Efficient, stable, and reusable Lewis acid-surfactant-combined catalyst: One-pot Biginelli and solvent-free esterification reactions

Article abstract of DOI:10.1016/j.molcata.2014.04.031

Cerium(III) trislaurylsulfonate (Ce(LS)₃), a Lewis acid and surfactant combined catalyst, was prepared and characterized by SEM, SEM-EDX, XRD, NMR, FT-IR, TG, and elemental analysis. Ce(LS)₃ was found to be stable and efficient to catalyze one-pot Biginelli and solvent-free esterification reactions. Furthermore, Ce(LS)₃ is easy to recycle after reaction by pouring into cold water and filtration. Present work will shed deep insight into the understanding of the catalytic nature of LASCs, and extend its application in important organic transformations.

Full text of DOI:10.1016/j.molcata.2014.04.031

Accepted Manuscript
Title: Efficient, Stable, and Reusable Lewis
Acid–Surfactant–Combined Catalyst: One–pot Biginelli and
Solvent–free Esterification Reactions
Author: Yunfeng Qiu Hongnan Sun Zhuo Ma Wujiong Xia
PII:
S1381-1169(14)00169-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2014.04.031
MOLCAA 9093
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
24-2-2014
21-4-2014
22-4-2014
Please cite this article as: Y. Qiu, H. Sun, Z. Ma, W. Xia, Efficient, Stable, and
Reusable Lewis AcidndashSurfactantndashCombined Catalyst: Onendashpot Biginelli
and Solventndashfree Esterification Reactions, Journal of Molecular Catalysis A:
Chemical (2014), http://dx.doi.org/10.1016/j.molcata.2014.04.031
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Graphical Abstract
Efficient, Stable, and Reusable Lewis Acid–Surfactant–Combined
Catalyst: One–pot Biginelli and Solvent–free Esterification Reactions
Yunfeng Qiu,a Hongnan Sun,a Zhuo Ma,b Wujiong Xiaa *
a State Key Lab of Urban Water Resource and Environment (SKLUWRE) & Academy
of Fundamental and Interdisciplinary Science, Harbin Institute of Technology, Harbin,
Heilongjiang, 150080, China
b
School of Life Science and Technology, Harbin Institute of Technology, Harbin,
Heilongjiang, 150080, China
*
Corresponding author. Tel.: +86 451 86403760; fax: +86 451 86403760; e–mail:
xiawj@hit.edu.cn (Wujiong Xia).
Abstract:
Cerium(III) trislaurylsulfonate (Ce(LS)3), a Lewis acid and surfactant combined
catalyst, was prepared and characterized by SEM, SEM–EDX, XRD, NMR, FT–IR,
TG, and Elemental analysis. Ce(LS)3 was found to be stable and efficient to catalyze
one–pot Biginelli and solvent–free esterification reactions. Furthermore, Ce(LS)3 is
easy to recycle after reaction by pouring into cold water and filtration. Present work
will shed deep insight into the understanding of the catalytic nature of LASCs, and
extend its application in important organic transformations.
Page 1 of 23

High lights
Preparation of Cerium(III) trislaurylsulfonate (Ce(LS)3) and characterization by
SEM, SEM–EDX, XRD, NMR, FT–IR, TG, and Elemental analysis.
Extend the application of Ce(LS)3 in one–pot Biginelli reaction and esterification
under neat condition.
Ce(LS)3 is an efficient, air stable and reusable micro–reactor.
Page 2 of 23

Efficient, Stable, and Reusable Lewis Acid–Surfactant–Combined
Catalyst: One–pot Biginelli and Solvent–free Esterification Reactions
Yunfeng Qiu,a Hongnan Sun,a Zhuo Ma,b Wujiong Xiaa *
a State Key Lab of Urban Water Resource and Environment (SKLUWRE) & Academy
of Fundamental and Interdisciplinary Science, Harbin Institute of Technology, Harbin,
Heilongjiang, 150080, China
b
School of Life Science and Technology, Harbin Institute of Technology, Harbin,
Heilongjiang, 150080, China
*
Corresponding author. Tel.: +86 451 86403760; fax: +86 451 86403760; e–mail:
xiawj@hit.edu.cn (Wujiong Xia).
_____________________________________________________________________
Abstract: Cerium(III) trislaurylsulfonate (Ce(LS)3), a Lewis acid and surfactant
combined catalyst, was prepared and characterized by SEM, SEM–EDX, XRD, NMR,
FT–IR, TG, and Elemental analysis. Ce(LS)3 was found to be stable and efficient to
catalyze one–pot Biginelli and solvent–free esterification reactions. Furthermore,
Ce(LS)3 is easy to recycle after reaction by pouring into cold water and filtration.
Present work will shed deep insight into the understanding of the catalytic nature of
LASCs, and extend its application in important organic transformations.
_____________________________________________________________________
Keywords: Lewis acid–surfactant combined catalyst, Biginelli, Esterification, Miro
reactor, Solvent–free
1. Introduction:
Homogeneous catalytic systems usually exhibit high activity in organic reactions,
however, suffer from the difficulty of recovery whereas heterogeneous catalysts are
easily separated from the reaction mixture and show high catalytic activity by rational
design of novel structures or components[1]. Nevertheless, heterogeneous catalytic
Page 3 of 23

systems still have to face the low efficiency of mass transfer in multiphase reaction.[2]
To address the drawbacks of both homogeneous and heterogeneous catalysts, it is
appealing to design a novel catalytic system, e.g. colloidal dispersion or reverse
micelles formed by Lewis acid–surfactant combined catalysts (LASCs).[3–6]
With the unique characteristics in multifunctional catalytic property, LASCs
firstly developed by Kobayashi,[5, 7] as one of the most widespreadly investigated
catalytic system, has attracted increasing attentions during the past decades. Not only
act LASCs as a Lewis acid to activate substrate molecules, but also serve as a
surfactant to form stable colloidal dispersion systems with organic substrates. It is
worth noting that the self–assembled process of LASCs will concentrate acid catalysts
at the interface of the micelles to enhance the catalytic efficiency. To realize the best
functions, exploration of LASCs designed to have specific catalytic sites, fascinating
stability and practical reusability has fueled research on tailoring the combination of
lewis acids and surfactants with expectations of achieving novel or enhanced catalytic
properties. So far, most studies on LASCs focused on their application in aldol,[7]
Diels–Alder,[8, 9] allylation of aldehydes,[10, 11] propargylamines reactions,[12, 13]
and also in asymmetric hydroxylation,[14] hydroxymethylation,[15] ring–opening
reactions and so on.[16] However, some of the reported LASCs are trivial to separate
from the reaction system after reaction, and some have severe hygroscopicity, which
would make it inconvenient for practical application.[17, 18] Therefore, room still
exists for developing novel LASCs and extending its application in a wider range of
reactions. Additionally, few papers are addressed on the characterization of catalysts
Page 4 of 23

in detail. Therefore, the systematic study on the characterization of LASCs would
provide deep insight into the understanding of catalytic nature, and it is also of great
significance to develop a new strategy to build functional LASCs with satisfied
efficiency, stability and reusability to enhance the catalytic performance in important
organic transformations.
Recently, Biginelli reaction has attracted considerable attentions owing to its
usefulness for the synthesis of dihydropyrimidines (DHPMs) and their derivatives.[19]
DHPMs are important class of compounds exhibiting pharmacological activities such
as calcium channel blockers, anti–inflammatory, antitumor, α–1a–adrenergic receptor
antagonist, and antihypertensive agents.[20–22] Traditional approach for
HCl–catalyzed three–component cyclocondensation reaction of aldehyde, β–ketoester
and urea in reflux ethanol was firstly described by Biginelli in 1893, however, there
existed some drawbacks including lower yields (20% to 60%), particularly for
substituted aromatic and aliphatic aldehydes and long reaction time from 24 to
36h.[23] Subsequently, more complex multistep approaches could lead to higher
overall yields but lack the simplicity of one–pot cyclocondensation protocols.[24–26]
Previous work found that Lewis acids could catalyze one–pot Biginelli reactions,
however, some of the reagents are expensive, harmful, and difficult to recover due to
homogeneous phase, and some nanocomposites needed sophisticated preparation
procedure.[27–30]
It has been widely recognized that organic esters prepared from carboxylic acids
and alcohols are important fine chemicals due to their practical application in the
Page 5 of 23

production of fragrances, polymers, plasticizers, biofuels, and emulsifiers.[31–33]
The pioneering work of polyesterification catalyzed by dodecylbenzene sulfonic acid
(DBSA) was reported by Saam et al..[34, 35] Subsequently, Landfester et al. and
Takasu et al. reported that DBSA and scandium trisdodecylsulfate [Sc(DS)3] could
catalyze polyesterification, respectively.[36, 37] And another representative work on
esterification is systematically studied by Kobayashi et al..[38] Additionally, DBSA,
copper dodecylbenzene sulfonate (CDBS) and cerium(III) trisdodecylsulfate
trihydrate [Ce[DS]3∙3H2O] could also effectively catalyze the solvent–free
esterification reaction.[17, 18] It is worth mentioning that DBSA or CDBS is trivial to
separate from the reaction system after reaction, and Ce[DS]3∙3H2O has severe
hygroscopicity, which make it inconvenient for practical application.
Herein, we present the work on synthesis and characterization of Ce(III)
trislaurylsulfonate, an air stable LASCs, and its application in catalyzing one–pot
Biginelli reaction and solvent–free esterification reaction.
2. Experimental
2.1 Chemicals
All reagents and solvents were commercially available and were used as such.
2.2 General remarks
Morphologies and components of catalysts were performed on a field–emission
scanning electron microscope (FE–SEM) (Model S–4300, Hitachi, Japan). Small
angle X–ray diffraction (SAXRD) patterns were analyzed by Glancing–angle X–ray
diffraction (GA–XRD; Philips X’Pert, Holland) using a CuKα radiation. Fourier
Page 6 of 23

transform infrared spectroscopy (FTIR) was recorded on a Perkin–Elmer 1710 Fourier
transform spectrometer. Metal content in catalysts were measured by inductively
1
coupled plasma–optical (ICP) emission spectroscopy (Optima 5300DV). H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were obtained on Bruker AV–400
instrument, using CDCl3 as solvent and TMS as reference. High resolution mass
spectra were recorded in an Accurate Mass Q–TOF, LC/MS, Agilent technologies
6520. Analyses of esters was measured by gas chromatography (GC) on a Tianmei
GC–5790 chromatograph with FID detector, equipped with a polar polyethylene
glycol column BP 20, 12 m, 0.32 i.d. and film thickness of 0.25 μm. Oven
temperature ranged from 200 to 250 oC, using a heating rate of 2 oC min–1.
2.3 Catalysts preparation
Cerium(III) trislaurylsulfonate monohydrate (Ce[SO3C12H25]3 or denoted as
Ce[LS]3) was synthesized according to a published procedure as follows.[39] (i) 2.94
g of sodium laurylsulfonate (SLS, Aladdin, 98%) were added to 50 mL of distilled
o
water and dissolved at 60 C in a water bath; (ii) 5.59 g of cerium(III) chloride
heptahydrate (CeCl3·7H2O, Aladdin, 99%) were completely dissolved in 50 mL of
distilled water at room temperature and warmed up at 60 oC in a water bath; (iii) After
dissolution, the CeCl3 solution was added under stirring, and the resulted slurry was
stirred for 30 min. The white precipitate was filtered, recrystallized with hot distilled
water for 3 times, and dried in vacuum at room temperature (25 oC) overnight.
Other catalysts were prepared following the similar procedure, and denoted as
La[LS]3, Fe[LS]3, Co[LS]3, Ni[LS]2, Cu[LS]2, Zn[LS]2, and Mn[LS]2. Ce[DS]3 was
Page 7 of 23

also synthesized by the similar procedure except using sodium dodecylsulfate (SDS)
instead of sodium laurylsulfonate (SLS) as starting material.
2.4 General procedure for the synthesis of 3,4–dihydropyrimidinones/thiones
To a mixture of aldehyde 1 (1 mmol), ethyl acetoacetate 2 (1.5 mmol) and urea or
thiourea 3 (1.5 mmol) in a round–bottomed flask (10 mL), M[LS]x (10 mol%) and one
drop concentrated HCl in ethanol (3 mL) was added. The reaction mixture was stirred
at 80 oC for 6 h in an oil–bath (Table 1). At the end of reaction (monitored by TLC),
the mixture was poured into crushed ice/water mixture. Stirring was maintained for 5
min, and the solid mixture was filtered, washed with cold water (2 × 15mL).
Subsequently, the solid cake was dissolved in acetone, and the undissolved catalyst
could be easily filtered. The acetone phase was collected and dried by rotavap, then
the crude powder was recrystallized from ethyl acetate/n–hexane or ethanol to afford
pure product. All products were identified by comparing their spectral and physical
data with those of authentic samples. Used acetone could be recycled for next
experiment, which was found to have no influence on reaction yield.
2.5 General procedure for the synthesis of esters
Carboxylic acid (1 mmol), alcohol (6 mmol) and 5 mol% catalyst were added to a
10 ml round–bottom flask with a reflux condenser. The reaction mixture was
o
continuously stirred using a magnetic stirrer (800 rpm) at 80 C in an oil–bath for an
appropriate time, and the progress of reaction was monitored by TLC. At the end of
reaction, the mixture was cooled to room temperature and poured into water.
Afterwards, the filtered cake was purified by chromatography on silica gel using
Page 8 of 23

petroleum ether/ethyl acetate (20:1) as eluent to give the pure product.
Fig. 1. (a) FT–IR spectra of SLS precursor (black curve), as–prepared Ce[LS]3
catalyst (red curve), and after four runs (blue curve); (b) FT–IR spectra of as–prepared
Ce[DS]3 (black curve), and kept in air for 24h (red curve). There are no position and
intensity changes of Ce[LS]3 characteristic peaks after four runs. However, the weight
of Ce[DS]3 increased ca. 7.4 wt% (hygroscopicity) and obvious H2O characteristic
peaks (marked by *) could be observed in (b) after kept in air for 24h (humidity: ca.
58%).
Table 1. FT–IR assignments for SLS, as–prepared Ce[LS]3, and recycled Ce[LS]3
after four runs.
Wavenumber (cm–1)
Item
Assignments
SLS
2957, 2873
2921, 2851
1468
Ce[LS]3
2956, 2873
2918, 2850
1468
Ce[LS]3 recycled
2956, 2872
2917, 2849
1468
ν(CH3)
ν(CH2)
δ(CH2)
α–CH2
δ(CH3)
–CH2–
alkyl
chain
1415
1413
1413
1377
722
1378
722
1377
722
–
533, 553, 619 522, 544, 605, 621 522, 545, 604, 621
SO3
–
SO3
1065, 1180,
1204
1069, 1081, 1166, 1069, 1081, 1167,
1186 1186
–
SO3
3. Results and discussion:
Page 9 of 23

3.1 FT–IR analysis
FT–IR characterization has proven to be a powerful technique for the study of
components and structure of catalyst including organic segments. Fig. 1 shows the
FT–IR spectra of SLS, as–prepared Ce[LS]3, and after four runs. As summarized in
table 1, peaks at 2957, 2873, and 1378 cm–1 observed from Fig. 1 (black curve) of
SLS, were ascribed to stretching and formation vibration of –CH3, respectively.[18,
40] Meanwhile, stretching vibration of –CH2 was found at 2921, 2851 cm–1. The peak
centered at 1415 and 722 cm–1 were associated with wagging vibration of α–CH2 and
rocking vibration of –CH2–, respectively. These bands were assigned to the
characteristic peaks of alkyl chain in SLS. Comparatively, Ce[LS]3 catalyst shows
similar characteristic peaks of alkyl chain, as illustrated in Fig. 1 (red curve) and table
1. The spectrum of SLS shows bands at 533, 553, and 619 cm–1 corresponding to the
–
bending vibration of SO3 , and peaks at 1065, 1180, and 1204 cm–1 ascribing to the
–
–
stretching vibration of SO3 .[41] However, the bending vibration of SO3 in Ce[LS]3
–
located at 522, 544, 605, and 621 cm–1, and the stretching vibration of SO3 were
–
positioned at 1069, 1081, 1166, and 1186 cm–1.[42] The position and intensity of SO3
was found to be very sensitive to the changes of chemical environments caused by
metal ions coordination.[41] Comparing FT–IR spectra of SLS and Ce[LS]3, we
–
found that the bending and stretching vibration of SO3 degenerated obviously, and
positions changed greatly. We assumed that the intense shifting and splitting of both
symmetric and asymmetric modes could be ascribable to the interaction of
laurylsulfonate anions with Ce(III) cations.
Page 10 of 23

3.2 XRD analysis
In order to further study the structure of Ce[LS]3, small angle XRD was
performed for both Ce[LS]3 and SLS. As shown in Fig. 2, strong reflections of
Ce[LS]3 were observed at lower diffraction angles at 2θ = 2.36°, 2.65°, 4.66°, 5.26°,
6.99° and 7.9°, corresponding to 3.74, 3.33, 1.89, 1.68, 1.26 and 1.12 nm calculated
by Bragg’s law, respectively. Concomitantly, the characteristic peaks of SLS are
located at respective 2θ = 2.39°, 2.59°, 3.16°, 4.79°, and 7.15°, ascribing to 3.69, 3.41,
2.79, 1.84 and 1.24 nm. XRD patterns of Ce[LS]3 and SLS are regarded as
characteristics of lamellar arrangements. According to Bragg equation, the interplanar
spacing (dhkl) illustrated a periodicity of 3.74 nm for Ce[LS]3 and 3.69 nm for SLS. It
has been generally known that four crystalline phases of SDS all have similar bilayer
structures, in which the dodecylsulfate molecules are stacked in a head to head, tail to
tail mode, alternating alkyl chains and sulfate head–group.[43] SLS and SDS have
almost identical chemical structures. Dias et al. reported that the interplanar spacing
are 3.76 nm in the crystal morphology of Ce[DS]3, which is dominated by the (0 0 1)
face.[18] In present case, the interplanar spacing is 3.74 nm and 3.69 nm for Ce[LS]3
and SLS, which agree with the reported value as abovementioned. Therefore, we
assumed that (0 0 1) face is the dominant face in both Ce[LS]3 and SLS. As also
confirmed in Fig. 1, the relative intensity and position of infrared regions attributing
to the alkyl chain vibration modes (see Table 1) for Ce[LS]3 and SLS are nearly
identical. The results illustrated that the structure of Ce[LS]3 might be bilayered
arrangement, and packed in a head to head, tail to tail mode. However, the interlayer
Page 11 of 23

distance of d001 is 3.76 nm, a little bigger than that of SLS, which probably ascribed to
the bigger radius of CeIII or less tilting angle of alkyl chains from (0 0 1) plane.[44]
Fig. 2. XRD patterns of (a) SLS precursor, and (b) as–prepared Ce[LS]3.
Table 2. Elemental analysis for Ce[LS]3 determined by CHOS and TGA
measurements.
Ce[C12H25O3S]3·H2O
Element
Expected (%)
47.71
Found (%)
47.43
8.44
17.08
10.82
16.27
Carbon
Hydrogen
Oxygen
Sulfur
8.56
17.65
10.61
15.46
Cerium a
a Determined by TG analysis.
3.3 Morphology and composition study
SEM image of Ce[LS]3 in Fig. 3 shows that agglomerates range from 2 µm to 15
µm in length along longer axis, which are consisted of irregular sheet–like structures.
The Energy–dispersive X–ray spectroscopy (EDX) mapping images of Ce, S, C, and
O taken on the same sample show that Ce, S, C, and O are evenly distributed in
material (data not shown). The observed Ce and S atomic ratio of 0.54:1.52 is close to
1:3, further confirming the chemical composition of Ce[LS]3. In addition, table 2
shows the element analysis of as–prepared catalyst. The content of carbon, hydrogen,
Page 12 of 23

oxygen, sulfur, and cerium was consistent with the expected theoretical values for
Ce[C12H25O3S]3·H2O, which was further verified by TGA measurement.
Fig. 3. (a) SEM image of Ce[LS]3 and (b) typical SEM–EDX results of randomly
selected area in image a. EDX results has been reproduced for three times.
Fig. 4. TG curves of SLS and Ce[LS]3 in air atmosphere (25 to 600 °C).
3.4 TGA ananlysis
As demonstrated in Fig. 4, the total weight loss of SLS from 125 to 463 °C was
73.1%, which is related to the elimination of alkyl chains and SO3 (weight loss
expected: 73.9%).[45] The remained product is stable up to 600 °C, and the weight of
residues left after calcinations (26.9%) attributed to expected value for the formation
of Na2SO4 (26.1%). Comparatively, the decomposition of Ce[LS]3 in air atmosphere
Page 13 of 23

takes place from 128 to 500 °C, which is associated with the loss of water molecules,
alkyl chains and SO3.[46] The completely decomposed residue was CeO2
corresponding to an observed loss of 81.2% (weight loss expected: 81.0%).
3.5 NMR study
Fig. S1 depicts the 1H NMR (400 MHz) of as–prepared Ce[LS]3. It was observed
that the chemical shifts emerged at d = 0.87 ppm (triplet, 9H, and J = 6.8 Hz);
1.25–1.29 ppm (m, 54H); 1.52–1.60 ppm (m, 6H); and 2.41 ppm (triplet, 6H, and J =
8.0 Hz) in DMSO–d6. In DMSO, water signal appears at d = 3.40 ppm, and is related
to H2O molecules from catalyst and solvent. 13C NMR (100 MHz) spectrum of
Ce[LS]3 in DMSO–d6 exhibits characteristic peaks of laurylsulfonate compound at δ =
13.88, 22.02, 25.00, 28.36, 28.64, 28.84, 28.87, 28.94, 28.96, 28.99, 31.22, and 51.45
ppm.
4. Catalytic reactions studies
4.1 Biginelli reaction
Preliminarily, we employed as–prepared Ce[LS]3 as a catalyst in one–pot reaction
of benzaldhyde (1 mmol), ethyl acetoacetate (1.5 mmol) and urea (1.5 mmol). To our
delight, 3,4–dihydropyrimidinone was obtained in 83% yield in the presence of
Ce(LS)3 (2 mol%) and the value of TOF is 5.1875 h–1 (Table 3, entry 1). Further
studies revealed that the yields were improved to as high as 98% at quantitative
conversion when the amount of catalyst increased from 5 to 20 mol% (Table 3, entries
2–4). In comparison, we also prepared a series of catalysts and subjected them to the
experiments. As it can be seen, moderate to good yields, but a little lower than that of
Page 14 of 23

Ce[LS]3, were observed owing to their relatively strong Lewis acid activity (Table 3,
entries 5–12). The application of C12H25SO3Na and SDBS led to 82% and 84% yield,
respectively (Table 3, entries13–14). However, these homogeneous systems suffer
from the difficulty in recovery, which is against the basic principle of green
chemistry.[47–49]
Table 3. Biginelli reactions of benzaldehyde, ethyl acetoacetate and urea catalyzed by
LASCsa
CHO
O
O
Catalysts
+
H2N NH2
O
NH
Ethanol
80 oC, 8h
O
O
N
O
O
H
Entry
1
2
3
4
5
6
7
8
LASCs
Ce(LS)3
Ce(LS)3
Ce(LS)3
Ce(LS)3
Ce(DS)3
La(LS)3
Fe(LS)3
Co(LS)3
Ni(LS)2
Cu(LS)2
Zn(LS)2
Using amount
2 mol%
TOF (h–1)
5.1875
2.1
Yields (%)b
83
84
93
98
78
82
67
83
73
78
87
84
82
84
5 mol%
10 mol%
20 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol %
1.1625
0.6125
0.975
1.025
0.8375
1.0375
0.9125
0.975
1.0875
1.05
9
10
11
12
13
Mn(LS)2
C12H25SO3Na
SDBS
1.025
1.05
14
a
The reactions were carried out in the presence of benzaldehyde (1.0 mmol),
ethyl acetoacetate (1.5 mmol), urea (1.5 mmol), LASCs, and one drop of concentrated
HCl in 3ml ethanol at 80 °C for 6h. b Isolated yields.
Different solvents, such as THF, CH3CN, acetone, DMF, etc. were also screened
in the reaction affording the product in 9% to 75% yields, as shown in Table S1. [50]
It is noteworthy that the Biginelli reaction catalyzed by Ce[LS]3 (10 mol%) in water
was also tested, and only gave moderate yield of 45%, and simultaneously had 4.5%
of Hantzsch byproduct, which has been reported in previous literature.[51–53]
Page 15 of 23

However, the reaction performed in neat reaction can afforded 83% yield.
Table 4. Ce[LS]3 catalyzed the synthesis of DHPMs.
O
X
O
R
R
H
+
O
Ce(C12H25SO3)3
NH2
H2N
O
NH
O
Ethanol
80 oC, 8h
N
H
X
O
Entry
1
2
3
4
5
6
7
8
R
C6H5
X
O
O
O
O
O
O
O
O
O
O
S
S
S
S
O
O
O
O
O
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
R2
Yields (%)a,b
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
93, 89d, 92e
4–(CH3)–C6H4
4–(F)–C6H4
4–(NO2)–C6H4
4–(OH)–C6H4
2–(Cl)–C6H4
i–Bu
94
92
50 (73)c
90
83
38 (40) c
69 (76) c
56 (64) c
34 (34) c
79
Furyl–
4–(OH)–3–(OCH3)–C6H3
1–Naphth–
9
10
11
12
13
14
15
16
17
18
19
4–(F)–C6H4
4–(OH)–C6H4
C6H5
4–(CH3)–C6H4
C6H5
4–(OH)–C6H4
4–(F)–C6H4
4–(CH3)–C6H4
C6H5
85
89
97
90
81
93
95
86
OMe
OMe
OMe
OMe
OCH2Ph
a Isolated yield. b All product are characterized by 1H NMR, 13C NMR, and MS (m/z)
and they are in good agreement with authentic samples. c Ce[LS]3 (20 mol%). d after 4
runs. e after kept in air for one year.
With this optimized reaction conditions in hand we tended to investigate the
generality and limitation of this method. Therefore, the reaction of various
aromatic/heterocyclic aldehydes, 1, 3–dicarbonyl compounds and urea or thiourea
were explored under this protocol to produce a series of structurally diverse DHPMs,
and the results are summarized in Table 4. The reactions proceeded very smoothly in
reflux ethanol with 10 mol% Ce[LS]3 and were completed within 6h. The main
Page 16 of 23

characteristics of reactions are good to excellent activity in most cases, giving
73–97% isolated yields. Present catalytic system was tolerant to the variation in all
three components, and showed slight loss of activity after 4 runs. Aromatic aldehydes
carrying either electron–donating groups (EDG) or electron–withdrawing groups
(EWG) in the ortho, meta, and para positions are well tolerated in reaction without
significant impact on yields. More importantly, aldehydes bearing two different
substituents (entry 9) with steric hindrance also afforded the corresponding product in
76% yield, which, however, was obtained in poor yield in classical Biginelli reaction
conditions.[23] We also found that ethyl acetoacetate, ethyl benzolyacetate, and
methyl acetoacetate all could be used to synthesize the derivatives (entries 1–10,
15–19). Recently, synthesis of DHPMs containing sulfur atom attracted much
attention due to their biological activity, such as monastrol, which is a new class of
anticancer agents acting as cell division (mitosis) blockers.[54] Therefore, thiourea
was applied in the reaction instead of urea which successfully led to the
corresponding DHPMs in good to excellent yields (entries 11–14).
To test the stability and recyclability of the catalyst, it was filtered and washed
with acetone and distilled water after reaction, and then dried in vacuum at r.t.
1
overnight. H NMR (data not shown) and FT–IR results (Fig. 1a and table 1) proved
the chemical shifts and main characteristic peaks of Ce[LS]3 maintained after four
runs. It should also be pointed out that recovered catalysts exhibited 4% loss of
activity after four runs (Table 4, entry 1). Importantly, the catalyst didn’t lose its
activity obviously and gave 92% yield after storage in air for one year (Table 4, entry
Page 17 of 23

1).
Most researchers have investigated the mechanism of the Biginelli reaction, and
regarded the key intermediate as N–acylininium ion formed in situ by the reaction of
aldehyde with urea. In present work, we assumed that this process took place in
reverse micelles constructed by Ce[LS]3 in ethanol.
Table 5. Ce[LS]3 catalyzed the synthesis of esters.
Ce[LS]3•H2O
(R)ArCO2H + HOR'
(R)ArCO2R'
neat, 80 °C, 6h
Ar = Aromatic/Heteroaromatic;
R = Alkyl/Aryalkyl/Cycloalkyl;
R' = Alkyl/Alkenyl/Alkynyl/Arylalkyl/Cycloalkyl
Entry
1
2
3
4
5
6
7
8
acid
alcohol
methanol
ethanol
Yields (%)a,b
myristic acid
myristic acid
myristic acid
myristic acid
myristic acid
myristic acid
myristic acid
myristic acid
palmitic acid
stearic acid
90
93
46
isopropanol
n–butanol
cyclohexanol
Benzyl alcohol
phenol
β–naphthol
methanol
methanol
93 (91c)
51
88
68
63
87
90
86
62
9
10
11
12
crotonic acid
cinnamic acid
n–butanol
n–butanol
a Isolated yield. b All product ere characterized by 1H NMR, 13C NMR and MS (m/z)
and they are in good agreement with the authentic samples. c after five runs.
4.2 Solvent–free esterification
Generally, esterification reaction is accelerated by using water separation or
adding molecular sieves. Researchers found that dodecylbenzene sulfonic acid
(DBSA) or dodecylbenzene sulfonate (CDBS) could form reverse micelles to catalyze
esterification reaction.[17, 55] These micelles have a hydrophilic interior, thus esters
generated during reaction are effectively removed from the droplets due to intrinsic
Page 18 of 23

hydrophobicity. Nevertheless, water molecules are staying in the interior of
micelles.[38] Furthermore, self–assembled process will concentrate acid catalysts at
the interface of droplets. Based on these two aspects, the reaction equilibrium would
shift towards the desired side of esters. It should be noted that DBSA or CDBS suffer
from their recovery after reaction. We therefore further investigate the catalytic
performance of Ce[LS]3 in esterification reaction to extend its wider application.
As depicted in Table 5, in the presence of 10 mol% of Ce[LS]3, myristic acid,
palmitic acid or stearic acid reacted with methanol smoothly, giving the corresponding
esters in good yields (entries 1, 9, 10), which is an important reaction in biodiesel
production. In addition, we also found that Ce[LS]3 was tolerant to other alcohols
with different alkyl chains length (entries 2–4), cyclic alcohol (entry 5), and aromatic
alcohols (entries 6–8). α, β–unsaturated carboxylic acids also reacted smoothly with
n–butanol giving moderate to good yields. The resulted α, β–unsaturated esters were
proved to possess various pharmacological activities including antioxidant,
antimicrobial and anticancer activities, besides extensive use in other synthetic
applications.[56–59] Furthermore, Ce[LS]3 shows high stability in solvent–free
esterification, and gives 91% yield when applying in esterification of mrystic acid and
n–butanol after five runs.
Fig. 5 shows that the plots of the concentration of myristic acid versus time in the
presence of 10 mol% Ce[LS]3. It was obvious that the concentration of myristic acid
decreased due to the esterification with n–butanol. The plots of ln(C0/Ct) versus time
yielded good linear correlations as indicated in Fig. 5a, revealing that the
Page 19 of 23

esterification followed pseudo–first–order kinetics. The values of pseudo–first–order
constants and turnover frequency (TOF) were 0.42 h–1 and 1.58 h–1. And this TOF is
two times bigger than that reported previously.[17]
Fig. 5. a) The circles and squares were the ln(Ct/C0) and Ct/C0 versus reaction time for
the esterification of myristic acid and n–butanol over Ce[LS]3 nanocomposite,
respectively. C0 and Ct were respective concentrations of myristic acid initially and at
time t. b) Ct’/C0’ versus reaction time for hydrolysis of butyl tetradecanoate. C0’ and
Ct’ were the concentration of butyl tetradecanoate initially and at time t.
We hypothesized that the carbonyl oxygen of the carboxylic group combines
with CeIII of Ce[LS]3 to form an activated complex.[17] Subsequently, an intermediate
was formed by the attack of nucleophilic alcohol. Finally, the intermediate eliminates
water to afford the product ester. During this process, the reverse micelles with
hydrophilic interior assembled by Ce[LS]3 serve as micro–reactors, which
automatically separate water from ester like mini–separators. Separation of water
from ester not only avoids hydrolysis of ester (see Fig. 5b), but also rapidly promotes
the equilibrium reaction towards ester. Thus, azeotropic distillation equipment or
molecular sieves is not required.
Page 20 of 23

5. Conclusion
In summary, we have successfully developed an efficient, air stable and reusable
catalyst for one–pot synthesis of dihydropyrimidin–ones or thiones and solvent–free
esterification. More importantly, Ce[LS]3 could catalyze the Biginelli reaction in
homogeneous during reaction and be easily recovered by filtration after pouring into
cold water after reaction. In the case of esterification reaction, not only avoids this
micro–reactor hydrolysis of ester, but also rapidly promotes the equilibrium reaction
towards ester.
6. Acknowledgements
Financial supports from the Fundamental Research Funds for the Central
Universities (Grant No. HIT. NSRIF. 2011025), SKLUWRE of HIT (QA201022),
China Postdoctoral Science Foundation (No. 20100471060), and Natural Science
Foundations of China (Nos. 21103035).
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