Nano-zirconia as an excellent nano support for immobilization of sulfonic acid: A new, efficient and highly recyclable heterogeneous solid acid nanocatalyst for multicomponent reactions

Article abstract of DOI:10.1039/c5nj02430g

Nano-zirconia-supported sulfonic acid [nano-ZrO₂-SO₃H (n-ZrSA)] is synthesized by immobilizing sulfonic acid groups on the surface of nano zirconium dioxide to produce a novel heterogeneous reusable solid acid nanocatalyst. This new nanocatalyst is characterized by FT-IR spectroscopy, thermogravimetric analysis (TGA), X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), the Hammett acidity function and pH analysis. The introduced nano-zirconia-supported sulfonic acid is used as an efficient and recyclable catalyst for different heterocyclic multicomponent reactions such as the synthesis of hexahydroquinoline, 1,8-dioxo-decahydroacridine, polyhydroquinoline and 1,8-dioxo-octahydroxanthene derivatives. Optimization of the reaction conditions was studied using a central composite design (CCD) which is one of the most widely used response surface methodologies. The newly prepared heterogeneous solid acid nanocatalyst is easily separated and reusable for five cycles without any apparent loss of its catalytic activity, which confirmed the stability of the covalent bonding of the sulfonic acid groups. n-ZrSA has advantages such as its low cost, low toxicity, ease of preparation, good stability, high reusability and operational simplicity.

Full text of DOI:10.1039/c5nj02430g

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Nano-zirconia as an excellent nano support for immobilization of sulfonic
acid: A new, efficient and highly recyclable heterogeneous solid acid
nanocatalyst for multicomponent reactions
Ali Amoozadeh
∗, Salman Rahmani, Mehrnoosh Bitaraf, Fatemeh Bolghan Abadi and Elham
Tabrizian
Faculty of Chemistry, Semnan University, Semnan 35131ꢀ19111, Iran
Abstract
Nanoꢀzirconiaꢀsupported sulfonic acid [nanoꢀZrO2ꢀSO3H (nꢀZrSA)] is synthesized by
immobilizing sulfonic acid groups on the surface of nano zirconium dioxide to produce novel
heterogeneous reusable solid acid nanocatalyst. This new nanocatalyst is characterized by
FTꢀIR spectroscopy, thermal gravimetric analysis (TGA), Xꢀray diffraction (XRD), field
emission scanning electron microscopy (FEꢀSEM), transmission electron microscopy (TEM),
Hammett acidity function and pH analysis. The introduced nanoꢀzirconiaꢀsupported sulfonic
acid is used as an efficient and recyclable catalyst for different heterocyclic multicomponent
reactions such as synthesis of hexahydroquinoline, 1,8ꢀdioxoꢀdecahydroacridine,
polyhydroquinoline and 1,8ꢀdioxoꢀoctahydroxanthene derivatives. Optimization of the
reactions conditions was studied by central composite design (CCD) which is one of the most
widely used response surface methodologies. The newly prepared heterogeneous solid acid
nanocatalyst is easily separated and reused for five times without apparent loss of its catalytic
activity that confirmed the stability of the covalent bonding of sulfonic acid groups. nꢀZrSA
has advantages such as low cost, low toxicity, ease of preparation, good stability, high
reusability and operational simplicity.
Keywords:
NanoꢀZrO2ꢀsupported
sulfonic
acid,
Heterogeneous
nanocatalyst,
Multicomponent reaction, Design of experiment.
1. Introduction
∗
Corresponding author. Tel.: +98 (23) 33366177; fax: +98 (23) 33354110; eꢀmail: aamozadeh@semnan.ac.ir
1

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Nowadays, using heterogeneous solid acid catalysts for chemical reactions and processes is
widely expanded. Acid catalyzed organic synthesis is an important way to produce numerous
organic products. Sulfuric, nitric, hydrochloric, phosphoric and fluorhydric acid are common
homogeneous acid catalysts that are widely used in chemical synthesis and industrial
processes.1, 2 However, these catalysts are not environmentally benign because of their
problems such as difficult separation from the products and corrosive properties. These
disadvantages of homogeneous acid catalysts cause different problems such as using
specialized reaction equipments, increasing operational difficulties, high consuming of
energy and the formation of large amounts of waste products. In recent years, due to these
drawbacks, the development of novel, low cost, nontoxic, well separable and recyclable
heterogeneous catalysts has been the most important challenge of scientists.3ꢀ8
Heterogenization of homogeneous catalysts by immobilization of sulfonic acid on various
solid supports leads to the production of novel heterogeneous solid acid catalysts. This topic
has attracted much attantion of extensive researcher during the past decade.9ꢀ14 Transition
metal nanoparticles are used as efficient catalysts for various synthetic organic
transformations due to their high surface areaꢀtoꢀvolume ratio and coordination sites which
are mainly responsible for their catalytic activity.15 These properties lead to their wide
applications as excellent supports to produce new, efficient, nontoxic, environmental and
reusable heterogeneous solid acid nanocatalysts.
Zirconium is one of the important transition metals on the earth crust (130 mg/kg),
which is not found in nature as a native metal. The silicate mineral of zirconium, known as
zircon (ZrSiO4), is its principal source furthermore the zirconium dioxide (ZrO2) is
commercially available. It is mainly used as a refractory and opacifier, although it is used in
small amounts as an alloying agent for its strong resistance to corrosion. Considering the
multiple potential applications, zirconium dioxide is commonly used in numerous research
2

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fields such as laboratory crucibles, metallurgical furnaces, as a refractory material,16 oxygen
sensors, fuel cell membranes, ceramics production,17 protective coating on particles of
19
titanium dioxide pigments,17 strontium adsorption,18 acylation of 1,nꢀdiols
applications.
and other
Given the excellent properties of ZrO2 and the significance of heterogeneous solid
acid catalysis, in continuation of our last studies about heterogeneous solid acid
nanocatalysts,20ꢀ22 we decided to investigate nanoꢀZrO2 as a new nano support. As sulfonation
with chlorosulfonic acid is a convenient, fast and efficient method for heterogenization of
homogeneous catalysts after Zolfigol's report,23 the catalytic properties of nanoꢀZrO2 has been
improved by its reaction with chlorosulfonic acid to produce nanoꢀZrO2ꢀsupported sulfonic
acid (nanoꢀZrO2ꢀSO3H) (Scheme 1).
Scheme 1. Preparation of nanoꢀZrO2ꢀSO3H (nꢀZrSA).
2. Experimental
2.1. Materials and Instruments
Chemicals were purchased from Merck chemical companies. ThinꢀLayer Chromatography
(TLC) on commercial plates of silica gel 60 F254 was used to monitor the progress of
1
reactions. The products were characterized by FTꢀIR spectra, HNMR, 13CNMR and CHN
1
analyzer. H and 13C NMR spectra which were recorded on Bruker Advance Spectrometer
400 & 500 MHz using CDCl3ꢀd and DMSOꢀd6 as solvent. The chemical shifts are expressed
in parts per million (ppm) and tetramethylsilane (TMS) was used as an internal reference.
Elemental analyses were performed by Perkin Elmer CHN analyzer, 2400 series II. Melting
points were recorded on a THERMO SCIENTIFIC 9100 apparatus. Wide angle Xꢀray
3

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diffraction spectrum was obtained by a Siemens D5000 (Siemens AG, Munich, Germany) Xꢀ
ray diffractometer using CuꢀKa radiation of wavelength 1.54 Å. Field emission scanning
electron microscope (FEꢀSEM) images were carried out using Philips XL30 field emission
scanning electron microscope (Royal Philips Electronics, Amsterdam, The Netherlands)
instrument operating at 20 kV. The sample was mounted on a double sided adhesive carbon
disk and sputterꢀcoated with a thin layer of gold to prevent sample charging problems.
Fourier transform infrared spectrum (FTꢀIR) was recorded on Shimadzo FTꢀIR 8400
instrument. The nꢀZrSA sample was mixed with KBr powder and compressed into a pellet,
wherein, the nꢀZrSA powder was evenly dispersed. Thermo gravimetric analyses (TGA) were
conducted on a Du Pont 2000 thermal analysis apparatus under air atmosphere at a heating
rate of 5 °C/min.
2.2. Preparation of nano-ZrO2
The zirconium dioxide nanoparticles were prepared through chemical precipitation method.
10 g ZrOCl2.8H2O was dissolved in 100 mL bidistilled water using hot plate magnetic stirrer.
The desired volume of 2 M NaOH was added to the above mentioned precursor solution until
the pH value became 10. After 15 minutes, the precipitate was filtered off, washed and dried
at 120 °C overnight. The dried ZrO2·nH2O was calcined at different temperatures from 500 to
1200 °C at a rate of 10 °C/min and kept at the respective temperature for 1h.24
2.3. Preparation of nano-ZrO2-SO3H (n-ZrSA)
The chlorosulfonic acid (0.5 mL, 7.5 mmol) (CAUTION: a highly corrosive and water
absorbant. Be careful when using this liquid. Protective gloves, protective clothing and eye
and face protection equipment are also needed.) was added dropwisely over a period of 30
min under room temperature to the nanoꢀZrO2 (3.08 g, 25 mmol) in dry CH2Cl2 (20 mL). A
suction flask equipped with a constantꢀpressure dropping funnel and a gas inlet tube for
conducting HCl gas over an adsorbing solution (i.e., water) was used. Stirring was continued
until HCl evolution was finished. Then, the mixture was shaken for 30 min. A light cream
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powder of nanoꢀzirconiaꢀsupported sulfonic acid was obtained. Afterward, the CH2Cl2 was
removed under reduced pressure and the solid powder was washed with ethanol (10 mL) and
dried at 100 °C.
2.4. Investigating of n-ZrSA as a solid acid nanocatalyst for multicomponent one-pot
synthesis of heterocyclic compounds
2.4.1. General procedure for the synthesis of hexahydroquinoline derivatives
In a typical experiment, 1,3ꢀcyclic diketone (1 mmol), different aromatic aldehyde (1 mmol),
ammonium acetate (1 mmol), malononitrile (1 mmol) and nꢀZrSA (0.019 g) in solvent free
condition were taken in a 25 mL round bottomed flask. The flask was stirred at 100 °C for an
appropriate time. After completion of reaction (monitored by TLC), the reaction mixture was
cooled, eluted with hot ethanol (5 mL), and centrifuged to collect the catalyst. The solvent
was evaporated with reduced pressure to collect the formed precipitate. The crude product
was recrystallized from ethanol to yield pure hexahydroquinoline derivatives.
2.4.2. General procedure for the synthesis of 1,8-dioxo-decahydroacridine derivatives
A mixture of 1,3ꢀcyclic diketone (2 mmol), aromatic aldehyde (1 mmol), ammonium acetate
(1 mmol) and nꢀZrSA (0.027 g) in solvent free condition were taken in a 25 mL round
bottomed flask. The flask was stirred at 100 °C for an appropriate time. The reaction mixture
was cooled, eluted with hot ethanol (5 mL), and centrifuged to collect the catalyst. The
solvent was evaporated with reduced pressure to collect the formed precipitate. The crude
product was recrystallized from ethanol to yield pure 1,8ꢀdioxoꢀdecahydroacridines.
2.4.3. General procedure for the synthesis of polyhydroquinoline derivatives
In a 25 mL round bottomed flask, nꢀZrSA (0.019 g) was added to the mixture of 1,3ꢀcyclic
diketone (1 mmol), aromatic aldehyde (1 mmol), ammonium acetate (1 mmol) and
ethylacetoacetate (1 mmol) in solvent free conditions. The flask was stirred at 100 °C for an
appropriate time. The reaction mixture was cooled, eluted with hot ethanol (5 mL),
centrifuged to collect the catalyst. The solvent was evaporated with reduced pressure to
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collect the formed precipitate. Recrystallization of crude product from ethanol yield pure
polyhydroquinolines.
2.4.4. General procedure for the synthesis of 1,8-dioxo-octahydroxanthene derivatives
A wellꢀstirred mixture of various 1,3ꢀcyclic diketone (2 mmol), aromatic aldehyde (1 mmol)
and nꢀZrSA (0.039 g) as catalyst in a 25 mL round bottomed flask was heated at 100 °C (in
an oil bath) in solvent free conditions for the appropriate time. Upon completion of the
reaction (monitored by TLC), the reaction mixture was cooled, eluted with hot ethanol (5
mL), centrifuged to collect the catalyst and the solvent was evaporated with reduced pressure
to give the crude product. The formed solid powder was washed with acetone. For further
purification, it was crystallized from ethanol to afford pure 1,8ꢀdioxoꢀoctahydroxanthene
derivatives.
2.4.5. General procedure for recycling of n-ZrSA
Recyclability of nꢀZrSA (0.019 g) was examined for the synthesis of 2ꢀaminoꢀ7,7ꢀdimethylꢀ
5ꢀoxoꢀ4ꢀphenylꢀ1,4,5,6,7,8ꢀhexahydroquinolineꢀ3ꢀcarbonitrile between dimedone (1mmol),
benzaldehyde (1 mmol), ammonium acetate (1 mmol) and malononitrile (1 mmol) under
solvent free conditions for 15 minutes at 100 °C. After completion of the reaction, the
nanocatalyst was separated from the production mixture by centrifuge, washed with ethanol
(2 × 15 mL) and acetone (2 × 10 mL) to remove the organic compounds and dried in oven to
be used in the next cycles. In every run, the yield of product was performed in constant time.
This process was repeated six more times, affording the desired product in good yields, with
undiminishing efficiency.
3. Results and Discussion
3.1. Characterization of nano-ZrO2-SO3H
Nanoꢀzirconiaꢀsupported sulfonic acid was synthesized by immobilizing sulfonic acid groups
on the surface of nano zirconium dioxide and characterized by FTꢀIR spectroscopy, thermal
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gravimetric analysis (TGA), Xꢀray diffraction (XRD), field emission scanning electron
microscopy (FEꢀSEM) and transmition electron microscopy (TEM), Hammett acidity
function and pH analysis.
The FTꢀIR spectroscopy is employed to monitor the immobilization process by comparing
the support and modified surface (Figure 1). In the graph a of Fig. 1, the absorbance bands at
around 520, 580 and 727 cmꢀ1 is due to ZrꢀOꢀZr vibration, and the absorbance bands at
around 3400ꢀ3500 cmꢀ1 was certified to the adsorbed water (Fig. 1, graph a and b) which is
consistent with the reported IR spectra for nanoꢀZrO2.25 In the graph b of Fig. 1, the
absorption range in 1165ꢀ1248 and 1007ꢀ1065 cmꢀ1 was certified the O=S=O asymmetric and
symmetric stretching modes lies respectively. The SꢀO stretching mode lies in 560ꢀ608 cmꢀ1.
These absorption and stretching obtained bands completely differ from stretching vibrations
of O=S=O and SꢀO groups in sulfated zirconia.26 According to the obtained results, presence
of sulfonic acid group is proved which is consistent with the reported IR spectra of ꢀSO3H.27
Fig. 1. The FTꢀIR spectra of (a) The nanoꢀZrO2 powder and (b) nanoꢀZrO2ꢀSO3H.
The thermal gravimetric analysis (TGA) was used to determine the percentage of the
chemisorbed sulfonic acid group onto the surface of nanoꢀZrO2. The TGA curve of nanoꢀ
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ZrO2 (Fig. 2a) displays a weight loss (5 wt.%) below 100 °C which corresponds to the loss of
the physically adsorbed water. Likewise, there is a slight weight loss (4 wt.%) between 100
°C and 800 °C, which may contribute to the dehydroxylation of nanoꢀZrO2.
In the TGA curve of nanoꢀZrO2ꢀSO3H (Fig. 2b) threeꢀstage decomposition is seen
corresponding to different mass lose ranges. In the first region, a mass loss approximately 4%
weight occurred below 100 °C that displayed that was attributable to the loss of trapped water
from the catalyst. A mass loss of approximately 4% weight occurred between 100 and 330 °C
that related to the slow mass loss of SO3H groups. Finally, a mass loss of approximately 14%
weight occurred between 330ꢀ700 °C that it was related to the sudden mass loss of SO3H
groups.27, 28 From the TGA, it can be concluded that nanoꢀZrO2ꢀSO3H could be safely used in
organic reactions due to high thermal stability (up 150 °C).
Fig. 2. TGA cure of (a) nanoꢀZrO2 and (b) nanoꢀZrO2ꢀSO3H.
The crystal phases of nanoꢀZrO2 and nꢀZrSA were examined by powder Xꢀray diffraction
technique. The following peak signals with miler indices (100), (011), (110), (111),
(111),(002), (200), (021), (211), (121), (112), (202), (022), (220), (122), (202), (013), (130),
(310), (131), (131), (113), (213), (311), (023) and (222) in Fig. 3a confirm the formation of
nano zirconium dioxide monoclinic crystal phase which coincides with JCPD 07ꢀ0343
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standard. The average diameter of the nanoꢀZrO2 powder was also determined from Xꢀray
pattern using the Scherrer formula given as t=0.9λ/B1/2cosθ, that t is the average crystal size,
λ the Xꢀray wavelength used (1.54 Å), B1/2 the angular line width at half maximum intensity
and θ the Bragg′s angle. The average crystal size of the nanoꢀZrO2 powder for 2θ = 27.875 º
is calculated to be around 21.28 nm and average crystal size of the nanoꢀZrO2ꢀSO3H powder
for 2θ = 27.745 º is calculated to be around 21.27 nm. According to the PXRD data for the
peak at 27.875 º (Fig. 3a), the maximum crystal growth of nanoꢀZrO2 is 554. Fig. 3b
illustrates XRD patterns of the modified nanoꢀZrO2. As shown in Fig. 3b, the peak intensities
of nanoꢀZrO2ꢀSO3H (nꢀZrSA) are almost the same as those of nanoꢀZrO2 (Fig. 3a) indicating
retention of the monoclinic crystal phase structure during functionalization of nanoꢀZrO2.
Fig. 3. The Xꢀray diffraction pattern of (a) the nanoꢀZrO2 powder and (b) nanoꢀZrO2ꢀSO3H.
The morphology of nanoꢀZrO2 is shown in Fig. 4. The field emission scanning electron
microscopy (FEꢀSEM) images of nanoꢀZrO2 powder ascertain the spherical nanoꢀZrO2
powder with a minimum particle sizes of about 30ꢀ40 nm (Fig. 4a, b). While the FEꢀSEM
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images of nꢀZrSA show nearly spherical nano particles with a minimum diameter of about
35ꢀ40 nm (Fig. 4c, d). It is clear that modification process has been achieved successfully.
Fig. 4. The FEꢀSEM of (a,b) nanoꢀZrO2 and (c,d) nanoꢀZrO2ꢀSO3H.
Fig. 5 displays TEM images of nanoꢀZrO2ꢀSO3H which confirms sphericalꢀlike and
nanometerꢀsized particles of the catalyst.
Fig. 5. The TEM images of nanoꢀZrO2ꢀSO3H.
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The acid strength of a catalyst can be effectively expressed by the Hammett indicator
method 29 which can be calculated using the following equation:
H0= pK(I)aq + log([I]s/[IH+]s),
Here, ‘I’ indicates the indicator base (mainly substituted nitroanilines) and [IH+]s and [I]s are
the molar concentrations of the protonated and unprotonated forms of the indicator,
respectively. The pK(I)aq values are already known (for example the pK(I)aq value of 4ꢀ
nitroaniline is 0.99) and can be obtained from many references. The value of [I]s/[IH+]s can
be specified and calculated using the UVꢀvisible spectrum cccording to the LambertꢀBeer
law. In this experiment, 4ꢀnitroaniline was chosen as the basic indicator and CCl4 as the
solvent due to its aprotic property. The maximal absorbance of the unprotonated form of 4ꢀ
nitroaniline was observed at 331.5 nm in CCl4 as Fig. 6. Then, 20 mg of the catalyst was
added to the solution and mixed for 30 min with magnetic stirring, and the UV spectrum of
the solution was recorded. The absorbance of the unprotonated form of the indicator in nꢀ
ZrO2ꢀSO3H decreased and was weak as compared to the sample of the indicator in CCl4,
which indicated that the acidic protons was trapped and the indicator was partially in the form
of [IH+].
Fig. 6. Absorption spectra of (a) 4ꢀnitroaniline (indicator) and (b) nanoꢀZrO2ꢀSO3H (catalyst) in CCl4.
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The obtained results are listed in Table 1, which shows the acidity strength of nanoꢀ
ZrO2ꢀSO3H. These results of the Hammett acidity function (H0) also approve the synthesis of
new catalyst with a good density of acid sites (ꢀSO3H groups) on the surface of nanoꢀZrO2
(Table 1).
Table 1. Calculation of Hammett acidity function (H0) of nꢀZrSA.
Entry
Catalyst
ꢀ
nꢀZrSA
Amax
2.135
1.112
[I]s (%)
100
52.18
[IH+]s (%)
0
H0
ꢀ
1.30
1
2
47.82
Condition for UVꢀvisible spectrum measurement: solvent, CCl4; indicator, 4ꢀnitroaniline (pK(I)aq= 0.99),
1.44*10ꢀ4mol/L; catalyst, nꢀZrSA (20 mg), 25 °C.
The acid capacities of nꢀZrSA determined by acidꢀbase potentiometric titration of the
aqueous suspension of the weighed amount of thoroughly washed catalyst. For this purpose,
the prepared nꢀZrSA stored in vacuum desiccator over anhydrous silica gel, then, was dried in
120 °C for 6 hours. Next, the surface acidic protons of nanoꢀZrO2ꢀSO3H were ionꢀexchanged
with a saturated solution of NaCl (10 mL) by sonication. This process was repeated twice
more, yielding 30 mL of protonꢀexchanged brine solution and the obtained solution was
titrated by NaOH (0.01 M) solution in presence of pH meter. The loading of acid sites on the
synthesized catalyst was obtained to about 3.9 mmol H+/g of nꢀZrSA.
The obtained results of characterization methods showed that sulfunic acid groups (ꢀ
SO3H) have been supported on the surface of nanoꢀZrO2. It is notable that nanoꢀZrO2ꢀSO3H
acts as a Lewis and a Brønsted acid simultaneously in which nanoꢀZrO2 functions as a Lewis
acid and sulfonic acids function as the Brønsted. Brønsted acids could usually provide a
hydrogen bond which can initiate the catalytic procedure. According to the obtained results,
we expected better catalytic activity for nanoꢀZrO2ꢀsupported sulfonic acid comparing with
nanoꢀZrO2. In order to approve this hypothesis, we have decided to investigate its catalytic
activity in some of organic reactions.
3.2. Invastigating of nano-ZrO2-SO3H in one-pot multicomponent reactions
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Considering our researches toward development of solid acid catalysts and evaluating their
catalytic activity for the synthesis of organic compounds,30ꢀ32 nanoꢀtitaniaꢀsupported sulfonic
acid20 and nanoꢀWO3ꢀsupported sulfonic acid21 as novel and efficient nanocatalysts were
recently reported. On the basis of the informations obtained from the above mentioned
studies, in this context, catalytic activity of nanoꢀZrO2ꢀsupported sulfonic acid as a highly
efficient, low cost, heterogeneous, reusable and inexpensive solid acid nanocatalyst was
examined in multicomponent reactions for the synthesis of heterocyclic compounds such as
hexahydroquinoline, 1,8ꢀdioxoꢀdecahydroacridine, polyhydroquinoline and 1,8ꢀdioxoꢀ
octahydroxanthene derivatives. The structures of the some final products were well
characterized by using spectral (IR, 1H NMR, 13C NMR) data.
3.2.1. Synthesis of hexahydroquinoline derivatives
Quinolines having a 1,4ꢀdihydropyridine nucleus are very important compounds because of
their pharmacological properties. These compounds have wide applications in medicinal
chemistry, being used as antimalarial, antiꢀinflammatory, antiasthamatic, antibacterial
antihypertensive, and tyrosine kinase inhibiting agents.33ꢀ35 In recent years, several methods
have been reported for the synthesis of hexahydroquinolines using of a variety of catalysts
and reagents.36ꢀ38
However, many of these methods suffer from disadvantages such as long reaction
times, unsatisfactory yields, harsh reaction conditions, expensive reagents, hazardous and
toxic solvents or tedious workꢀup. Therefore, introduction of efficient and economical
catalysts that solves these drawbacks is desirable. For this purpose, we decided to examine
the applicability of nꢀZrSA in the promotion of the synthesis of hexahydroquinolines. To
study the role of catalyst, the reaction was carried out in catalyst free condition. The obtained
result was not desirable (25%). So, the prepared nanoꢀZrO2ꢀSO3H, was tested for the
synthesis of hexahydroquinolines by multicomponent oneꢀpot reaction between dimedone (1)
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(1 mmol), benzaldehyde (2) (1 mmol), ammonium acetate (3) (1 mmol) and malononitrile (4)
(1 mmol) under solvent free condition as a model reaction (Scheme 2).
Scheme 2. Synthesis of hexahydroquinoline derivatives by nanoꢀZrO2ꢀSO3H.
In order to find the optimal conditions for the synthesis of hexahydroquinoline
derivatives, the central composite design (CCD), one of the most applicable types of response
surface model (RSM), was applied. It has been accepted as a more effective optimization
method in attainment to improved responses via a fitted quadratic model which can be
expressed by following equation:
ꢃ
ꢃ
ꢃ
ꢃ
ꢇ
Y = βꢀ + ꢁ βꢂ Xꢂ + ꢁ ꢁ βꢂꢆ XꢂXꢆ + ꢁ βꢂꢂ Xꢂ
ꢂꢄꢅ
ꢂꢄꢅ ꢆꢄꢅ
ꢂꢄꢅ
In which Y is response, Xi and Xj are independent variables,
βꢀ is the constant model,
βꢂ, βꢂꢂ and βꢂꢆ are coefficients for the linear, quadratic and interaction effects, respectively.
First of all, preliminary experiments were carried out to investigate the appropriate
parameters and to determine the experimental domain. Considering these experiments, the
effects of catalyst amount (X1), temperature (X2), and reaction time (X3) were performed on
reaction yield as response. A fiveꢀlevel CCD of three independent variables with their
corresponding values is shown in Table S1 (in the supporting Information). Based on CCD
method, total number of experiments was found to be 20 which consisted of eight full
factorial points, six axial points and six central points. Conditions of 20 trials companied to
their respective yields are shown in Table S2 (in the supporting Information).
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The analysis of variance (ANOVA) performed on the model can give valuable
information on the significance of fitted model and its terms. From the ANOVA, as shown
in Table 2, pꢀvalues of model and lack of fit are lower and higher than 0.05, respectively
which means that, fitted model is significant at a confidence level of 95% and it does not
require to reduce to lower orders. Also, the amounts of Rꢀsquared and adj Rꢀsquared are
above 0.9 and close to each other which indicates fitted model has high accuracy and
reliability in prediction of the reaction yield. In other words, there is a good agreement
between experimental and the predicted responses which confirms the suitability of the
following fitted model in terms of significantly linear, quadratic and interaction terms on the
basis of their pꢀvalues.
Y = −544.56 + 21.00Xꢅ + 5.59Xꢇ + 14.23Xꢈ + 0.04XꢅXꢇ − 0.55Xꢅꢇ − 0.03Xꢇꢇ − 0.37Xꢈꢇ
Table 2. The results of ANOVA in CCD for the synthesis of 2ꢀaminoꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ4ꢀphenylꢀ1,4,5,6,7,8ꢀ
hexahydroquinolineꢀ3ꢀcarbonitrile.
Sum of
Squares
4188.54
713.91
43.42
Mean
Square
465.39
713.91
43.42
F
pꢀvalue
Prob > F
< 0.0001
< 0.0001
0.0059
Source
df
Value
129.79
199.09
12.11
342.53
5.09
Model
X1ꢀCatalyst amount
X2ꢀTemperature
X3ꢀTime
9
1
1
1
1228.25
18.24
1228.25
18.24
< 0.0001
0.0477
X1X2
1
X1X3
8.86
1
8.86
2.47
0.1470
X2X3
0.097
1
1
1
1
10
5
5
19
0.097
0.027
316.34
37.75
341.40
0.8728
< 0.0001
0.0001
2
X12
1134.36
135.38
1224.22
35.86
24.67
11.19
1134.36
135.38
1224.22
3.59
4.93
2.24
X22
X3
< 0.0001
Residual
Lack of Fit
Pure Error
Cor Total
R2= 0.99
2.20
0.2030
4224.40
AdjꢀR2= 0.98
PredꢀR2= 0.95
It can be realized from response equation that the X1 has a more linear effect on the
product yield, so the amount of catalyst can be considered as the main factor in progressing
of the reaction.
In order to investigate the main interaction effects between two parameters on the
yield of reaction, threeꢀdimensional profiles of yield versus a pair of parameters were applied
15

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(Fig. 7). According to their pꢀvalues, interaction of X1X2 is significant; it means that
simultaneous increment of the catalyst amount and reaction temperature cause to increase the
product yield until 0.020 g of the catalyst and 100 ºC of reaction temperature. While, higher
loading of the catalyst and also the temperature, not only did not improve the yield to a higher
extent, but also decreased the product yields most probably due to the formation of
undesirable byꢀproducts.
Fig. 7. Three dimensional response surfaces for the effect of factors on the reaction yield.
The main goal of this design was to optimize and maximize the yield of the reaction
corresponded to the conditions of an experiment in which the response equation was
maximized. In this work, determination of optimal conditions was done with the aid of
desirability function by using DesignꢀExpert 7.0.0. It was fistly selected desired goals for
each factor and for response to obtain the maximum product yield with high desirability
function (close to one). Then, conditions possessing high desirability were tested three times.
Negligible difference between the average yields and the prediction values of software,
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confirms the high accuracy and precision of optimum conditions.The results showed that
0.020 g of the catalyst, 100 ºC reaction temperatures, and 16 min reaction time were the
optimum conditions for the synthesis of 2ꢀaminoꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ4ꢀphenylꢀ1,4,5,6,7,8ꢀ
hexahydroquinolineꢀ3ꢀcarbonitrile.
To compare the efficiency of the solventꢀfree versus solvent conditions, the model
reaction was performed under optimum condition. The results showed that higher yield and
shorter reaction time were obtained when the reaction was carried out under solventꢀfree
condition.
After optimizing the conditions, the generality of method was successfully studied by
using various aromatic aldehydes (including aldehydes with electronꢀreleasing substituents,
electronꢀwithdrawing substituents and halogens on the aromatic ring) and cyclic 1,3ꢀdiketone
compounds. The obtained results are summarized in Table 3.
Table 3. Synthesis of hexahydroquinoline derivatives by nanoꢀZrO2ꢀSO3Ha.
Time
(min)
Yieldb
(%)
Melting point
(ºC)
Literature m. p.
(ºC)
Entry
Ar
R1= R2 Product
1
2
ꢀC6H5
oꢀClꢀC6H4
H
15
13
15
14
23
25
15
13
16
22
22
14
12
14
12
14
25
18
90
91
93
93
89
87
91
93
94
91
90
93
94
95
95
94
90
92
256ꢀ259
286ꢀ288
288ꢀ289
285ꢀ286
258ꢀ260
275ꢀ278
242ꢀ243
259ꢀ262
234ꢀ237
>300
257 36
286 36
5a
H
5b
3
pꢀClꢀC6H4
H
289 36
5c
4
pꢀFꢀC6H4
H
286 36
5d
5
pꢀH3CꢀC6H4
pꢀH3COꢀC6H4
mꢀO2NꢀC6H4
pꢀO2NꢀC6H4
ꢀC6H5
H
258 36
5e
6
H
278 36
5f
7
H
243 36
5g
8
H
260 36
5h
9
CH3
275ꢀ277 37
294ꢀ295 37
289ꢀ293 37
282ꢀ283 38
273ꢀ276 37
290ꢀ291 38
299ꢀ300 38
295ꢀ296 38
>300 38
6a
10
11
12
13
14
15
16
17
18
pꢀH3CꢀC6H4
pꢀH3COꢀC6H4
mꢀO2NꢀC6H4
oꢀClꢀC6H4
CH3
6b
CH3
287ꢀ290
280ꢀ284
273ꢀ275
288ꢀ291
298ꢀ301
295ꢀ297
>300
6c
CH3
6d
CH3
6e
pꢀClꢀC6H4
CH3
6f
pꢀFꢀC6H4
CH3
6g
pꢀBrꢀC6H4
CH3
6h
pꢀ(CH3)2NꢀC6H4
2,6ꢀCl2ꢀC6H3
CH3
6i
CH3
>300
>300 38
6j
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), 4 (1 mmol), nꢀZrSA (0.020 g) under solventꢀfree
condition at 100 °C.
bIsolated yield.
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The present method not only affords the products in excellent yields but also avoids
the problems associated with catalyst cost, handing, safety and pollution.
As indicated in Table 3, the reaction works easily for a vast variety of aromatic
aldehydes with both electronꢀdonating and electronꢀwithdrawing groups and different cyclic
diꢀketones to give corresponding hexahydroquinoline derivatives in good to excellent yields.
In almost all cases, the reactions proceeded smoothly within 12ꢀ25 minutes.
3.2.2. Synthesis of 1,8-dioxo-decahydroacridine derivatives
As acridines and their fused derivatives are important heterocycles that are known to possess
multiple biological activities,39 vasorelaxing,40 antiꢀviral41 and other applications, it was
decided to develop the catalytic activity of nanoꢀZrO2ꢀSO3H by investigating their synthesis.
For this purpose, 1,8ꢀdioxoꢀdecahydroacridines was synthesized by condensation between
dimedone (1) (2 mmol), benzaldehyde (2) (1 mmol) and ammonium acetate (3) (1 mmol)
under solvent free conditions as a model reaction (Scheme 3).
Scheme 3. Synthesis of 1, 8ꢀdioxoꢀdecahydroacridine derivatives by nanoꢀZrO2ꢀSO3H.
Due to the effect of nꢀZrSA, the synthesis of 1,8ꢀdioxoꢀdecahydroacridine was studied
in catalyst free condition which the obtained result illustrate that the yield was low (8%). The
activity of nꢀZrSA is compared with the nanoꢀZrO2. The obtained results showed that the nꢀ
ZrSA (91%, yield) was a more suitable option rather than the nanoꢀZrO2 (6%, yield).
To examine the limitation and the scope of the reaction, the synthesis of different 1,8ꢀ
dioxoꢀdecahydroacridine derivatives have been investigated. The obtained results are
summarized in Table 4.
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Table 4. Synthesis of 1,8ꢀdioxoꢀdecahydroacridines by nanoꢀZrO2ꢀSO3H.
Yieldb
(%)
Literature m. p.
Melting Point
Time
(min)
Entry
Ar
R1=R2 Product
(ºC)
(°C)
1
2
ꢀC6H5
pꢀClꢀC6H4
H
50
45
45
55
65
60
45
45
55
60
52
40
40
38
40
35
37
50
50
89
92
91
87
84
86
93
91
88
86
89
93
93
92
92
94
93
88
89
280ꢀ282
295ꢀ297
310ꢀ312
254ꢀ256
304ꢀ305
302ꢀ304
280ꢀ282
290ꢀ291
274ꢀ276
307ꢀ308
269ꢀ270
292ꢀ294
299ꢀ302
221ꢀ224
308ꢀ311
312ꢀ314
282ꢀ284
358ꢀ359
264ꢀ267
279ꢀ280 42
297ꢀ298 42
310ꢀ312 42
255ꢀ257 42
303ꢀ305 42
303ꢀ305 42
282ꢀ284 42
290ꢀ291 42
276ꢀ278 42
303ꢀ305 42
269ꢀ271 43
292ꢀ294 43
298ꢀ300 42
220ꢀ222 43
313ꢀ315 43
290ꢀ292 43
293ꢀ295 43
265ꢀ267 43
220ꢀ222 43
7a
H
7b
3
pꢀBrꢀC6H4
H
7c
4
pꢀH3CꢀC6H4
pꢀHOꢀC6H4
pꢀH3COꢀC6H4
mꢀO2NꢀC6H4
ꢀC6H5
H
7d
5
H
7e
6
H
7f
7
H
7g
8
CH3
8a
9
pꢀH3COꢀC6H4
pꢀHOꢀC6H4
pꢀH3CꢀC6H4
pꢀFꢀC6H4
CH3
8b
10
11
12
13
14
15
16
17
18
19
CH3
8c
CH3
8d
CH3
8e
pꢀClꢀC6H4
CH3
8f
oꢀClꢀC6H4
CH3
8g
pꢀBrꢀC6H4
CH3
8h
pꢀO2NꢀC6H4
mꢀO2NꢀC6H4
2ꢀNaphtaldehyde
pꢀ(CH3)2NꢀC6H4
CH3
8i
CH3
8j
CH3
8k
CH3
8l
a Reaction condition: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), nꢀZrSA (0.027 g) in solvent free conditions at 100 °C.
b Isolated yield.
As indicated in Table 4, the new conditions are very suitable for a vast variety of
aromatic aldehydes with both electronꢀdonating and electronꢀwithdrawing groups to give
corresponding 1,8ꢀdioxoꢀdecahydroacridine derivatives in good to excellent yields. In nearly
all cases, the reactions proceeded smoothly within 35ꢀ65 minute. However, it is notable that
substituted aromatic aldehydes with electronꢀwithdrawing groups increase the rate of reaction
(Table 4, entries 2, 3, 7, 12ꢀ17) probably by activating the carbonyl group as electrophile
center. Contrarily in the case of electronꢀdonating groups, the reaction was more slowly
(Table 4, entries 4ꢀ6 and 9-11).
3.2.3. Synthesis of polyhydroquinoline derivatives
The synergistic use of solid acid catalyst and MCRs allows efficient synthesis of diverse Nꢀ
containing heterocycles. Among these compounds, polyhydroquinoline and 1,4ꢀ
dihydropyridines (1,4ꢀDHPs) attracted immense attention because of their wide
pharmaceutical activity range acting, for example, as vasodilator, bronchodilator,
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antiatherosclerotic, antitumour, antidiabetic, geroprotective, and hepatoprotective agents,
HIV protease inhibition and most importantly as calcium channel blockers.44, 45
Synthesis of polyhydroquinolines was performed by three component condensation
between dimedone (1) (1 mmol), benzaldehyde (2) (1 mmol), ammonium acetate (3) (1
mmol) and ethylacetoacetate (9) (1 mmol) with 0.019 g of nꢀZrSA at 100 ºC under solvent
free condition as a model reaction (Scheme 4).
Scheme 4. Synthesis of polyhydroquinoline derivatives by nanoꢀZrO2ꢀSO3H.
According to the low yield of the product reaction under catalyst free conditions
(22%), the catalytic activity of nꢀZrSA was compared with the nanoꢀZrO2. The obtained
results showed that the nꢀZrSA (94%, yield) was a more suitable option rather than the nanoꢀ
ZrO2 (18%, yield). To examine the versatility of the optimum reaction conditions and its
tolerance of functional groups on the hantzsch reaction, the synthesis of different
polyhydroquinolines have been examined. The obtained results are summarized in Table 5.
Table 5. Synthesis of polyhydroquinolines by nanoꢀZrO2ꢀSO3Ha.
Time
(min)
Yieldb
(%)
Melting Point
(ºC)
Literature m. p.
(ºC)
Entry
Ar
R1, R2
Product
240ꢀ242 46
1
2
ꢀC6H5
H
H
37
42
45
33
32
50
30
32
30
35
30
32
91
93
94
91
86
84
90
89
89
94
96
94
239ꢀ241
242ꢀ244
192ꢀ194
244ꢀ245
236ꢀ237
220ꢀ221
191ꢀ193
199ꢀ201
203ꢀ204
210ꢀ211
203ꢀ205
170ꢀ171
10a
10b
10c
10d
10e
10f
241ꢀ242 47
193ꢀ195 47
243ꢀ244 47
234ꢀ235 47
220ꢀ222 47
190ꢀ191 47
198ꢀ200 47
204ꢀ20547
202ꢀ204 46
207ꢀ208 48
182ꢀ184 48
pꢀH3CꢀC6H4
pꢀH3COꢀC6H4
pꢀFꢀC6H4
3
H
4
H
5
pꢀClꢀC6H4
pꢀHOꢀC6H4
oꢀO2NꢀC6H4
mꢀO2NꢀC6H4
pꢀO2NꢀC6H4
ꢀC6H5
H
6
H
7
H
10g
10h
10i
8
H
9
H
10
11
12
CH3
CH3
CH3
11a
11b
11c
oꢀO2NꢀC6H4
mꢀO2NꢀC6H4
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202ꢀ203 48
208ꢀ209 46
245ꢀ247 46
184ꢀ186 48
250ꢀ251 48
232ꢀ234 46
258ꢀ259 46
260ꢀ262 48
263ꢀ264 46
244ꢀ246 46
247 46
13
14
15
16
17
18
19
20
21
22
23
25
26
27
pꢀO2NꢀC6H4
oꢀClꢀC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H, Ph
H, Ph
H, Ph
28
30
30
30
30
45
45
40
45
30
50
35
40
32
96
94
95
95
95
89
90
91
89
90
88
93
88
92
207ꢀ209
207ꢀ209
243ꢀ245
180ꢀ181
250ꢀ251
232ꢀ233
255ꢀ256
283ꢀ284
263ꢀ265
243ꢀ245
246ꢀ248
213ꢀ215
236ꢀ238
190ꢀ192
11d
11e
11f
pꢀClꢀC6H4
pꢀFꢀC6H4
11g
11h
11i
pꢀBrꢀC6H4
pꢀHOꢀC6H4
pꢀH3COꢀC6H4
pꢀH3CꢀC6H4
pꢀ(CH3)2NꢀC6H4
2,6ꢀDiClꢀC6H3
2ꢀHOꢀ5ꢀBrꢀC6H3
ꢀC6H4
11j
11k
11l
11m
11n
12a
12b
12c
213ꢀ215 46
236ꢀ238 46
190ꢀ192 46
pꢀH3COꢀC6H4
pꢀClꢀC6H4
a Reaction condition: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), 9 (1 mmol), nꢀZrSA (0.019 g) as catalyst under
solventꢀfree conditions at 100 °C.
b Isolated yields.
As indicated in Table 5, the nꢀZrSA catalyzed Hantzsch reaction very suitable for
synthesis of a vast variety of polyhydroquinoline derivatives by condensation between
different aromatic aldehydes with both electronꢀdonating and electronꢀwithdrawing groups
and cyclic diꢀketones to give corresponding product in good to excellent yields.
3.2.4. Synthesis of 1,8-dioxo-octahydroxanthene derivatives
Xanthenes, especially dioxoꢀoctahydroxanthenes have developed as a powerful tool in
organic synthesis due to their broad applications in different fields.49ꢀ51 In recent years,
several methods have been reported for the synthesis of octahydroxanthenes using of a
variety of catalysts and reagents.49, 52, 53
The synthesis of 1,8ꢀdioxoꢀoctahydroxanthene derivatives was studied by
condensation between dimedone (1) (2 mmol) and benzaldehyde (2) (1 mmol) under solvent
free condition as a model reaction (Scheme 5). In order to explore the efficiency of nꢀZrSA,
the model reaction was carried out under the catalyst free conditions and compared with nꢀ
ZrSA and nanoꢀZrO2. The obtained results showed higher yield for nꢀZrSA (94%, yield)
compared to catalyst free (21%, yield) and the nanoꢀZrO2 (25%, yield).
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Scheme 5. Synthesis of 1,8ꢀdioxoꢀoctahydroxanthene derivatives by nanoꢀZrO2ꢀSO3H.
The scope of octahydroxanthenes synthesis in presence of nanoꢀZrO2ꢀSO3H was
successfully studied by using various aromatic aldehydes (including aldehydes with electronꢀ
releasing substituents, electronꢀwithdrawing substituents and halogens on the aromatic ring)
and cyclic 1,3ꢀdiketone compounds. The results are summarized in Table 6.
Table 6. Synthesis of 1,8ꢀdioxoꢀoctahydroxanthene derivatives by nanoꢀZrO2ꢀSO3Ha.
Time Yieldb
Melting point
(ºC)
Literature m. p.
(ºC)
Entry
Ar
R1
R2
Product
(h)
2.1
2.1
2.2
1.8
1.7
2
(%)
92
88
87
93
90
94
88
89
90
86
94
93
90
94
92
95
84
90
84
90
89
89
91
1
2
ꢀC6H5
pꢀH3CꢀC6H4
pꢀH3COꢀC6H4
pꢀO2NꢀC6H4
pꢀBrꢀC6H4
H
H
H
213ꢀ215
244ꢀ246
190ꢀ191
234ꢀ236
222ꢀ225
203ꢀ204
230ꢀ232
212ꢀ214
242ꢀ244
246ꢀ247
206ꢀ207
237ꢀ239
264ꢀ267
244ꢀ245
168ꢀ169
222ꢀ224
256ꢀ258
234ꢀ236
268ꢀ271
196ꢀ198
234ꢀ236
204ꢀ208
212ꢀ215
213ꢀ215 21
244ꢀ246 21
190ꢀ191 21
234ꢀ236 21
222ꢀ225 21
205ꢀ206 54
230ꢀ232 21
220ꢀ222 52
250ꢀ251 52
246ꢀ248 55
208ꢀ209 55
236ꢀ237 52
263ꢀ265 56
246ꢀ248 55
167ꢀ168 54
229ꢀ230 52
256ꢀ258 21
234ꢀ235 21
268ꢀ271 21
196ꢀ198 21
234ꢀ236 21
204ꢀ208 21
212ꢀ215 21
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
14f
H
3
H
H
4
H
H
5
H
H
6
ꢀC6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
7
oꢀH3CꢀC6H4
pꢀH3CꢀC6H4
pꢀH3COꢀC6H4
pꢀHOꢀC6H4
pꢀFꢀC6H4
2.1
2.2
2.2
2.3
1.6
1.6
1.7
1.8
1.8
1.7
2.3
2.1
2.3
2.1
2.2
2.2
1.9
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
pꢀClꢀC6H4
14g
14h
14i
pꢀBrꢀC6H4
oꢀO2NꢀC6H4
mꢀO2NꢀC6H4
pꢀO2NꢀC6H4
C6H5ꢀCH=CHꢀ
2ꢀNaphtaldehyde
2ꢀOHꢀ5ꢀBrꢀC6H3
ꢀC6H5
14j
14k
14l
14m
14n
15a
15b
15c
15d
pꢀClꢀC6H4
H
Ph
pꢀH3CꢀC6H4
pꢀH3COꢀC6H4
H
Ph
H
Ph
aReaction conditions: cyclicꢀdiketone (2 mmol), aromatic aldehyde (1 mmol), nꢀZrSA (0.039 g) under solventꢀ
free conditions at 100 °C.
bIsolated yield.
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As showed in Table 6, fortunately the new catalyst also works very well for a vast
variety of 1,8ꢀdioxoꢀoctahydroxanthene derivatives.
3.2.5. Reusability of the nano-ZrO2-SO3H
For practical applications of this new heterogeneous solid acid nanocatalyst, the level of
reusability was also tested. The recycled catalyst could be reused for at least five times with
no appreciable decrease in yield (Fig. 8). It signified that the nature of the catalyst remains
intact after each run and SO3H moiety was tightly anchored with nanoꢀZrO2, probably
through a covalent linkage.
Fig. 8. Reusability of nanoꢀZrO2ꢀSO3H
4. Conclusion
In summary, for the first time, the preparation and characterization of nꢀZrO2ꢀSO3H as an
active and efficient heterogeneous acidic nanocatalyst was described. The catalytic activity of
the catalyst was probed through the synthesis of hexahydroquinoline, 1,8ꢀdioxoꢀ
octahydroacridine, polyhydroquinoline and 1,8ꢀdioxoꢀoctahydroxanthene derivatives by a
oneꢀpot multicomponent reactions strategy under solventꢀfree conditions. All the reactions
work easily for a variety of aldehydes with both electronꢀdonating and electronꢀwithdrawing
groups to give corresponding products in excellent yields. The catalyst was reused for five
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consecutive cycles with consistent activity. Easy preparation and separation, high reusability
and excellent catalytic performance are the main superiorities of the synthesized catalyst.
Acknowledgements
We gratefully acknowledge the department of chemistry of Semnan University for supporting
this work.
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Graphical Abstract
Nano-zirconia-supported sulfonic acid as a novel, highly efficient and recyclable
heterogeneous nanocatalyst is reported for the synthesis of multicomponent reactions