Bronsted acidic ionic liquid [C3SO3HDoim]HSO4 catalyzed one-pot three-component Biginelli-type reaction: An efficient and solvent-free synthesis of pyrimidinone derivatives and its mechanistic study

Article abstract of DOI:10.1016/j.cclet.2015.10.010

A series of Bronsted acidic ionic liquids (ILs) were prepared and used for Biginelli-type condensation reaction among aromatic aldehydes, urea or thiourea and cyclopentanone. Through this reaction, the synthesis of various pyrimidinones could be achieved. Of interest, it was found that the reaction was efficiently catalyzed by a novel, eco-friendly functionalized IL [C₃SO₃HDoim]HSO₄, which could be reused for at least 7 times without significantly loss of catalytic activity. The reaction proceeded efficiently at 80 °C to afford the desired products in good yield (up to 96%). In addition, a possible mechanism that accounted for the IL [C₃SO₃HDoim]HSO₄-catalyzed reaction was proposed.

Full text of DOI:10.1016/j.cclet.2015.10.010

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CCLET-3457; No. of Pages 5
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Bronsted acidic ionic liquid [C3SO3HDoim]HSO4 catalyzed one-pot
three-component Biginelli-type reaction: An efficient and solvent-free
synthesis of pyrimidinone derivatives and its mechanistic study
*
Zhi-Lei Zhou, Peng-Cheng Wang, Ming Lu
School of Chemical Engineer, Nanjing University of Science & Technology, Nanjing 210094, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of Bronsted acidic ionic liquids (ILs) were prepared and used for Biginelli-type condensation
reaction among aromatic aldehydes, urea or thiourea and cyclopentanone. Through this reaction, the
synthesis of various pyrimidinones could be achieved. Of interest, it was found that the reaction was
efficiently catalyzed by a novel, eco-friendly functionalized IL [C3SO3HDoim]HSO4, which could be
reused for at least 7 times without significantly loss of catalytic activity. The reaction proceeded
efficiently at 80 8C to afford the desired products in good yield (up to 96%). In addition, a possible
mechanism that accounted for the IL [C3SO3HDoim]HSO4-catalyzed reaction was proposed.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 6 September 2015
Received in revised form 26 September 2015
Accepted 15 October 2015
Available online xxx
Keywords:
Bronsted acidic ionic liquids
Catalysis
Biginelli-type reaction
Pyrimidinone
Organic synthesis
Applied chemistry
1. Introduction
additional reagent and mixed CH3CN/DMF as a reaction solvent
were necessary to obtain the targets. In recent years, various
The pyrimidinone skeleton has received considerable attention
in recent years because of its existence in many natural or
synthetic biologically active materials, and its derivatives have
been applied to various pharmaceutical and biochemical fields
[1,2]. It is of great interest that, specifically functionalized
pyrimidinone may possess specific biological properties, such as
antihypertensive, antiviral, antifungal and anticancer activities
[3,4]. This has led to the development of various methods for the
synthesis of pyrimidinone and its derivatives in the last few years.
Biginelli [5] reported that in concentrated hydrochloric acid,
3,4-dihydropyrimidine-2(H)-ketones were generated through a
ring condensation reaction of ethyl acetoacetate, aromatic
aldehydes and urea, which was now widely known as the
Biginelli-type reaction. Its operation is simple, but the yield is
low (20%–50%). In 2005, Pan [6] first described an efficient method
synthetic methods for pyrimidine ketones have been developed,
which can be roughly categorized as catalytic synthesis [7–10],
solid synthesis [11], microwave-promoted synthesis [12] and so
on. However, these methods mainly related to the study of classical
Biginelli reaction, and the synthesis of pyrimidine ketone and its
derivatives were seldom reported [13].
Metal-catalyzed reactions [14] are recognized as attractive and
environmentally benign methods in synthetic organic chemistry.
In this area, remarkable progress has been made in the applications
of lanthanide reagents as catalysts in organic synthesis recently
[15]. Zhang [16] described
a method for the synthesis of
pyrimidinones using three-component condensation with
a
aromatic aldehydes, cyclopentanone, and urea catalyzed by
ytterbium chloride. But the costly metal catalysts are not readily
available and they cannot be recycled and reused. In addition,
reagent wasting and long reaction time make this method less
appealing.
Considering the characteristics mentioned above, the room
temperature ionic liquids have been described as one of the most
promising new reaction mediums [17] because of their relatively
benign characters, low volatility, thermal stability, efficiency as a
catalyst and promoter, and reusability [18]. Bronsted acid ionic
liquids (ILs) containing acidic protons that are adjustable to exhibit
for the synthesis of pyrimidinones by
a three-component
condensation with aromatic aldehydes, cyclopentanone, and urea
or thiourea as starting materials. Although the reaction could
proceed smoothly, the use of stoichiometric amount of TMSCl as an
*
Corresponding author.
E-mail address: luming@mail.njust.edu.cn (M. Lu).
http://dx.doi.org/10.1016/j.cclet.2015.10.010
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Z.-L. Zhou, et al., Bronsted acidic ionic liquid [C3SO3HDoim]HSO4 catalyzed one-pot three-component
Biginelli-type reaction: An efficient and solvent-free synthesis of pyrimidinone derivatives and its mechanistic study, Chin. Chem. Lett.
(2015), http://dx.doi.org/10.1016/j.cclet.2015.10.010

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Z.-L. Zhou et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
desired catalytic activity. On the basis of previous pioneering work,
a novel environment-friendly ionic liquid [C3SO3HDoim]HSO4 was
designed to catalyze the Biginelli-type condensation reaction,
which exhibited dramatically efficiency in the course of the
reaction with its sulfonic functional groups and long carbon chain.
In addition, [C3SO3HDoim]HSO4 can be successfully recovered and
reused for several times.
2. Experimental
Fig. 1. Four kinds of ionic liquids.
All reagents were of analytical grade and were purchased from
commercial sources and used without any further purification.
Melting points were determined on a Thomas Hoover capillary
apparatus and were uncorrected. 1H NMR (500 MHz) was recorded
on a Bruker 500 spectrometer with tetramethylsilane (TMS) as an
internal standard. Mass spectra was recorded on an Agilent
technologies 6110 quadrupole LC/MS equipped with an electro-
spray ionization (ESI) probe operating in the positive ion mode.
Yields refer to the isolated yields of the products after purification.
All starting chemicals were commercially available. [HMim]X
(X = HSO4, HNO3), [TEPSA]HSO4 and [C3SO3HMim]HSO4 were
prepared according to literature procedures [19–21].
product was isolated by filtering through a Bu¨chner funnel and
washed with water, diethyl ether and acetone, followed by
crystallization from ethanol, and then dried to give the crystalline
or powdered products [6].
The spectral data of known compounds characterized by 1H
NMR were found to be identical with those reported in the
literature [16,24].
3. Results and discussion
The experimental process could be easily achieved with
simple operation under solvent-free conditions. Four ILs were
prepared and used as catalysts for the Biginelli-type reaction,
including [HMim]HSO4, [TEPSA]HSO4, [C3SO3HMim]HSO4,
[C3SO3HDoim]HSO4. The structures were shown in Fig. 1.
The catalytic performance of different ILs was summarized in
Table 1. During the experimental process, a mixture of three
reagents, benzaldehyde, cyclopentanone, and urea was stirred at a
suitable temperature in air in the presence of IL, which acted as a
model reaction to optimize reaction conditions. As can be seen,
2.1. Preparation of [C3SO3HDoim]HSO4
The synthetic process of [C3SO3HDoim]HSO4 was shown in
Scheme 1. First, imidazole (6.8 g, 0.1 mol) was dissolved in 100 mL
of ethanol sodium ethoxide. The mixture was heated to 70 8C and
kept at this temperature with stirring for 8 h under reflux
[22]. Then an equal mole of 1-bromododecane was added and
the system was allowed to stir for 8 h under reflux. The white
precipitate was filtered off and the filtrate was extracted three
times by diethyl ether followed by vacuum distillation to remove
organic solvents to obtain N-dodecyl imidazole, a yellow viscous
liquid at room temperature. N-Dodecyl imidazole was character-
ized by LC/MS.
Table 1
Optimization of the reaction conditions.a
Second, an equal mole of 1,3-propanesultone was added
dropwise over a period of 10 min under stirring in an ice bath
[23], after which the mixture was heated to 70 8C and kept at this
temperature with stirring for 10 h, followed by the addition of an
equal mole of sulfur acid (98%) with stirring. The mixture was then
warmed to 90 8C and kept at this temperature for 2 h [21]. After
that, diethyl ether was added and 1-dodecyl-3-(3-sulfopropyl)-
imidazolium hydrogen sulfate ([C3SO3HDoim]HSO4) was precipi-
tated as a highly viscous and pale-yellow oily liquid. The product
was dried under vacuum at 50 8C for 6 h giving a yield of 98%–99%.
[C3SO3HDoim]HSO4 was characterized by IR, 1H NMR, 13C NMR
and LC/MS.
Entry
ILs
Loading
(mmol)
T
Time
(h)
1a:2a:3
Yield
(%)b
(8C)
1
Nonec
0
5
80
80
80
80
80
80
80
80
80
50
100
120
80
80
80
80
80
80
80
1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:1
2:1:2
2:2:1
2:2:2
2:3:2
49
65
65
74
75
80
75
80
79
73
78
77
72
78
75
80
79
79
78
2
[HMim]HSO4
1
3
[HMim]NO3
5
1
4
[TEPSA]HSO4
5
1
2.2. Typical procedure for the synthesis of pyrimidinones
5
[C3SO3HMim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
[C3SO3HDoim]HSO4
5
1
6
5
1
A mixture of aromatic aldehydes (50 mmol), cyclopentanone
(2.1 g, 25 mmol), urea or thiourea (25 mmol) and [C3SO3H-
Doim]HSO4 (5 mmol) was well stirred at 80 8C for a given time.
After that, the system was cooled to room temperature. The pure
7
2
1
8
8
1
9
10
5
1
10
11
12
13
14
15
16
17
18
19
1
5
1
5
1
5
0.5
1.5
2
5
5
5
1
5
1
5
1
5
1
a
Reaction conditions: benzaldehyde/urea/cyclopentanone = 2:1:1, 80 8C, 1 h,
[C3SO3HDoim]HSO4 5 mmol relative to aromatic aldehyde, solvent-free.
b
Yields refer to those of purified isolated products.
Scheme 1. The synthesis of 1-dodecyl-3-(3-sulfopropyl)-imidazolium hydrogen
c
98% H2SO4 (5 mL) was added in the reaction.
sulfate.
Please cite this article in press as: Z.-L. Zhou, et al., Bronsted acidic ionic liquid [C3SO3HDoim]HSO4 catalyzed one-pot three-component
Biginelli-type reaction: An efficient and solvent-free synthesis of pyrimidinone derivatives and its mechanistic study, Chin. Chem. Lett.
(2015), http://dx.doi.org/10.1016/j.cclet.2015.10.010

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Z.-L. Zhou et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
3
Table 3
[C3SO3HDoMim]HSO4 was the most efficient one, giving the
highest yield.
Synthesis of pyrimidinones 4(a–j) from aromatic aldehydes, cyclopentanone and
urea.a
As shown in Table 1 (entries 1–6), in the absence of IL, the yield
was only 49% using sulfuric acid as catalyst. The IL, [C3SO3H-
Doim]HSO4, was found to give the best result at 80 8C compared
with other imidazolium salt-based ILs such as [HMim]HSO4 and
[C3SO3HMim]HSO4, or hyamine-based ILs. The possible reason for
this was that [C3SO3HDoim]HSO4 with
a distinct sulfonic
functional group and long carbon chain could make it soluble in
organic phase, which was beneficial for the interactions between
catalyst and substrates. On the other hand, imidazole cation could
form coordination bonds with the carbonyl oxygen, which
performed better than the hyamine ion. With [C3SO3HDoim]HSO4
as a model catalyst, the screening of catalyst loading was then
carried out. The result revealed that 5 mmol% was the most
suitable proportion, more loading or less could not enhance the
product yield (entries 6–9). Reaction temperature significantly
affected the reaction. The rise of the temperature from 50 8C to
80 8C led to an increased yield from 73% to 80% (entries 6 and 10),
while a decreased yield was obtained when the temperature was
over 100 8C (entries 11 and 12). Then the impact of reaction time
on yield (entries 6 and 13–15) was investigated and the highest
yield was obtained after 1 h. These results indicated that lower
temperature and shorter reaction time may result in incomplete
reaction while overheating and prolonged time led to complicated
side reactions.
Entry
Ar
Time (h)
Yield (%)b
Product
1
2
3
4
5
6
7
8
9
10
Ph
1
2
2
2
2
1
1
1
1
1
80
4a
4b
4c
4d
4e
4f
p-CH(CH3)2Ph
p-CH3OPh
o-CH3OPh
m-CH3OPh
o-ClPh
59(54)c
75(70)c
77
66
76
m-ClPh
82
4g
4h
4i
p-ClPh
85
m-NO2Ph
p-NO2Ph
89
96
4j
a
Reaction conditions: aldehyde/urea/cyclopentanone = 2:1:1, 5 mmol [C3SO3H-
Doim]HSO4 relative to aromatic aldehyde, 80 8C.
b
Yields refer to those of purified isolated products characterized by spectro-
scopic data (1H NMR).
c
The reaction time was run for 1 h.
The ratio of benzaldehyde, urea and cyclopentanone should be
2:1:1 to produce pyrimidinones in theory. To explore the influence
of the ratio on this reaction, we attempted to modify the ratio in
various ways. Corresponding control reactions were performed
and the results indicated that even when the amount of
cyclopentanone or urea was doubled, there is almost no increase
in yield (entries 6 and 16–19). In other words, excessively used
cyclopentanone and urea barely enhanced the yield with the
participation of [C3SO3HDoim]HSO4, which is contrasted to the
research of Zhang [16].
In addition, using [C3SO3HDoim]HSO4 as a catalyst, the effect of
gas and solvent on the reaction was also investigated, as shown in
Table 2. N2 was used as a protection gas to screen the reaction
conditions compared with air (entries 1 and 2). The results showed
that N2 protection could increase the yield. In other words,
materials in air containing CO2, O2, H2O, etc. did not have an
influence on the Biginelli-type reaction. Besides, four common
organic reagents, such as toluene, benzene, n-hexane, n-heptane,
were chosen as solvents in this reaction (entries 3–6). It was found
that solvent-free condition under atmosphere gave the best result
with a yield of 80% after 1 h. A probable reason would be that
solvation effect hindered the catalytic effect of IL. So N2 protection
and organic solvent could be avoided to afford a simple and green
process. Thus the reaction worked well while being exposed to air
under solvent-free conditions.
Several substituted aromatic aldehydes were applied to this
condensation reaction with cyclopentanone and urea to produce
corresponding pyrimidinones. The results were summarized in
Table 3. Aromatic aldehydes with both electron donating (entries
2–5) and electron withdrawing groups (entries 6–10) could
participate this reaction effectively. Aldehydes with electron
withdrawing groups reacted with cyclopentanone and urea
smoothly to give the corresponding products in higher yields
compared with the ones with electron donating groups. So we
attempted to prolong the reaction time moderately for aldehydes
with electron donating groups to increase the yields as much as
possible (entries 2–5). In addition, the high stereo-hindrance effect
was another vital reason for the relatively low yield as seen in the
case of para-isopropylbenzaldehyde. We found that the nature and
position of substitution on the aryl ring did have an influence on
reactivity. Apparently, substrates with strong electron-withdraw-
ing group (entries 9 and 10) gave evidently increased yields,
compared with the weak ones (entries 6–8). In addition, the para-
substituted aldehyde could afford a higher yield than the meta- and
ortho-substituted ones. So it was proposed that as for the attack of
carbon in aldehyde group by nucleophilic species, benzaldehyde
with electron-withdrawing substituent group was easier than that
with the electron-donating one.
Considering the widespread use of sulfur-containing inter-
mediates in the medical fields [24], thiourea was used in place of
urea in this reaction. Under the optimized conditions, the synthesis
of pyrimidinones with aromatic aldehydes, cyclopentanone and
thiourea was achieved, as shown in Table 4. In view of electronic
effect, sulfur exhibited stronger electron-donating ability than
oxygen. Thus, unlike urea, reactions of thiourea proceeded
smoothly to give targeted products in yields ranging from 66%
to 90% with high purity. But reaction time would be prolonged to
achieve a higher yield. We believed that expanding the reaction
from urea to thiourea would be meaningful to synthesize
biologically active pyrimidinone scaffolds.
In order to examine the scope and generality of this procedure,
we extended the methodology to different aromatic aldehydes.
Table 2
The effect of solvent and gas on the reaction.a
Entry
Solventb
Gas
Yield (%)c
1
2
3
4
5
6
–
–
80
80
77
77
78
78
–
N2
N2
N2
N2
N2
Toluene
Benzene
n-Hexane
n-Heptane
On the basis of our experimental results and literature
reports about the synthesis of pyrimidinones [16,25], and
previous studies of ILs-catalyzed condensation reactions [26,27],
a possible mechanism for the synthesis of pyrimidinones catalyzed
by [C3SO3HDoim]HSO4 was proposed as shown in Scheme 2.
a
Reaction conditions: benzaldehyde/urea/cyclopentanone = 2:1:1, 80 8C/1 h, the
loading of ILs [C3SO3HDoim]HSO4 (5 mmol) relative to benzaldehyde.
b
The volume of added solvent was 50 mL.
c
Yields refer to those of purified isolated products.
Please cite this article in press as: Z.-L. Zhou, et al., Bronsted acidic ionic liquid [C3SO3HDoim]HSO4 catalyzed one-pot three-component
Biginelli-type reaction: An efficient and solvent-free synthesis of pyrimidinone derivatives and its mechanistic study, Chin. Chem. Lett.
(2015), http://dx.doi.org/10.1016/j.cclet.2015.10.010

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Table 4
Table 5
Synthesis of pyrimidinones 5(a–g) from aromatic aldehydes, cyclopentanone and
thiourea.a
Recyclability of recovered [C3SO3HDoim]HSO4.a
Entry
Run
Yield (%)b
1
2
3
4
5
6
7
Fresh
80
81
80
79
78
78
77
1
2
3
4
5
6
a
Reaction conditions: aldehyde/urea/cyclopentanone = 2:1:1, 5 mmol [C3SO3H-
Entry
Ar
Time (h)
Yield %)b
Product
Doim]HSO4 relative to aromatic aldehyde, 80 8C/1 h.
Yields refer to those of purified isolated products characterized by spectro-
scopic data (1H NMR).
b
1
2
3
4
5
6
7
Ph
2
3
3
3
3
4
4
81
66
75
78
65
83
90
5a
5b
5c
5d
5e
5f
p-CH(CH3)2Ph
p-CH3OPh
o-CH3OPh
m-CH3OPh
o-ClPh
reaction was finished, [C3SO3HDoim]HSO4 was recovered and
catalyzed the reaction over and over.
p-NO2Ph
5g
At last, the recycling performance of [C3SO3HDoim]HSO4 was
also investigated using the model reaction. After the separation of
the products, the solvents in the filtrate were moved through
rotary evaporation to recover [C3SO3HDoim]HSO4, which could be
reused without further purification. The data listed in Table 5
showed that the [C3SO3HDoim]HSO4 could be reused at least
7 times without obvious reduction of the catalytic activity.
Compared with the traditional catalysts, the easy recycling
performance is also an attractive property of the [C3SO3H-
Doim]HSO4 for the environmental protection and economic
reasons. The reason for the minimal loss in yield could be that
the ILs run off with filtration and purification of the products. Upon
our research, it can be seen that this ILs-catalyzed condensation
reaction for the synthesis of pyrimidinones constituted an efficient,
convenient, eco-friendly and most importantly recyclable system.
Firstly, no poisonous auxiliary solvents were injected into the
reaction, and the purification of the products was just performed
through filtration, washing and crystallization. Second, the
reaction worked well while being exposed to the air, so the steps
of drying and protecting were avoided. In addition, reusability of
ILs led to an economical and environmental benign process.
a
Reaction conditions: aldehyde/thiourea/cyclopentanone =2:1:1, 5 mmol
[C3SO3HDoim]HSO4 relative to aromatic aldehyde, 80 8C.
b
Yields refer to those of purified isolated products characterized by spectro-
scopic data (1H NMR).
[C3SO3HDoim]HSO4 showed remarkable reactivity as an organic-
phase catalyst, which considerably accelerated the reactions. It
was probably due to its long chain with twelve carbons that
allowed it to dissolve in the organic phase more easily compared
with [C3SO3HMim]HSO4 containing only one methyl. Thus, a
hydrogen proton from [C3SO3HDoim]HSO4 combined with ketonic
oxygen in cyclopentanone to produce an enol form. Then the cross-
aldol condensation of benzaldehyde with the enol form took place
to generate keto-aldehyde 1 with the assistance of [C3SO3H-
Doim]HSO4, which was similar to the Yb(OTf)3-catalyzed process
reported by Wang [28]. Afterwards, keto-aldehyde 1 further
reacted with another benzaldehyde resulting in the formation of
keto-aldehyde 2 in the same way. Then compound 3 was generated
through a Michael addition of urea or thiourea with keto-aldehyde
2, followed by the removing a H2O molecule and cyclizing to form
the targeted compound 4. When one round of condensation
4. Conclusion
X
NH
HN
Ph
In conclusion, the present procedure using a novel function-
alized IL [C3SO3HDoim]HSO4 as catalyst, provides a very simple
and efficient methodology for the synthesis of pyrimidinone and
its derivatives through the condensation of aromatic aldehydes,
cyclopentanone and urea or thiourea. In addition to short reaction
time, low energy consumption, high yields, and reusability of ILs,
no hazardous organic solvents are used in the entire processes
including workup and purification. These eco-friendly features
provide an attractive method to synthesize pyrimidinones.
Ph
4
+
-H2O
N
N
OH
O
OH
C12H25
(CH2)3SO3H
H+
C12H25
N
H2N
X
H
N
+
O
(CH2)3SO3H
Ph
N
H
N
NH
C12H25
(CH2)3SO3H
O
C
H
Ph
O
Ph
3
References
+
N
N
C12H25
(CH2)3SO3H
Ph
+
N
N
H
O
C12H25
O
(CH2)3SO3H
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PhCHO
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(CH2)3SO3H
Ph
Ph
CO(NH2)2
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2
1
+
N
N
C
12H25
Ph
O
+
N
N
C12H25
(CH2)3SO3H
Scheme 2. The possible mechanism for the synthesis of pyrimidinones catalyzed by
[C3SO3HDoim]HSO4 (X = O, S).
Please cite this article in press as: Z.-L. Zhou, et al., Bronsted acidic ionic liquid [C3SO3HDoim]HSO4 catalyzed one-pot three-component
Biginelli-type reaction: An efficient and solvent-free synthesis of pyrimidinone derivatives and its mechanistic study, Chin. Chem. Lett.
(2015), http://dx.doi.org/10.1016/j.cclet.2015.10.010

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Z.-L. Zhou et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
5
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Please cite this article in press as: Z.-L. Zhou, et al., Bronsted acidic ionic liquid [C3SO3HDoim]HSO4 catalyzed one-pot three-component
Biginelli-type reaction: An efficient and solvent-free synthesis of pyrimidinone derivatives and its mechanistic study, Chin. Chem. Lett.
(2015), http://dx.doi.org/10.1016/j.cclet.2015.10.010