L-Proline supported on ionic liquid-modified magnetic nanoparticles as a highly efficient and reusable organocatalyst for direct asymmetric aldol reaction in water

Article abstract of DOI:10.1039/c3gc40772a

Grafting l-proline on imidazolium-based ionic liquid (IL)-functionalized magnetic nanoparticles afforded a magnetically recoverable l-proline catalyst. Characterization technologies suggested the presence of an l-proline backbone, an IL linker, and a magn

Full text of DOI:10.1039/c3gc40772a

View Article Online
View Journal
Green Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: D. Yin, Y. Kong and L. Zhao, Green
Chem., 2013, DOI: 10.1039/C3GC40772A.
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
Volume 12 | Number 9 | September 2010 | Pages 1481–1676
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1463-9262
COMMUNICATION
CRITICAL REVIEW
Luque, Varma and Baruwati
Dumesic et al.
Magnetically seperable organocatalyst Catalytic conversion of biomass
for homocoupling of arylboronic acids to biofuels
1463-9262(2010)12:9;1-U
www.rsc.org/greenchem
Registered Charity Number 207890

Page 1 of 11
Green Chemistry
View Article Online
DOI: 10.1039/C3GC40772A
Graphical Abstract
L
-Proline supported on ionic liquid-modified magnetic nanoparticles
as a highly efficient and reusable organocatalyst for direct
asymmetric aldol reaction in water
Yu Kong a, Rong Tan, *a Lili Zhao, a Chengyong Li a and Donghong Yin, *a,b
a Institute of Fine Catalysis and Synthesis, Key Laboratory of Chemical Biology and Traditional Chinese
Medicine Research (Ministry of Education), Hunan Normal University, Changsha, Hunan, 410081, China
b Technology Center, China Tobacco Hunan Industrial Corporation, NO. 426 Laodong Road, Changsha,
Hunan, 410014, China
L-proline was covalently grafted on the MNPs through an imidazolium-based IL linker, which provided a
highly efficient and magnetically recoverable L-proline catalyst for the asymmetric direct aldol reaction in
water.
O
H
N
N
Si
N
O
N
C
O
H
Br
O
O
OH
O
O
NO2
catalyst 1 (10 mol%)
H
+
H2O, 12 h, 30 oC
NO2
yield: 92%
dr: 88/12 (anti/syn)
ee value: 85% (for anti- isomer)
* Corresponding authors. Fax: +86-731-8872531. Tel: +86-731-8872576
E-mail: yiyangtanrong@126.com (R. Tan); yindh@hunnu.edu.cn (D. Yin)

View Article Online
DynamiDcOAI: 1r0ti.1c0l3e9/LC3iGnCk4s07►72A
Green Chemistry
Page 2 of 11
Journal Name
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
L-Proline supported on ionic liquid-modified magnetic nanoparticles as
a highly efficient and reusable organocatalyst for direct asymmetric
aldol reaction in water
Yu Kong a, Rong Tan, *a Lili Zhao a and Donghong Yin *a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
Grafting L-proline on imidazolium-based ionic liquid (IL)-functionalized magnetic nanoparticles afforded a magnetically recoverable
L-proline catalyst. Characterization technologies suggested the presence of an L-proline backbone, an IL linker, and a magnetic ferrite
core in the catalyst. The resulting L-proline catalyst was efficient for direct asymmetric aldol reaction in water without need for organic
10 solvents and co-catalysts. Such efficiency is attributed to the fact that the IL moiety facilitated the accessibility of hydrophobic reactants
to active sites in water and stabilized the formed enamine intermediate during the reaction. High activity (yield = 92%),
diastereoselectivity (dr; 88/12) and enantioselectivity (ee; 85%) were obtained using 10 mol% catalyst for the reaction between
cyclohexanone and 2-nitrobenzaldehyde within 12 h, where the pristine L-proline and IL-free counterpart were almost inactive. The
catalyst was easily separated using a permanent magnet externally and can be reused for several times without significant loss of activity.
product are difficult to achieve.2e ILs are also used as alternative
15 Introduction
modifiers to make L-proline efficient and reusable in aqueous
7
35 direct asymmetric aldol reactions.6c, However, the separation
Direct asymmetric aldol reactions between unmodified
process of IL-tagged L-proline is undesirable. Excessive organic
solvent is often required to selectively precipitate the catalyst out
of the reaction mixture. Thus far, the preparation of an efficient
and recoverable L-proline catalyst for direct asymmetric aldol
40 reaction in water remains challenging.
ketones and aldehydes are useful carbon–carbon bond-forming
reactions that serve as a convenient method of synthesizing chiral
organic compounds.1 Proline is gaining increased attention in
20 direct asymmetric aldol reactions because it is efficient,
environmentally benign, easily accessible, and available in both
enantiomeric forms.2 Unlike natural aldolases that are efficient
for the aldol reaction in water, proline is an organocatalyst
typically used with an excess of reacting ketone,3 organic
25 solvent,2a, 2g, 4 or ionic liquids (ILs).5 If bulk water is used as the
reaction medium, low reactivity or even no reaction progress is
detected probably because of the limited affinity between the
hydrophobic reactants and proline catalyst in water.2e, 6 Long-
chain hydrocarbon fragments have been introduced into the
30 framework of proline to make hydrophobic substrates compatible
in aqueous medium. The resulting yield is high and the selectivity
is excellent, but efficient recovery of catalyst and high purity of
Magnetic nanoparticles (MNPs) especially Fe3O4 coated with
silica (SiO2@Fe3O4) are emerging as interesting supports for the
immobilization of homogeneous catalysts.8 Different from many
traditional porous supports, the nonporous MNPs induce the
45 distribution of catalytically active sites throughout the outer
surface; thus, the pore diffusion constraint is practically avoided.
Importantly, magnetic separation renders the recovery of catalysts
from liquid-phase reactions much easier and more efficient than
by filtration and centrifugation. Some pioneer contributions of
50 organocatalysis are also known in this emerging field.9, 4b For
example, Luo et al.9b prepared MNP-supported chiral primary
amine catalysts that are efficient and recyclable for direct
asymmetric aldol reaction. This successful preparation paves the
way for a range of MNP-supported asymmetric organocatalysts.
55 Lately, Yang et al.4b covalently grafted L-proline onto
SiO2@Fe3O4 nanoparticles and proved that the MNP-based L-
proline catalyst is efficient for asymmetric aldol reaction in
ethanol and can be recovered simply by magnetic separation.
However, the catalyst is also almost inactive when only water is
60 used as the reaction medium because of the limited mass transfer.
This problem can be solved by attaching L-proline to an IL-
modified MNP. Apart from the active role of an IL linker in the
overall reaction mechanism, such linker may fine tune the
dispersion of the supported catalyst in water and make the
65 catalyst more compatible with organic substrates and solvent.
a
*
Institute of Fine Catalysis and Synthesis, Key Laboratory of
Chemical Biology and Traditional Chinese Medicine Research
(Ministry of Education), Hunan Normal University, Changsha,
Hunan, 410081, China;
b
Technology Center, China Tobacco Hunan Industrial Corporation,
NO. 426 Laodong Road, Changsha, Hunan, 410014, China.
Fax:
+86-731-8872531;
Tel:
+86-731-8872576;
E-mail:
yiyangtanrong@126.com (R. Tan) or yindh@hunnu.edu.cn (D. Yin)
†Electronic Supplementary Information (ESI) available: General
procedure for the direct asymmetric aldol reaction, detailed NMR
spectra and HPLC analysis for the aldol products. See
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

View Article Online
DOI: 10.1039/C3GC40772A
Page 3 of 11
Green Chemistry
Therefore, the problems associated with the transport of reactants
to catalytic sites can be circumvented.
In this study, we reported a novel L-proline catalyst composed
the N-Boc-L-proline moiety to covalently tether onto the surface
of the silica magnetic microspheres. Removal of the protecting
group (Boc-) using TFA gave catalyst 1 as a brown powder.
NH
of
a Fe3O4 core, which made the catalyst magnetically
H
Br
O
C
5
recoverable, and a shell consisting of L-proline appended by an
amine-functionalized IL. The novel L-proline catalyst (L-proline-
IL-SiO2@Fe3O4) was efficient in direct asymmetric aldol
reaction in water without need of organic solvents and co-
catalysts. Furthermore, the catalyst can be easily separated with
10 an external magnet without using extra organic solvents or
additional filtration steps. Thus, the technology is green and
solves the problems associated with mass transfer and catalyst
recycling in aqueous aldol reaction.
N
Br
ClCO2Et, Et3N, THF, reflux 24 h
NH2 HBr
.
HN
COOH
C
N
N
O
BOC
BOC
1. Toluene, N2, reflux, 12 h
2. TFA, dichloromethane
N
N
Br
(CH3CH2O)3Si
Dry toluene, reflux 24 h
O
N
N
OH
OH
OH
SiO2@Fe3O4
N
Si
N
O
Si
O
O
O
O
catalyst 1
60
Scheme 1 Synthesis of the catalyst 1.
Results and Discussion
For comparison, the IL-free counterpart of L-proline-NH2-
SiO2@Fe3O4 (denoted as catalyst 2), in which L-proline was
15 Preparation and Characterization of Catalysts
65 directly
grafted
onto
amino-functionalized
magnetic
MNPs are used as heterogeneous catalytic supports because of
their high surface area that result in high catalyst loading capacity,
high dispersion, outstanding stability, and convenient catalyst
recycling.8b-d MNPs generally require further modification to
20 confer high dispersion in a range of media for catalytic reactions
and/or sufficient stability under the harsh conditions needed for
catalytic reactions and catalyst recycling.8c ILs, as modifiers in
support systems, fine tune the surface properties of the support
and transfer the properties of the ILs to materials,10 which are
25 expected to improve the compatibility of the hydrophobic
substrates in an aqueous system. Imidazolium-based ILs have
also been found to activate L-proline in direct asymmetric
reactions.2f Thus, we decided to immobilize L-proline on
imidazolium-based IL-functionalized MNPs by covalent linkage
30 to produce efficient and magnetically recoverable L-proline
catalysts for direct asymmetric aldol reaction in water. Given that
the five-membered nitrogen containing the L-proline heterocycle
is regarded as one of the “privileged” backbones of the
asymmetric reaction,2a, 11 we designed a strategy in the present
35 study to covalently tether the L-proline derivative containing the
intact “privileged” chiral pyrrolidine unit and a halogenerated
hydrocarbon group to imidazole-modified MNPs by forming an
imidazolium-based IL linker.
microspheres, was also prepared according to a preparation
procedure similar to that of catalyst 1, as shown in Scheme 2.
During
the
procedure,
the
organosiloxane
of
3-
aminopropyltriethoxysilane was used instead of N-[3-
70 (triethoxysilyl)propyl]-4,5-dihydroimidazole to modify the
surface of SiO2@Fe3O4. The abundant surface amino groups (–
NH2) present on SiO2@Fe3O4 were readily reacted with the
carboxyl group of N-Boc-L-proline by the mixed anhydride
method,14 giving the Boc-protected L-prolinamide-SiO2@Fe3O4.
75 Removal of the protecting group (Boc-) also afforded catalyst 2
as brown powder.
OH
O
(CH3CH2O)3Si
NH2
Si
NH2
OH
O
Dry toluene, reflux 24 h
OH
O
SiO2@Fe3O4
N
COOH
O
1)
, ClCO2Et, THF, reflux, 24 h
H
BOC
Si
N
O
N
C
O
H
2) TFA, dichloromethane
O
catalyst 2
Scheme 2 Synthesis of the catalyst 2.
80
The magnetic catalyst 1 can be well dispersed in both aqueous
and organic solvents to form a stable suspension in the absence of
a magnetic field (Fig. 1b). We speculated that the high dispersion
was related to the nanoscale size of support and the special
solubility of the imidazolium-based IL coating. Actually, catalyst
The preparation of L-proline-IL-SiO2@Fe3O4 (denoted as
40 catalyst 1) is shown in Scheme 1. SiO2@Fe3O4 was readily
synthesized by a chemical co-precipitating method similar to a
previously reported one,12 followed by an SiO2-coating
procedure.13 N-tert-butoxycarbonyl-L-proline (N-Boc-L-proline)
85 1 exhibited better dispersion in water than the IL-free counterpart,
as shown in Fig. 1 (Figs. 1b vs. 1a).
was synthesized according to
a procedure described in
45 reference.14 First, 3-bromopropylamine liberated from 3-
bromopropylamine hydrobromide by NaOH aqueous reaction
was directly reacted with N-Boc-L-proline in the presence of
triethylamine and ethyl chloroformate, thereby affording the
corresponding
N-Boc-L-prolinamide-derived
brominated
50 hydrocarbon. Then, the bifunctional alkoxysilane reagent of N-
[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole was used to
modify MNPs through the formation of Si–O bonds based on the
reaction of alkoxy with the abundant surface hydroxyl groups (–
OH) on SiO2@Fe3O4. The successive alkylation of the N-
55 alkylimidazole group on the modified MNPs with the brominated
hydrocarbon group (–C3H6Br) in the L-proline derivative induced
Fig. 1 Photographs of the dispersion of catalyst 2 (a) and catalyst 1 (b) in
water and the separation of catalyst 1 with an external magnet (c).
90
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C3GC40772A
Green Chemistry
Page 4 of 11
The high dispersion of the catalyst in water and easy
accessibility to the active sites result in high reactivity in aqueous
direct asymmetric aldol reaction. Interestingly, the nanoparticles
of catalyst 1 can be aggregated using moderate magnetic field
strengths (Fig. 1c). This observation suggested that the magnetic
catalyst was easy to separate from the reaction mixtures using a
permanent magnet externally through a magnetic concentration
step.
5
Characterization of Samples
10 TEM
TEM images were used to obtain information on the particle
size and morphology of as-prepared samples of SiO2@Fe3O4,
catalyst 1, and catalyst 2. The typical TEM images are shown in
Fig. 2. Particles with an approximately spherical shape and
15 average diameter of ca. 14 nm were observed on the image of
SiO2@Fe3O4 (Fig. 2a). The diameter of the particles is somewhat
larger than the typical diameter of bare Fe3O4 prepared by
chemical co-precipitation (ca. 10 nm),15 suggesting that these
core–shell samples of SiO2@Fe3O4 were coated by a thin silica
20 layer ca. 4 nm thick. This type of silica coating reduced the
irreversible aggregation of individual particles and provided
abundant reaction sites for grafting L-proline. The size and
morphology of the MNPs did not significantly change after
anchoring the L-proline moiety onto the silica shell using an
25 imidazolium-based IL linker (Fig. 2b). This finding suggested
that the magnetic ferrite core was intact during immobilization
and that the functional reaction occurred only on the particle
surface. Meanwhile, no detectable outer IL-tagged L-proline shell
within the sensitivity limit of TEM (Fig. 2b) was observed. A
30 reasonable explanation may be the existence of a monolayer of
IL-tagged L-proline shell, which was too thin to be recognized.
The structural features of catalyst 1 particularly the good
dispersion of catalytically active centers on the surface made the
catalyst efficient in aqueous aldol reaction. The prepared IL-free
35 counterpart (catalyst 2) also showed an approximately spherical
particle morphology with an average particle diameter of ca. 14
nm in the TEM image (Fig. 2c).
55
Fig. 2 TEM images of the SiO2@Fe3O4 (a), catalyst 1 (b), catalyst 2 (c)
and the catalyst 1 after the 5th reaction (b’).
2.75
(b')
2.38
(b)
1.98
(c)
(a)
0
20
40
60
Partical size (µm)
60
Fig. 3 Hydrodynamic diameter of the SiO2@Fe3O4 (a), catalyst 1 (b),
catalyst 2 (c) and the catalyst 1 after the 5th reaction (b’).
Particle Size Distribution Analysis
In order to determine the change in the size of the
40 nanoparticles after modification, the particle size distribution of
SiO2@Fe3O4, catalyst 1, and catalyst 2 was measured by a
MS2000 Laser Particle Size Analyzer, as shown in Fig. 3. The
samples for measurement were sonicated in deionized water for
1.5 h. It was found that the mean hydrodynamic diameter of
45 SiO2@Fe3O4 (ca. 19.8 nm) was greater than the particles size
estimated by TEM images (ca. 14 nm) due to the presence of
hydration layer on the particles (Fig. 3a).16 The modification of
organic moiety on the surface indeed resulted in an increase in
the average hydrodynamic diameter. Catalyst 1 with an IL-
50 tagged L-proline shell showed the mean hydrodynamic diameter
of 27.5 nm (Fig. 3b), while the IL-free counterpart of catalyst 2
showed a smaller average hydrodynamic diameter (ca. 23.8 nm)
than that of the catalyst 1 (Fig. 3c vs. 3b).
XRD
Fig. 4 displays the high-angle powder XRD patterns of
65 catalysts 1 and 2 together with those of SiO2@Fe3O4 and L-
proline. Fig. 4c shows that the XRD pattern of SiO2@Fe3O4 had
the typical peaks at 30.08°, 35.42°, 43.08°, 53.56°, 56.98°, and
62.62°, which corresponded to the (220), (311), (400), (422),
(511), and (440) reflections of pure Fe3O4 with a spinel structure,
70 respectively.8f These characteristic peaks were also present in the
powder XRD patterns of the MNP-based catalysts 1 and 2,
suggesting that the surface modification of MNPs did not
significantly affect the phase composition of SiO2@Fe3O4 (Figs.
4a and 4b vs. Fig. 4c). Moreover, compared with the XRD pattern
75 of pristine L-proline, the XRD patterns of catalysts1 and 2 did
not show any distinct diffraction peak corresponding to the
crystalline L-proline phase (Figs. 4a and 4b vs. Fig. 4d), which
confirmed the high dispersion of L-proline on the surface of
MNPs.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

View Article Online
DOI: 10.1039/C3GC40772A
Page 5 of 11
Green Chemistry
3 1 1
a
5 1 1
4 2 2
2 2 0
4 4 0
a
4 0 0
1655
1655
2864
2941
2941
b
1680
1680
b
2870
2877
c
2926
c
1207
1131
581
d
4000
3500
3000
2500
2000
1500
1000
500
Wavenumbers (cm-1)
10
20
30
40
50
60
70
80
2-theat, degrees
Fig. 5 FT-IR spectra of N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole
modified MNPs (a), catalyst 1 (b) and catalyst 2 (c).
Fig. 4 Powder X-ray diffraction patterns of catalyst 1 (a), catalyst 2 (b),
SiO2@Fe3O4 (c), and L-proline (d).
Thermal Analysis
FT-IR
45
Thermal analysis was performed to monitor the decomposition
profiles of catalyst 1, catalyst 2, and pristine L-proline for
comparison. The results are shown in Fig. 6. Catalyst 1 showed
six distinct steps of weight losses in the combined TG-DTG
curves upon heating from room temperature to 800 °C under
5
The covalent binding of L-proline to the surface of IL-modified
SiO2@Fe3O4 in catalyst 1 was further confirmed by FT-IR
analysis. Fig. 5 shows the FT-IR spectra of catalysts 1 and 2, as
well as imidazole-modified SiO2@Fe3O4 for comparison. The
FT-IR spectrum of imidazole-modified SiO2@Fe3O4 had the
50 airflow (Fig. 6b). The first weight loss at 90 °C was due to the
removal of surface-adsorbed water. The second weight loss at
141 °C, which was absent in the combined TG-DTG curves of
catalyst 2 (Fig. 6b vs. 6a), accounted for the release of bromine
anions in the IL moiety as hydrogen bromine.20 The third weight
55 loss at 170–244 °C was probably due to the loss of structural
water within amorphous SiO2.4b The fourth weight loss at 245–
360 °C was assigned to the successive cleavage of L-proline
moiety. Interestingly, the decomposition temperature of the
supported L-proline moiety increased compared with that of
60 pristine L-proline (Fig. 6b vs. 6c), because of the mutual
stabilization of L-proline and MNP support. This finding
indirectly proved the covalent linkage of L-proline moieties onto
the surface of MNPs through the IL moiety. The L-proline content
of catalyst 1 was ca. 0.45 mmol/g, which was estimated
65 according to the weight loss within the temperature range. The
fifth weight loss was at 393 °C, followed by an additional weight
loss at 480 °C that extended up to ca. 540 °C. The two steps that
were well distinguished in the DTG curve can be associated with
the complete decomposition of the imidazolium-functionalized
70 trialkoxysilane moiety.21 The total weight loss was determined to
be 29% for catalyst 1, and the non-removable residue was
produced by the formation of iron oxide and silica in air at a high
temperature. The IL-free counterpart of catalyst 2 showed a
decomposition profile similar to catalyst 1, except for the
75 disappearance of the decomposition steps associated with the
imidazolium-based IL moiety (Fig. 6a). TGA analysis revealed
that the L-proline content of catalyst 2 was ca. 0.41 mmol/g. The
total weight loss of catalyst 2 was determined to be 11%.
Separated TG-DTG curves of catalyst 1, catalyst 2, and pristine
80 L-proline are provided in the Supplementary material (Fig. S42).
10 characteristic Fe–O vibrations at around 581 cm−1 and the
characteristic Si–O vibrations at around 1131 cm−1.17 The
presence of the imidazole group on the surface of SiO2@Fe3O4
was evident from the characteristic bands at 1655 (–NH–
stretching vibration of imidazole ring), 2864, and 2941 cm−1
15 (C−H and/or N−H stretching vibration) (Fig. 5a).18 The imidazole
modifier was responsible for the covalent anchoring of L-proline
on SiO2@Fe3O4 by forming an imidazolium-based IL linker, as
shown in Scheme 1. After L-proline anchoring, a new band at
around 1680 cm-1 appeared in the FT-IR spectrum of catalyst 1,
20 which was the characteristic stretching vibration of the C=O band
in the –CONH– group (Fig. 5b).19 The –CONH– group in
catalyst 1 suggested the successful introduction of the L-
prolinamide
derivative
moiety
to
imidazole-modified
SiO2@Fe3O4. However, the characteristic stretching vibrations of
25 the five-membered nitrogen containing the L-proline heterocycle
overlapped with the stretching modes of the imidazolium group.
The FT-IR spectrum of catalyst 2 was similar to that of catalyst
1 (Fig. 5c vs. 5b), except for the absence of the characteristic
−NH− stretching vibration of imidazole ring (near 1655 cm−1).
30 The difference was related to the absence of the imidazolium-
based IL moiety in the framework of catalyst 2. The
characteristic band derived from the stretching vibration mode of
C=O in –CONH– (at around 1680 cm-1) in the FT-IR spectrum of
catalyst 2 provided direct evidence that L-proline was directly
35 anchored onto amino-functionalized MNPs by forming L-
prolinamide (Fig. 5c), as shown in Scheme 2. Notably, compared
with catalyst 2, a significant feature observed for catalyst 1 was
the presence of the imidazolium-based IL linker that positively
affected the catalytic performance of L-proline catalyst in the
40 aldol reaction in water.
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C3GC40772A
Green Chemistry
Page 6 of 11
45 reaction conditions (Table 1, entry 4 vs. 3). Only 10% yield of the
aldol product was obtained over catalyst 2 within 12 h (Table 1,
entry 4). This observation clearly indicated that the imidazolium-
based IL moiety played a critical role in aqueous direct
asymmetric aldol reaction. The midway addition of 1-methyl-3-
50 buthylimidazolium bromine IL (equivalent to the IL amount in
catalyst 1) to the catalyst 2-mediated aldol reaction system
indeed led to increased yield from 10% to 17% (Table 1, entry 5
vs. 4), whereas the yield was far lower than that obtained over
catalyst 1 (Table 1, entry 5 vs. 3). Thus, the proximity of the IL
55 unit to the active site made the active center a kind of IL that
rendered catalytic sites more accessible, thereby tuning catalyst 1
into an efficient catalyst for this reaction. In fact, apart from the
compatibility, the high polarity and ionic character of the IL
moiety exerted synergistic effects on stabilizing the formed
60 enamine intermediate in the direct asymmetric aldol reaction,
which in turn improved the catalytic efficiency of L-proline. 5c
a
A
B
100
80
60
40
20
0
11%
29%
a
b
b
c
c
100 200 300 400 500 600 700 800
Temperature (oC)
100 200 300 400 500 600 700 800
Temperature (oC)
Fig. 6 Thermogravimetric (A) and differential thermogravimetric (B)
results of catalyst 2 (a), catalyst 1 (b), and pristine L-proline (c).
Catalytic Performances
Table 1 Direct asymmetric aldol reaction between cycloalkanones and
aromatic aldehydes catalyzed by L-proline in water a
5
Catalytic asymmetric aldol reactions in water have been
extensively researched in recent years because water is an
inexpensive, safe, and environmentally benign reaction medium
O
O
OH
O
catalyst (10 mol%)
H2O, 30 o
Ar
H
Ar
C
n
that often exerts
a synergistic effect on reactivity and
n
selectivity.11a, 22 Although the addition of a small amount of water
1-6
n = 3, 2
65
Yield b
(%)
Trace
ee d
(%)
nd e
10 may accelerate reactions and/or improve enantioselectivity,23
water as a reaction solvent often results in a low yield with low or
no enantioselectivity because of poor mass transfer.2e, 6 The IL-
tagged catalyst 1 was designed for direct asymmetric aldol
reaction performed in water. We proposed that the presence of
15 imidazolium-based IL favored the reagents’ diffusion toward
active sites and enhanced the catalytic activity of catalyst 1 in
aqueous aldol addition. Hydrophobic cycloalkanones were
selected as the aldol donor to investigate the catalytic
performance of catalyst 1 in direct asymmetric aldol reaction in
20 water. The results are summarized in Table 1. The absolute
configurations of the products were deduced by comparing the
HPLC retention times with reported values.24
Substrate
Product
OH
Anti/syn c
nd e
Entry Catalyst
1
2
3
4
5
SiO2@Fe3O4
L-proline f
Trace
92
nd e
nd e
O
O
NO2
88:12 85
H
Catalyst 1
Catalyst 2
Catalyst 2 g
NO2
10
nd
nd
nd
nd
(1)
17
OH
O
O
96
75
76:24 75
H
6
7
Catalyst 1
Catalyst 1
NO2
O2N
(2)
O
OH
Interestingly, catalyst 1 was efficient for the direct asymmetric
aldol reaction of cyclohexanone with 2-nitrobenzaldehyde in
25 water. About 10 mol% of the novel catalyst 1 was sufficient for
affording an almost quantitative yield (92%) of the aldol product
with good diastereoselectivity (up to 88/12, anti/syn) and
enantioselectivity (up to 85% for the anti-isomer) in the direct
asymmetric aldol reaction of cyclohexanone with 2-
30 nitrobenzaldehyde within 12 h (Table 1, entry 3). However, no
reaction progress was detected even after 48 h in water when the
reaction was catalyzed by pristine L-proline (Table 1, entry 2).
The results suggested that the imidazolium-based IL modified
MNPs created a microenvironment advantageous for reactant
35 diffusion in water. The parent SiO2@Fe3O4 was found to be
inactive for aqueous aldol reaction (Table 1, entry 1).
O
Cl
H
99:1
89
Cl
(3)
OH
O
O
H
55
30
89:11 82
8
9
Catalyst 1
Catalyst 1
Br
Br
(4)
OH
O
O
O
O
98:2
45
H
(5)
OH
90
33:67 86
H
10
Catalyst 1
O2N
NO2
To elucidate the function of the imidazolium-based IL moiety
in an aqueous reaction, an IL-free counterpart (catalyst 2) was
prepared as a control catalyst by directly anchoring the L-proline
40 moiety onto amino-modified MNPs. We noticed that catalyst 2
offered a slightly higher yield of the desired aldol product than
pristine L-proline probably because of the improved mass transfer
originating from the hydrophobic alkyl spacer. However, catalyst
2 was far less active than the IL-tagged catalyst 1 under identical
(6)
a
Catalyst (10 mol% of aromatic aldehydes), aromatic aldehyde (0.25 mmol),
b
cycloalkanone (2.5 mmol), H2O (2 ml), 12 h, 30 °C. Isolated yield after
c
1
d
column chromatography. Determined by H NMR analysis. Determined by
e
HPLC (Daicel chiralpak AD column) on the anti-isomer product. Not
f
70 determined.
Pristine L-proline (10 mol% of 2-nitrobenzaldehyde), 2-
nitrobenzaldehyde (0.25 mmol), cyclohexanone (2.5 mmol), H2O (2 ml), 48 h,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

View Article Online
DOI: 10.1039/C3GC40772A
Page 7 of 11
Green Chemistry
g
30 °C.
Catalyst
2
(10 mol% of 2-nitrobenzaldehyde), 1-methyl-3-
entry 13 vs. 15, and entry 16 vs. 18). Furthermore, electron-
buthylimidazolium bromine (0.01 g, equivalent to the amount of IL in catalyst 60 deficient aldehydes were found to be more favorable for the aldol
1), 2-nitrobenzaldehyde (0.25 mmol), cyclohexanone (2.5 mmol), H2O (2 ml),
reaction, affording the relevant aldols in excellent yields. An
almost quantitative conversion of 2-nitrobenzaldehyde (93%
yield of product 7) was achieved over 10 mol% of catalyst 1 in
the aqueous reaction within 12 h (Table 2, entry 1). 4-
12 h, 30 °C.
5
Excellent performance of catalyst 1 was also observed in the
direct asymmetric aldol reaction of cyclohexanone with other 65 Nitrobenzaldehyde exhibited reactivity similar to that of 2-
aromatic aldehydes using water as a solvent. Table 1 shows that
the aromatic aldehydes in all cases underwent reaction with
10 cyclohexanone to produce the corresponding β-hydroxy ketone in
nitrobenzaldehyde in aqueous aldol reaction (Table 2, entry 4). 2-
Chlorobenzaldehyde and 4-bromobenzaldehyde smoothly
underwent aldol reaction in water over catalyst 1 (10 mol%),
giving products 9 and 10 in 75% and 55% yields, respectively,
moderate to high yields, diastereoselectivities, and ee values in
water within 12 h. In particular, the aromatic aldehydes carrying 70 with 77% ee values (Table 2, entries 7 and 10). Electron-rich
strong electron-withdrawing groups such as nitro groups were
good acceptors in the presence of catalyst 1 (10 mol%) at room
15 temperature. 2-Nitrobenzaldehyde gave the desired the
corresponding aldols in excellent yield (92%) with good
aldehydes, such as 4-acetamidobenzaldehyde, were less active
under the studied conditions (Table 2, entry 13). The relatively
bulkier 2-naphthaldehyde also showed a low yield (35%) even
though the enantioselectivity (82% ee) can be tolerated (Table 2,
diastereoselectivity (88/12, anti/syn) and enantioselectivity (85% 75 entry 16).
ee for the anti-isomer) (Table 1, entry 2). Unfortunately, attempts
to change the substituting group positions onto the aromatic
20 aldehydes resulted in lower diastereoselectivity (76/24, anti/syn)
and ee (75% ee for the anti-isomer), although the yields remained
good (96%) (Table 1, entry 6). These phenomena were probably
due to the electronic and steric effects of aromatic aldehydes. The
formation of aldol products was related to the electron-
25 withdrawing capacity of the substituent group on aldehydes for
the active aldehyde group and the steric hindrance at the 2-
position on the aromatic ring for enantioface discrimination in the
transition state.25 The halogenated aromatic aldehydes gave
moderate yields of the corresponding aldol products (55%–75%),
30 although the excellent diastereoselectivities (89/11–99/1,
anti/syn) and enantioselectivities (82–89% ee for the anti-isomer)
were encouraging. Relatively bulkier aromatic aldehydes, such as
2-naphthaldehyde, were also less reactive for aldol condensation
with cyclohexanone because of the steric hindrance originating
35 from the 2-naphthyl group that did not favor nucleophilic attack.
The reaction gave lower yield (30%) and ee (45% ee for the anti-
isomer) but a high anti/syn diastereomeric ratio (98/2) (Table 1,
entry 9). The hydrophobic cyclopentanone was also efficiently
reacted with 2-nitrobenzaldehyde over catalyst 1 (10 mol%) in
40 water. A high yield of 90% was found within 12 h, whereas the dr
and ee values of aldol were somewhat lower (Table 1, entry 10).
The remarkably enhanced catalytic efficiency of the novel
catalyst 1 due to the presence of the imidazolium-based IL
moiety was also observed when the water-soluble acetone was
45 used as the aldol donor in the aqueous reaction. The comparative
results are summarized in Table 2. Catalyst 1 had a higher
efficiency than its IL-free counterpart catalyst 2 in the aqueous
direct asymmetric aldol reaction of acetone with various aromatic
aldehydes bearing either electron-rich or electron-deficient
50 substituents under identical conditions (Table 2, entry 1 vs. 2,
entry 4 vs. 5, entry 7 vs. 8, entry 10 vs. 11, entry 13 vs. 14, and
entry 16 vs. 17). The satisfactory results obtained from the
reaction showed that the imidazolium-based IL moiety enhanced
catalyst activity by increasing the yields and enantioselectivities
55 of the corresponding aldol products. Notably, less yields and
enantioselectivities over catalyst 2 were also obtained in the
reactions even though the reaction time was prolonged to 48 h
(Table 2, entry 1 vs. 3, entry 4 vs. 6, entry 7 vs. 9, entry 10 vs. 12,
Table 2 Direct asymmetric aldol reaction between acetone and aromatic
aldehydes catalyzed by L-proline in water a
O
OH O
O
catalyst (10 mol%)
H3C CH3
Ar
CH3
H
Ar
H2O, 30 oC
7-12
Yield b
(%)
ee
Entry Catalyst
Substrate
O
Product
(%)
79
1
2
93
60
OH
O
Catalyst 1
Catalyst 2
51
H
NO2
NO2
Catalyst 2 c
3
4
5
88
96
65
51
70
50
d
(7)
OH
O
Catalyst 1
Catalyst 2
O
H
O2N
O2N
Catalyst 2 c
6
7
8
90
75
45
51
77
49
d
(8)
OH
O
Catalyst 1
Catalyst 2
O
H
Cl
Cl
Catalyst 2 c
9
50
55
35
47
77
45
e
(9)
10
11
OH
O
Catalyst 1
Catalyst 2
O
H
Br
O
Br
O
Catalyst 2 c
12
13
14
45
35
20
44
83
46
e
(10)
O
OH
O
Catalyst 1
Catalyst 2
H
N
N
H
H
Catalyst 2 c
15
27
46
e
(11)
(12)
16
17
35
15
82
44
OH
O
Catalyst 1
Catalyst 2
O
H
e
Catalyst 2 c
18
25
43
a
80 Catalyst (10 mol% of aromatic aldehydes), aromatic aldehyde (0.25 mmol),
acetone (2.5 mmol), H2O (2 ml), 12 h, 30 °C. b Isolated yield after column
c
chromatography. Catalyst 2 (10 mol% of aromatic aldehydes), aromatic
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C3GC40772A
Green Chemistry
Page 8 of 11
aldehyde (0.25 mmol), acetone (2.5 mmol), H2O (2 ml), 48 h, 30 °C. d Ee was
determined by HPLC (Daicel chiralpak OB-H column) on pure products. e Ee
value was determined by HPLC (Daicel chiralpak AD column) on pure
products.
581
a
5
Apart from the excellent catalytic efficiency in aqueous aldol
reaction, another important feature of the designed catalyst 1 was
its easy and reliable separation using an appropriate magnetic
field. Upon completion of the reaction, the heterogeneous
b
2870
2941
10 catalyst 1 can be quantitatively recovered from the reaction
mixture using an external magnetic field, as shown in Fig. 1 (Fig.
1c). The aqueous phase was then separated from the magnetic
catalyst by decantation. Notably, although ethyl acetate was used
to extract a small amount of aldols from the reaction solution in
15 the present work, this approach was expected in large-scale
industrial processes, in which the oily product phase can be
directly separated from water without using any organic solvent.
Catalyst 1 that was stationary inside the vessel can be readily
recycled by adding fresh reaction substrates.
1680
2000
1655
1131
4000
3500
3000
2500
1500
1000
500
Wavenumbers (cm-1)
50
Fig. 7 FT-IR spectra of fresh catalyst 1 (a) and catalyst 1 reused five
times (b).
20
Table 3 shows the results of the recovery and reusability of
catalyst in the direct asymmetric aldol reaction of
Conclusions
1
An efficient and magnetically recoverable L-proline catalyst
cyclohexanone with 2-nitrobenzaldehyde in water. The novel
catalyst 1 can be recycled for up to five times with no
appreciable decrease in yield and selectivity of the aldol product,
55 was successfully prepared by immobilizing L-proline onto IL-
modified MNPs. The presence of an IL linker in the supported L-
proline catalyst resulted in excellent catalytic activity of the
catalyst for a wide range of ketones and aromatic aldehydes in
direct asymmetric aldol reaction in water without need for any
60 organic solvent or additional additives. The catalyst can also be
well dispersed in the reaction medium, easily magnetically
recovered from the reaction mixture, and reused several times
without significant loss of activity. All these advantages made the
novel L-proline catalyst a green and promising organocatalyst for
65 other important aqueous reactions.
25 which demonstrated that the prepared catalyst 1 possessed
excellent stability and reusability. The reaction was completely
stopped by catalyst removal. Elementary analysis of the
recovered catalyst was used to examine L-proline leaching in
terms of nitrogen element percentage. About 3.92 wt% of
30 elemental nitrogen was observed in the recovered catalyst, and
this value was close to that in fresh catalyst (ca. 3.96 wt%). The
inactivity of supernatants and the maintenance of the nitrogen
element percentage in catalyst 1 indicated that any leaching of
active species into solution was insignificant. Further evidence of
35 the stability of the magnetic L-proline catalyst was provided by
the FT-IR spectra of fresh catalyst 1 and catalyst 1 reused five
times (Fig. 7a vs. 7b). No significant change in catalyst occurred
even after five times of reuse. TEM images (Fig. 2b’ vs. 2b), as
well as particle size analysis (Fig. 3b’ vs. 3b), also showed that
40 catalyst 1 still maintained its nanostructure after repeated reuse.
These observations suggested that the efficient catalyst 1 was
perfectly stable during the direct asymmetric aldol reaction and
was readily recyclable from the reaction system.
Experimental Section
Materials and Reagents
4-Nitrobenzaldehyde,
acetamidobenzaldehyde were obtained by TCI. 3-Bromopropylamine
70 hydrobromide, 3-methoxybenzaldehyde, 2-nitrobenzaldehyde, 2-
2-chlorobenzaldehyde
and
4-
naphthaldehyde and 4-bromobenzaldehyde were bought from Acros. 3-
Pentanone, cyclohexanone and cyclopentanone were purchased from
Aldrich.
N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole,
3-
aminopropyltriethoxysilane and tetraethyl orthosilicate (TEOS) were
75 purchased from Alfa Aesa. Other commercially available chemicals were
laboratory grade reagents from local suppliers. They were used without
further purification, except for aromatic aldehyde, which was purified by
distillation.
45
Table 3 Reuse of catalyst 1 in the direct asymmetric aldol reaction of
a
cyclohexanone with 2-nitrobenzaldehyde in water
Entry Run times
Yield b (%)
Anti/syn c
ee d (%)
85
1
2
3
4
5
Fresh
Second
Third
92
95
90
90
89
88:12
Methods
89:11
84
80 1H NMR spectra of samples were recorded at a Varian-500 spectrometer.
Fourier transform infrared (FT-IR) spectra were obtained as potassium
bromide pellets with a resolution of 4 cm-1 and 32 scans in the range 400–
4000 cm-1 using an AVATAR 370 Thermo Nicolet spectrophotometer.
The termogravimetric and differential thermogravimetric (TG-DTG)
85 curves were obtained on a NETZSCH STA 449C thermal analyzer.
88:12
85
Fourth
Fifth
88:12
85
88:12
85
a
Catalyst 1 (10 mol% of 2-nitrobenzaldehyde), 2-nitrobenzaldehyde (0.25
o
Samples were heated from room temperature up to 700 C under airflow
mmol), cyclohexanone (2.5 mmol), H2O (2 ml), 12 h, 30 °C. b The same as
Table 1. c The same as Table 1. d The same as Table 1.
using alumina sample holders. The sample weight was ca. 10 mg and the
heating rate was 10 K/min. X-ray diffraction (XRD) patterns were
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

View Article Online
DOI: 10.1039/C3GC40772A
Page 9 of 11
Green Chemistry
recorded on a Philips X’ PERT-Pro-MPD diffractometer using Cu Kα
solid was dried at 60 oC under vacuum for 24 h to give N-Boc-L-proline-
60 IL-SiO2@Fe3O4. The obtained N-Boc-L-proline-IL-SiO2@Fe3O4 was
dispersed in dichloromethane (10 mL). Trifluoroacetic acid (TFA) (4.0
mL) was then added and the mixture was stirred at room temperature for
8 h. After removal of the solvent, the precipitate was washed completely
with saturated NaHCO3, water and methanol for several times and dried
radiation (λ= 1.542 Å). A continuous scan mode was used to collect 2θ
from 5 to 80o. The particle size and morphology of the samples were
determined by transmission electronic microscopy (TEM, JEOL, JEM-
5 200CX) with an acceleration voltage of 200 kV. The TEM samples for
analysis were prepared by dropping the dilute suspensions of powders
onto the carbon-coated copper grids and let the solvent evaporate. The 65 in vacuum to get the catalyst 1. Elemental analysis: Found: C, 11.3; H,
average hydrodynamic diameter and size distribution of the samples were
determined by a MS2000 Laser Particle Size Analyzer (Malvern, UK).
10 The samples for measurement were sonicated in deionized water for 1.5 h.
Analytical high performance liquid chromatography (HPLC) was carried
1.61; N, 3.96%. FT-IR (KBr): γmax/cm-1 2941, 2870, 1680, 1655, 1540,
1455, 1397, 1252, 1207, 1131, 1029, 834, 801, 638, 581.
Preparation of the catalyst 2: The IL-free counterpart of catalyst 2,
in which L-proline was directly coupled to the amino-functionalized
out on Shimadzu LC-10Avp instrument using Daicel chiralpak OB-H, AD- 70 magnetic microspheres, was also prepared according to the similar
H or AD columns.
preparation procedure of the catalyst 1. During the procedure, the
organosiloxane of 3-aminopropyltriethoxysilane was used instead of the
N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole to modified the surface
of the SiO2@Fe3O4. The abundant surface amino groups (-NH2) present
75 on the SiO2@Fe3O4 were readily reacted with the carboxyl group of the
N-Boc-L-proline by the mixed anhydride method, giving the Boc-
protected-L-prolinamide-SiO2@Fe3O4. Removal of the Boc- protecting
group afforded the L-proline-NH2-SiO2@Fe3O4 (denoted as catalyst 2).
FT-IR (KBr): γmax/cm-1 3390, 2926, 2877, 1680, 1557, 1540, 1517, 1455,
80 1427, 1397, 1207, 1131, 1037, 843, 634, 581, 443.
Preparation of Catalysts
15
Preparation of (S)-N-(3-bromopropyl)-1-(tert-Butoxycarbonyl)-
pyrrolidine-2-carboxamide: 3-Bromopropylamine hydrobromide (3.28
g, 15 mmol) was treated with 50 ml NaOH aqueous solution (10 wt.%) at
0 oC for 30 min. The liberated 3-bromopropylamine was extracted with
dichloromethane (4 × 5 mL). N-Boc-L-proline (3.23 g，15 mmol) was
20 dissolved in dry THF (20 mL) and treated with triethylamine (1.5 g, 15
mmol). After cooling to 0 °C, ethyl chloroformate (1.62 g, 15 mmol) was
slowly added over a period of 15 min. The mixture was stirred for another
30 min and then the solution of 3-bromopropylamine in dichloromethane
was dropwise added. The resulting mixture was refluxed for 24 h. After
25 removal of the formed white solid by filtration, the filtrate was
concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL)
and washed with water (3 × 20 mL), NaHCO3 (3 × 20 mL) and NaCl (3
×20mL) in sequence. The combined organic layer was dried over
anhydrous Na2SO4. After the evaporation of ethyl acetate, the residue was
30 further purified by column chromatography (n-hexane: ethyl acetate= 2:1
(V/V)) to afford the (S)-N-(3-bromopropyl)-1-(tert-Butoxycarbonyl)-
pyrrolidine-2-carbo -xamide as a light yellow oil (3.9 g, 90% yield).
Elemental analysis: Calc. for C13H23BrN2O: C, 46.58; H, 6.92; N, 8.36%.
General Procedure for the Direct Asymmetric Aldol Reaction
The selected catalyst (10 mol%, based on L-proline content in the
catalyst), ketone (2.5 mmol), aldehyde (0.25 mmol) and deionized water
(2 mL) were added in a 10 mL round-bottom flask in turn. The mixture
85 was allowed to react at room temperature for 12 h. The reaction was
monitored constantly by TLC. After completion of the reaction, the
magnetic catalyst was separated by a magnet near the bottle. The reaction
solution was removed from the reaction vessel by decantation while the
external magnet held the magnetic catalyst inside the bottle. The magnetic
90 catalyst was then washed with ethyl acetate, separated by magnetic
decantation as described above, dried under vacuum overnight at room
temperature for the recycle experiment. Ethyl acetate (3 × 10 mL) was
used to extract the aldols from the reaction solution. The combined
organic layers were washed with brine and died with Na2SO4. After the
95 evaporation of ethyl acetate, the residue was purified by column
chromatography on silica gel (Acros, 40–60 μm, 60 Å, eluent n-
hexane/ethyl acetate = 3/1 (V/V)) to afford the desired aldol products. All
products had the NMR spectra in agreement with published data.
Enantiomeric excess of the corresponding aldol products was determined
1
Found: C, 46.79; H, 6.75; N, 8.57%. H NMR (D2O, 500MHz) δ (ppm):
35 7.98 ( t, J = 8.8 Hz, 1H), 4.23 (t, J = 8.8 Hz, 2H), 3.59 (t, J = 8.4 Hz, 2H),
3.40 (t, J = 7.2 Hz, 1H), 2.79 (t, J = 7.2 Hz,1H), 2.36 (m, 2H), 2.18 (m,
2H), 1.83 (t, J = 10.5 Hz, 2H), 1.68 (t, J = 7.2 Hz, 2H), 1.40 (s, 9H). FT-
IR (KBr): γmax/cm-1 3324, 2796, 1824, 1760, 1698, 1538, 1478, 1394,
1246, 1164, 1022, 977, 922, 881, 773, 644, 591, 547.
40
Preparation of N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole
modified SiO2@Fe3O4: SiO2@Fe3O4 nanoparticles (2.5 g) was dispersed
in 10 ml of dry toluene and sonicated for 30 min at room temperature. N- 100 by HPLC analysis with a UV-vis detector using the Daicel chiralpak AD-
[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole (2.74 g, 10 mmol) was
then added. The mixture was refluxed for 24 h under nitrogen protection.
H, OB-H or AD column. The syn and anti diastereomers of the aldols
were readily distinguished in 1H NMR spectroscopy by the diagnostic
chemical shifts of –CHOH– proton. Detailed NMR spectra and HPLC
analysis for aldol products are available in the Supporting Information.
45 After removal of dry toluene, the residua was washed with a large
quantity of deionized water and ethanol (3 ×20mL) by magnetic
decantation, and dried under vacuum at room temperature overnight to 105 (2R,10S)-2-(Hydroxy-(2-nitrophenyl)methyl)cyclohexan-1-one 1. Yield:
yield the N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole modified
SiO2@Fe3O4. FT-IR (KBr): γmax/cm-1 3749, 3440, 2929, 2864, 1655, 1560,
50 1540, 1456, 1434, 1399, 1131, 1040, 632, 581, 443.
92%; (anti/syn) =88: 12; ee value (anti): 85% determined by HPLC
(Daicel chiralpak AD column; 2-propanol/n-hexane =15: 85 (V/V)); flow
rate = 1.0 mL/min; 25 oC; λ = 254 nm; tR = 13.4 min (anti, major) and tR =
1
Preparation of catalyst 1: The obtained N-alkylimidazole modified
14.2 min (anti, minor)). H NMR (CDCl3, 500 MHz): δ (ppm) 7.84 (d, J
MNP was dispersed in dry toluene (30 ml). The solution of (S)-N-(3- 110 =8.1 Hz, 1H), 7.77 (d, J =7.8 Hz, 1H), 7.63 (t, J =7.0 Hz, 1H), 7.43 (t, J
bromopropyl)-1-(tert-Butoxycarbonyl)-pyrrolidine-2-carbo -xamide (3.34
g, 10 mmol) in dry toluene (10 ml) was dropwise added into the above
55 solution under vigorously stirring. The obtained mixture was refluxed for
12 h under nitrogen protection. After magnetic separation, the brown
=7.3 Hz, 1H), 5.43 (d, J =7.1 Hz, 1H), 4.20 (s, 1H), 2.78-2.75 (m, 1H),
2.51-2.43 (m, 1H), 2.38-2.30 (m, 1H), 2.12-2.04 (m, 1H), 1.86-1.83 (m,
1H), 1.83-1.60 (m, 4H).
(2R,10S)-2-(Hydroxy-(4-nitrophenyl)methyl)cyclohexan-1-one 2. Yield:
crude product was extracted thoroughly in toluene using a Soxlet 115 96%; (anti/syn) = 76: 24; ee value (anti): 75% determined by HPLC
apparatus to remove homogeneous and unreacted start materials. The
(Daicel chiralpak AD column; 2-propanol/n-hexane =15: 85 (V/V)); flow
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Green Chemistry
View ArtiPcleaOgneline10 of 11
DOI: 10.1039/C3GC40772A
rate = 1.0 mL/min; 25 oC; λ = 254 nm; tR = 16.2 min (anti, major) and tR =
= 15.2 min (major) and tR = 16.1 min (minor)). 1H NMR (CDCl3, 500
60 MHz): δ (ppm) 7.47–7.21 (m, 4H), 5.10 (d, J =8.7Hz, 1H), 3.43 (s, 1H),
2.86-2.76 (m, 2H), 2.19 (s, 3H).
1
21.4 min (anti, minor)). H NMR (CDCl3, 500 MHz): δ (ppm) 8.21 (d,
J=8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 4.90 (dd, J =8.4, 2.6 Hz, 1H),
4.08 (d, J = 3.1 Hz, 1H), 2.66-2.29 (m, 3H), 2.17-2.04 (m, 1H), 1.85-1.80
5 (m, 1H), 1.75-1.15 (m, 4H).
(4R)-(4-Acetamidophenyl)-4-hydroxy-2-butanone 11. Yield: 35%; ee
value: 83% determined by HPLC (Daicel chiralpak AD column; 2-
o
(2R,10S)-2-(Hydroxy-(2-chlorophenyl)methyl)cyclohexa -n-1-one 3.
Yield: 75%; (anti/syn) = 99: 1; ee value (anti): 89% determined by HPLC
(Daicel chiralpak AD column; 2-propanol/n-hexane =10: 90 (V/V)); flow
rate = 1.0 mL/min; 25 oC; λ = 220 nm; tR = 9.9 min (anti, major) and tR =
propanol/n-hexane =10: 90 (V/V)); flow rate = 0.8 mL/min; 25 C; λ =
65 254 nm; tR = 50.0 min (major) and tR = 55.7 min (minor)). 1H NMR
(CDCl3, 500 MHz): δ (ppm) 7.47–7.26 (m, 4H,), 5.12-5.11 (m, 1H), 3.34
(s, 1H), 2.89-2.77 (m, 2H), 2.20 (s, 3H), 2.17 (s, 3H).
1
10 11.1 min (anti, minor)). H NMR(CDCl3, 500 MHz): δ (ppm) 7.84 (dd,
(4R)-Hydroxy-4-(2-naphthyl)-2-butanone 12. Yield: 32%; ee value:
J=7.8, 1.5 Hz, 1H), 7.34-7.28 (m, 2H), 7.21 (m, 1H), 5.36 (d, J=7.9 Hz,
82% determined by HPLC (Daicel chiralpak AD column; 2-propanol/n-
1H), 4.03 (d, J=3.7 Hz, 1H), 2.72-2.67 (m, 1H), 2.48-2.44 (m, 1H), 2.38- 70 hexane =7.5: 92.5 (V/V)); flow rate = 0.8 mL/min; 25 oC; λ = 254 nm; tR
2.31 (m, 1H), 2.11-2.04 (m, 1H), 1.84-1.81 (m, 1H), 1.70-1.54 (m, 4H).
(2R,10S)-2-(Hydroxy-(4-bromophenyl)methyl)cyclohexa -n-1-one 4.
15 Yield: 55%; (anti/syn) = 89: 11; ee value (anti): 82% determined by
HPLC (Daicel chiralpak AD column; 2-propanol/n-hexane =10: 90
= 22.6 min (major) and tR = 27.0 min (minor)). 1H NMR (CDCl3, 500
MHz): δ (ppm) 7.80–7.43 (m, 7H,), 5.31-5.29 (m, 1H), 3.50 (s, 1H), 2.96-
2.84 (m, 2H), 2.18 (s, 3H).
o
(V/V)); flow rate = 1.0 mL/min; 25 C; λ = 220 nm; tR = 13.2 min (anti,
Acknowledgements
minor) and tR = 16.1 min (anti, major)). 1H NMR(CDCl3, 500 MHz): δ
(ppm) 7.48-7.45 (m, 2H), 7.21-7.18 (m, 2H), 4.75 (d, J = 8.6 Hz, 1H),
20 3.99 (d, J = 2.7 Hz, 1H), 2.60-2.52 (m, 1H), 2.51-2.43 (m, 1H), 2.40-2.30
(m, 1H), 2.13-2.06 (m, 1H), 1.85-1.74 (m, 1H), 1.73-1.49 (m, 3H), 1.34-
1.25 (m, 1H).
75
The project was financially supported by the National Natural
Science Foundation of China (Grant No. 21003044, 20973057),
the Natural Science Foundation of Hunan Province (10JJ6028)
and the Program for Science and Technology Innovative
Research Team in Higher Educational Institutions of Hunan
80 Province. The authors are grateful to Dr. Qiang Gao (China
University of Geosciences) for his help with the characterization
with TEM.
(2R,10S)-2-(Hydroxy-(2-naphthyl)methyl)cyclohexan-1-one 5. Yield:
30%; (anti/syn) = 98: 2; ee value (anti): 45% determined by HPLC
25 (Daicel chiralpak AD column; 2-propanol/n-hexane = 2: 98 (V/V)); flow
rate = 1.0 mL/min; 25 oC; λ = 220 nm; tR = 26.2 min (anti, major) and tR =
1
29.6 min (anti, minor)). H NMR(CDCl3, 500 MHz): δ (ppm) 7.75–7.85
Notes and references
(m, 4H), 7.46–7.50 (m, 3H), 5.01(d, J = 8.7 Hz, 1H), 4.10 (s, 1H), 2.71–
2.78 (m, 1H), 2.37–2.55 (m, 2H), 2.09–2.14 (m, 1H), 1.52–1.80 (m, 5H),
30 1.28–1.42 (m, 2H).
[1] (a) R. Mahrwald, Chem. Rev., 1999, 99, 1095; (b) T. D. Machajewski
85
90
and C. H. Wong, Angew. Chem. Int. Ed., 2000, 39, 1352; (c) Z. Tang, Z.
Yang, X. Chen, L. Cun, A. Mi, Y. Jiang and L. Gong, J. Am. Chem.
Soc., 2005, 127, 9285; (d) E. G. Doyagüez and A. F. Mayoralas,
Tetrahedron, 2012, 68, 7345.
(2R,10S)-2-(Hydroxy-(4-nitrophenyl)methyl)cyclopentan -one-1-one 6.
Yield: 90%; (anti/syn) = 33: 67; ee value (anti): 86% determined by
HPLC (Daicel chiralpak AD column; 2-propanol/n-hexane = 10: 90
[2] (a) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000,
122, 2395; (b) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas III, J.
Am. Chem. Soc., 2001, 123, 5260; (c) Z. Tang, F. Jiang, L. Yu, X. Cui,
L. Gong, A. Mi, Y. Jiang and Y. Wu, J. Am. Chem. Soc., 2003, 125
5262; (d) B. Alcaide and P. Almendros, Angew. Chem. Int. Ed., 2003,
42, 858; (e) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F.
Tanaka and C.F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734; (f) S. S.
Khan, J. Shah and J. Liebscher, Tetrahedron, 2010, 66, 5082; (g) S.
Calogero, D. Lanari, M. Orrù, O. Piermatti, F. Pizzo and L. Vaccaro, J.
Catal., 2011, 282, 112; (h) G. Chen, X. Fu, C. Li, C. Wu and Q. Miao,
J. Organomet. Chem., 2012, 702, 19; (i) S. Z. Luo, X. L. Mi, L. Zhang,
S. Liu, H. Xu, and J. Cheng, Angew. Chem. Int. Ed. 2006, 45, 3093.
[3] (a) A. Berkessel, B. Koch and J. Lex, Adv. Synth. Catal., 2004, 346,
1141; (b) Z. Tang, F. Jiang, X. Cui, L. Gong, A. Mi, Y. Jiang and Y.
Wu, Proc. Natl. Acad. Sci. U.S.A., 2004, 101, 5755; (c) D. Gryko and R.
Lipiʼnski, Eur. J. Org. Chem., 2006, 17, 3864.
o
(V/V)); flow rate = 1.0 mL/min; 25 C; λ = 220 nm; tR = 12.9 min (anti ,
1
35 major) and tR = 16.7 min (anti , minor)). H NMR(CDCl3, 500 MHz): δ
(ppm) 8.21-8.19 (m, 2H), 7.54-7.51 (m, 2H), 5.42 (d, J=9.0 Hz, 1H), 4.86
(s,1H), 2.49-1.99(m, 3H), 2.08-1.95 (m, 1H), 1.76-1.25 (m, 3H).
(4R)-Hydroxy-4-(2-nitrophenyl)-butan-2-one 7. Yield: 93%; ee value:
79% determined by HPLC (Daicel chiralpak OB-H column; 2-
40 propanol/n-hexane =15: 85 (V/V)); flow rate = 1 mL/min; 25 oC; λ = 254
nm; tR=7.3 min (minor) and tR = 8.4 min (major)). 1H NMR (CDCl3, 500
MHz): δ (ppm) 7.95–7.42 (m, 4H), 5.68 (d, J =10.7Hz, 1H), 3.73 (s, 1H),
3.15–2.72 (m, 2H), 2.24 (s, 3H).
95
100
(4R)-Hydroxy-4-(4-nitrophenyl)-butan-2-one 8. Yield: 96%; ee value:
45 70% determined by HPLC (Daicel chiralpak OB-H column; 2-
propanol/n-hexane =15: 85 (V/V)); flow rate = 1 mL/min; 25 oC; λ = 254
105 [4] (a) G. Yang, Z. Yang, L. Zhou, R. Zhu and C. Liu, J. Mol. Catal. A:
Chem., 2010, 316, 112; (b) H. Yang, S. Li, X. Wang, F. Zhang, X.
Zhong, Z. Dong and J. Ma, J. Mol. Catal. A: Chem., 2012, 363, 404.
[5] (a) P. Kotrusz, I. Kmentovά, B. Gotov, Š. Toma and E. Solčάniovά,
Chem. Commun., 2002, 21, 2510; (b) T. Loh, L. Feng, H. Yang and J.
1
nm; tR = 14.7 min (major) and tR = 16.9 min (minor)). HNMR (CDCl3,
500 MHz): δ (ppm) 8.22–7.28 (m, 4H), 5.27 (s, 1H), 3.67 (s, 1H), 2.87 (d,
J =6.7Hz, 2H), 2.23 (s, 3H).
50
(4R)-(2-Chlorophenyl)-4-hydroxy-2-butanone 9. Yield: 75%; ee value:
77% determined by HPLC (Daicel chiralpak AD column; 2-propanol/n-
hexane =7.5: 92.5 (V/V)); flow rate = 0.8 mL/min; 25 oC; λ = 254 nm; tR
= 10.9 min (major) and tR = 12.3 min (minor)). 1H NMR (CDCl3, 500
MHz): δ (ppm) 7.61–7.19 (m, 4H), 5.52-5.49 (m, 1H), 3.63 (s, 1H), 3.00-
110
115
120
Yang, Tetrahedron Lett., 2002, 43, 8741; (c) M. Lombardo, F. Pasi, S.
Easwar and C. Trombini, Adv. Synth. Catal., 2007, 349, 2061; (d) J.
Shah, H. Blumenthal, Z. Yacob and J. Liebscher, Adv. Synth. Catal.,
2008, 350, 1267.
[6] (a) S. Aratake, T. Itoh, T. Okano, N. Nagae, T. Sumiya, M. Shoji and
Y. Hayashi, Chem. Eur. J., 2007, 13, 10246; (b) M. Amedjkouh,
Tetrahedron: Asymmetry, 2007, 18, 390; (c) D. E. Siyutkin, A. S.
Kucherenko and S. G. Zlotin, Tetrahedron, 2009, 65, 1366.
[7] (a) D. E. Siyutkin, A. S. Kucherenko, M. I. Struchkova and S. G.
Zlotin, Tetrahedron Lett., 2008, 49, 1212; (b) D. E. Siyutkin, A.S.
Kucherenko and S.G. Zlotin, Tetrahedron., 2010, 66, 513.
55 2.65 (m, 2H), 2.21(s, 3H).
(4R)-(4-Bromophenyl)-4-hydroxy-2-butanone 10. Yield: 55%; ee value:
77% determined by HPLC (Daicel chiralpak AD column; 2-propanol/n-
hexane =7.5: 92.5 (V/V)); flow rate = 0.8 mL/min; 25 oC; λ = 254 nm; tR
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9

View Article Online
DOI: 10.1039/C3GC40772A
Page 11 of 11
Green Chemistry
[8] (a) U. Laska, C. G. Frost, G. J. Price and P. K. Plucinski, J. Catal.,
2009, 268, 318; (b) D. Li, W. Y. Teoh, J. J. Gooding, C. Selomulya and
R. Amal, Adv. Funct. Mater., 2010, 20, 1767; (c) Y. Zhu, L. P. Stubbs,
F. Ho, R. Liu, C. P. Ship, J. A. Maguire and N. S. Hosmane,
ChemCatChem., 2010, 2, 365; (d) S. Shylesh, V. Schünemann and W.
R. Thiel, Angew. Chem. Int. Ed., 2010, 49, 3428; (e) Y. Zhu, L. Tian, Z.
Jiang, Y. Pei, S. Xie, M. Qiao and K. Fan, J. Catal., 2011, 281, 106; (f)
M. Z. Kassaee, H. Masrouri and F. Movahedi, Appl. Catal. A, 2011,
395, 28; (g) V. Polshettiwar, R. Luque, A. Fihri, H. Zhu, M. Bouhrara
and J. Basset, Chem. Rev., 2011, 111, 3036; (f) M. B. Gawande, V. D.
B. Bonifácio, R. S. Varma, I. D. Nogueira, N. Bundaleski, C. A. A.
Ghumman, O. M. N. D. Teodoro and P. S. Branco, Green Chem., 2013,
DOI:10.1039/C3GC40375K; (g) S. Z. Luo, X. X. Zeng and J Cheng,
Chem. Commun., 2008, 5719.
5
10
15 [9] (a) S. Luo, X. Zheng, H. Xu, X. Mi, L. Zhang and J. Cheng, Adv.
Synth. Catal., 2007, 349, 2431; (b) S. Luo, X. Zheng and J. Cheng,
Chem. Commun., 2008, 44, 5719; (c) O. Gleeson, R. Tekoriute, Y. K.
Guńko, and S. J. Connon, Chem. Eur. J., 2009, 15, 5669; (d) V.
Polshettiwar, B. Baruwati and R. S. Varma, Chem. Commun., 2009, 14,
20
1837; (e) S. Shylesh, V. Schunemann and W. R. Thiel, Angew. Chem.
Int. Ed., 2010, 49, 3428; (f) B. G. Wang, B. C. Ma, Q. Wang and W.
Wang, Adv. Synth. Catal., 2010, 352, 2923.
[10] (a) Y. Gu and G. Li, Adv. Synth. Catal., 2009, 351, 817; (b) P.
Virtanen, H. Karhu, G. Toth, K. Kordas and J. P. Mikkola, J. Catal.,
2009, 263, 209; (c) M. I. Burguete, E. García-Verdugo, I. Garcia-Villar,
F. Gelat, P. Licence, S.V. Luis and V. Sans, J. Catal., 2010, 269, 150.
[11] (a) S. Bahmanyar, K. N. Houk, H. J. Martin and B. List, J. Am. Chem.
Soc., 2003, 125, 2475; (b) S. Aratake, T. Itoh, T. Okano, T. Usui, M.
Shoji and Y. Hayashi, Chem. Commun., 2007, 24, 2524.
25
30 [12] X. Liu, Z. Ma, J. Xing and H. Liu, J. Magn. Magn. Mater., 2004, 270,
1.
[13] Y. H. Deng, D. W. Qi, C. H. Deng, X. M. Zhang and D. Y. Zhao, J.
Am. Chem. Soc., 2008, 130, 28.
[14] D. Gryko and R. Lipiʼnski, Adv. Synth. Catal., 2005, 347, 1948.
35 [15] D. Yuan, Q. Zhang and J. Dou, Catal. Commun., 2010, 11, 606.
[16] Q. Zeng, I. Baker and J. Hoopes, Mater. Res. Soc. Symp. Proc., 2007,
962, 10.
[17] N. T. S. Phan and C. W. Jones, J. Mol. Catal. A: Chem., 2006, 253,
123.
40 [18] Y. Zhang, Y. Zhao and C. Xia, J. Mol. Catal. A: Chem., 2009, 306,
107.
[19] K. Su, T. Pan and Y. Zhang, The Analytic Method of Spectrum,
1st ed., (Eds.: G. Rong) East China Univ. of Science & Technology
Press, 2002, p. 106.
45 [20] R. Luo, R. Tan, Z. Peng, W. Zheng, Y. Kong and D. Yin, J. Catal.,
2012, 287, 170.
[21] G. Wang, N. Yu, L. Peng, R. Tan, H. Zhao, D. Yin, H. Qiu, Z. Fu
and D. Yin, Catal. Lett., 2008, 123, 252.
[22] (a) Y. Gu, C. Ogawa, J. Kobayashi, Y. Mori, Shu Kobayashi, Angew.
50 Chem. Int. Ed., 2006, 45, 7217; (b) Y. Chi, S. T. Scroggins, E. Boz and J.
M. J. Fréchet, J. Am. Chem. Soc., 2008, 130, 17287; (c) J. Tan, H. Li
and Y. Gu, Green Che.,, 2010, 12, 1772.
[23] (a) N. Zotova, A. Franzke, A. Armstrong and D. G. Blackmond, J.
Am. Chem. Soc., 2007, 129, 15100; (b) G. Angelici, R. J. Corrêa, S. J.
55
Garden and C. Tomasini, Tetrahedron Lett., 2009, 50, 814.
[24] A. R. Siamaki, A. E. R. S. Khder, V. Abdelsayed, M. S. El-Shall and
B. F. Gupton, J. Catal., 2011, 279, 1.
[25] G. Liu, H. Zhao, Y. Lan, B. Wu, X. Huang, J. Chen, J. Tao and X.
Wang, Tetrahedron, 2012, 68, 3843.
10 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]