowledgments Financial support by the Hungarian National
Science Foundation (OTKA Grant K 72065 and K 109278) is highly
MOPappreciated. This research was realized in the frames of TA
4.2.2.A-11/1/KONV-2012-0047 project.

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