Synthesis and characterization of nanocrystalline hydroxyapatite and its catalytic behavior towards synthesis of 3,4-disubstituted isoxazole-5(4H)-ones in water

Article abstract of DOI:10.1002/aoc.5118

In the present work, the nanocrystalline particles of hydroxyapatite (HAp) using an easy alkoxide-based sol–gel technique including triethyl phosphate [PO (OC₂H₅)₃] and Ca (NO₃)₂·4H₂O as P and Ca precursors have been synthesized. The sample characterization was performed by X-ray diffraction, Fourier transform-infrared analysis, scanning electron microscopy, thermal analysis (thermogravimetric analysis/differential thermal analysis), and elemental analysis of energy-dispersive X-ray analysis. It is interesting that single phase of HAp was obtained at a low firing temperature of 500°C. Modified Scherrer equation as the Williamson?Hall method was applied for the measurement of crystallite size distributions and micro-strain of the sample. The determined crystallite size by complementary technique of transmission electron microscopy has good consistency with those obtained from the Scherrer formula. Moreover, we reported the one-pot synthesis of 3,4-disubstituted isoxazole-5(4H)-ones through the aqueous solution reaction of three components of ethyl acetoacetate, hydroxylamine hydrochloride and various aromatic aldehydes at room temperature. This protocol offers several advantages, including a simple work-up procedure, very short reaction times (under 25?min), in accordance with the principles of green chemistry, recyclability, excellent yields (87–98%) and environmentally friendly.

Full text of DOI:10.1002/aoc.5118

Received: 18 April 2019
DOI: 10.1002/aoc.5118
Revised: 13 June 2019
Accepted: 22 June 2019
F U L L P A P E R
Synthesis and characterization of nanocrystalline
hydroxyapatite and its catalytic behavior towards synthesis
of 3,4‐disubstituted isoxazole‐5(4H)‐ones in water
Behrooz Maleki1
| Mohammad Chahkandi1 | Reza Tayebee1
|
Sepideh Kahrobaei1 | Heshmatollah Alinezhad2
| Saba Hemmati3
1 Department of Chemistry, Hakim
In the present work, the nanocrystalline particles of hydroxyapatite (HAp)
using an easy alkoxide‐based sol–gel technique including triethyl phosphate
[PO (OC2H5)3] and Ca (NO3)2·4H2O as P and Ca precursors have been synthe-
sized. The sample characterization was performed by X‐ray diffraction, Fourier
transform‐infrared analysis, scanning electron microscopy, thermal analysis
(thermogravimetric analysis/differential thermal analysis), and elemental anal-
ysis of energy‐dispersive X‐ray analysis. It is interesting that single phase of
HAp was obtained at a low firing temperature of 500°C. Modified Scherrer
equation as the Williamson−Hall method was applied for the measurement
of crystallite size distributions and micro‐strain of the sample. The determined
crystallite size by complementary technique of transmission electron micros-
copy has good consistency with those obtained from the Scherrer formula.
Moreover, we reported the one‐pot synthesis of 3,4‐disubstituted isoxazole‐
5(4H)‐ones through the aqueous solution reaction of three components of ethyl
acetoacetate, hydroxylamine hydrochloride and various aromatic aldehydes at
room temperature. This protocol offers several advantages, including a simple
work‐up procedure, very short reaction times (under 25 min), in accordance
with the principles of green chemistry, recyclability, excellent yields (87–98%)
and environmentally friendly.
Sabzevari University, Sabzevar 96179‐
76487, Iran
2 Faculty of Chemistry, University of
Mazandaran, P.O. Box, 47416‐95447
Babolsar, Iran
3 Department of Chemistry, Payame Noor
University, Tehran, Iran
Correspondence
Behrooz Maleki and Mohammad
Chahkandi, Department of Chemistry,
Hakim Sabzevari University, Sabzevar
96179‐76487, Iran.
Email: b.maleki@hsu.ac.ir; m.
chahkandi@hsu.ac.ir
Funding information
Hakim Sabzevari University
KEYWORDS
3,4‐disubstituted isoxazole‐5(4H)‐ones, green chemistry, nanocrystalline hydroxyapatite, sol–gel,
Williamson–Hall
1 | INTRODUCTION
crystallite size,[4] causing little or no bioresorption and
catalytic activity. The main driving force of crystallization
Because of its compatible structure to natural hard tissues,
hydroxyapatite (HAp) has been known as a Ca−P
bioceramic. Moreover, synthetic HAp has been used as
an important material of bone substitute and implant
fabrication for a long time.[1–3] Generally, higher tempera-
ture processes (e.g. calcination) increase crystallinity and
decreases the surface free energy, which leads to smaller
amorphous particles along with reducing the sintering
temperature to make the apatite nanocrystallites.[5] In
order to prepare HAp with the desired applications, some
of its properties, like structural composition, solubility
and particle size, should be controlled.[6–9] The sol–gel
Appl Organometal Chem. 2019;e5118.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5118

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MALEKI ET AL.
technique has remarkable advantages, such as high prod-
uct purity, low temperature of thermal treatment and
homogeneous molecular mixing, and has been applied as
a routine process for the generation of HAp and other dif-
ferent Ca−Ps.[6] The low‐temperature method produces
the nano‐to‐submicron crystallites with higher catalytic
activity.[10]
Over recent decades, chemical industries and pro-
cesses have been remarkably advanced. However,
chemical industries have a very destructive impact on
human life, the environment and animals. Therefore,
the elimination of harmful chemical processes or at least
the reduction of them has become popular within chem-
ical research, and so green chemistry has found a special
place among chemists. In fact, green chemistry is a term
given to 12 principles, and following these principles
makes a process and its reactions environmentally
friendly and healthy performing, reduces the risk of toxic
substances, lowers energy consumption, and enhances
the efficiency up to a maximum.[11–13]
phthalate (KHP),[47] 2‐hydroxy‐5‐sulfobenzoic acid (2‐
HSBA),[48] Dowex1‐x8OH resin,[49] montmorillonite
K10 supported SnII composite (SnII‐MontK10),[50] and
imidazole.[51] However, most of the techniques and
methods mentioned above have limitations and prob-
lems, i.e. using expensive catalysts, stringent reaction
conditions, strongly acidic or basic conditions, the use of
toxic reagents, cost‐effectiveness, long reaction times
and low products yields, which are not eco‐friendly and
are also less efficient. Therefore, we reported in this pro-
tocol a green, efficient and environmental synthesis of
3,4‐disubstituted isoxazole‐5(4H)‐ones by HAp nanoparti-
cles as an efficient and recyclable nanocatalyst at room
temperature (R.T.).
2 | EXPERIMENTAL
2.1 | Materials and methods
All commercially available chemicals were purchased
from Merck and Aldrich, and were used without further
purifications, except for benzaldehyde, which was used
as a fresh distilled sample. Analytical thin‐layer chroma-
tography (TLC) for monitoring reactions was performed
using Merck 0.2 mm silica gel 60 F‐254 Al‐plates. Melting
points were determined using an Electrothermal 9100
apparatus. Fourier transform‐infrared (FT‐IR) spectra
were acquired on a Shimadzu FT IR 8400S spectrometer.
1H‐NMR (300 MHz) spectra were obtained using a Bruker
DRX‐300 AVANCE spectrometer in DMSO‐d6 at ambient
temperature. Phase identification of the calcined gel was
executed using an X‐ray diffractometer (XRD, Philips,
X'pert Pro, Cu Kα) at a scanning speed of 1° in 2θ/min
from 10 to 60°. The morphology of calcined HAp
was studied using scanning electron microscopy
(SEM; S 360, Oxford, UK). Thermogravimetric analysis
(TGA)/differential thermal analysis (DTA) measurements
were performed in air using the TGA2950 (TA instru-
Hydroxyapatite, one of the most important inorganic
biomaterials, has extensive applications in drug delivery
systems,[14] bone grafts,[15,16] catalysts[17] and adsor-
bents[18] because of its high specific surface area, low
water solubility, availability, low cost and high stability.
Through multi‐component reactions (MCRs), more
than two duplicates are combined in one step, and the
desired products are produced in the shortest time and
the most efficient way. These reactions have advantages,
such as shorter reaction times, higher yields, economics,
and less wastage. In addition, it can be said that virtually
all the reactants participate in the production of products
and it is not necessary to isolate the intermediates, which
is actually consistent with the principles of green
chemistry.[19,20]
Isoxazole and its derivatives have several biological,
pharmacological and chemical properties, and some of
them have been activated in agrochemical compounds.
For example, it can be argued that there is a skeleton of
isoxazole in the merocyanine dyes for optical recording,
non‐linear optical research and some liquid crystalline
materials.[21–23] It also has biological properties, for exam-
ple anti‐obesity,[24] anti‐inflammatory,[25] antifungal,[26]
anticancer,[27] antitumor[28] and antibacterial.[29]
ments, USA). Samples weighing 8.01
0.1 mg were
heated in a platinum sample cell up to 950°C at
10°C/min. Ca, P, O and C elemental analyses were mea-
sured using energy‐dispersive X‐ray analysis (EDX;
Philips PW 2400 X‐Ray Fluorescence Spectrometer).
A number of catalysts used to synthesize such com-
pounds include sulfated polyborate,[30] sodium
saccharin,[31] tetrabutylammonium perchlorate (TBAP)/
sodium oxalate or glycine,[32] Fe2O3 nanoparticles,[33] Ni
(OAc)2·H2O,[34] citric acid,[35] sodium silicate,[36] sodium
benzoate,[37] sodium sulfide,[38] boric acid,[39] potassium
phthalimide (PPI),[40] phthalimide N‐oxyl salts,[41]
Ag/SiO2,[42] DABCO,[43] pyridine,[44] sodium citrate,[45]
N‐bromosuccinimide (NBS),[46] potassium hydrogen
2.2 | HAp sol–gel synthesis and physical
measurement
Firstly, triethyl phosphate [TEP; (C2H5O)3PO; Fluka] was
hydrolyzed for 24 hr at R.T. (the molar ratio of water to
phosphate is fixed at 8). Then, 4 M hydrolyzed TEP
diluted in anhydrous ethanol was added slowly to the
3 M Ca (NO3)2·4H2O (Merck) dissolved in distilled water

MALEKI ET AL.
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(Ca/P = 1.67). The resulting solution (sol) was continu-
ously agitated for 60 min at 80°C, and then the obtained
clear sol was aged at R.T. for 24 hr before drying. The
sample pH values before (~5.6) and during aging (3.9)
were recorded. The aged sol was dried at 150°C until a
white dried gel was obtained. Finally, the dried gel was
put in a tube furnace and subjected to 500°C calcination
temperatures for 2 hr at a constant heat rate of 2°C/min.
The calcined sample was analyzed using FT‐IR spectros-
and microstrain from diffraction data is complicated,
and different indirect methods, for example Williamson
−Hall, should be used.[6,52–54]
2.4 | General procedure for the synthesis
of 3,4‐disubstituted isoxazole‐5(4H)‐ones
A mixture of hydroxylamine hydrochloride (1 mmol,
0.07 g), β‐ketoester (1 mmol) and 0.03 g nanocatalyst
HAp was stirred in 2 ml of water/ethanol (2:1, v/v) for
5 min. Then, aldehyde (1 mmol) was added and the reac-
tion mixture was stirred at R.T. for the indicated times
(20–35 min). After completion of the reaction (as deter-
mined by TLC, n‐hexane:ethyl acetate, 2:1), 2 ml of hot
ethanol was added to the reaction mixture and it was
stirred for 2 min. Then, the reaction mixture was filtered
in hot conditions to separate the catalyst (HAp), was
poured into crushed ice, and the separated solid product
was filtered and recrystallized from ethanol to obtain
pure 3,4‐disubstituted isoxazole‐5(4H)‐ones (4a–o).
copy (Buck 500, KBr) in the range of 500–4000 cm−1
.
Phase identification of the calcined gel (Figure 1) was
executed using an XRD (Philips, X'pert Pro, Cu Kα) at a
scanning speed of 1° in 2θ/min from 10 to 60°.
2.3 | Particle size determination
Direct methods [e.g. transmission electron microscopy
(TEM); Leo 912 AB‐Germany] and indirect methods (e.
g. Scherrer and W‐H equations) were used to determine
the crystalline particle size and microstrain of synthesized
HAp,[6,52] The instrumental line broadening of the sam-
ple was determined by recording the XRD pattern of a
microcrystalline standard quartz powder. TEM was
equipped with a thermionic gun and was operated at
120 kV. Crystallite size can be estimated by the Scherrer
equation using the broadening XRD diffraction peak,
and it depends on some main variables, for example crys-
talline particle size, instrumental effects and inhomoge-
neous strain. Measuring more accurate crystallite size
3 | RESULTS AND DISCUSSION
In continuation of our previous researches on the design
and application of heterogeneous and reusable solid
catalysts in organic synthesis and MCRs,[55–71] here we
report an efficient and green method for the synthesis of
3,4‐disubstituted isoxazole‐5(4H)‐ones catalyzed by HAp
nanoparticles (Scheme 1).
In this study, HAp nanoparticles have been synthe-
sized through a new low‐temperature alcohol‐based sol–
gel method using Ca (NO3)2·4H2O and hydrolyzed TEP,
and used in the synthesis of 3,4‐disubstituted‐isoxazole‐
5(4H)‐4‐ones at R.T.
3.1 | Structural evolution of synthesized
HAp
The advantage of our sol–gel method for HAp synthesis
in comparison to other ones[52–54] is that TEP hydrolysis
(equation 1) accelerates the related polymerization reac-
tion of P and Ca (equation 2). Measuring the pH of the
sol during the aging process shows a remarkable reduc-
tion from ~5.6 to 3.9, which means that the preparation
reaction of amorphous HAp progresses to completion
FIGURE 1 X‐ray diffraction (XRD) patterns of hydroxyapatite
(HAp)
SCHEME 1 Synthesis of 3,4‐
disubstituted isoxazole‐5(4H)‐ones
catalyzed by hydroxyapatite (HAp).

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MALEKI ET AL.
(equation 2). This observation confirms the absence of
impurity phases in XRD pattern (Figure 1).
OP ðOEtÞ3 þ H2O→OP ðOEtÞ3−x ðOHÞx þ xC2H5OH (1)
OP ðOEtÞ3−x ðOHÞx þ Ca2þ
−
þ NO3−→ðNO3Þ ðOHÞ–Ca–O–PO ðOEtÞ3−x þ Hþ
þ C2H5OH þ H2O
(2)
The XRD pattern shows intense peaks of HAp, with
hexagonal unit cell matching the ICDD (No.: 01–084‐
1998) standard having main indices (002), (210) and (211)
(Figure 1).
In order to study the morphology of synthesized HAp,
a SEM image was taken (Figure 2). It shows particles big-
ger than 100 nm that are not in agreement with the TEM
image. Indeed, because of the high surface energy of par-
ticles of gels, the sol–gel method produces very small
particles with low crystallization temperatures (through
the calcination process) that results in remarkable
agglomeration and porosity. The SEM image indicates
high agglomeration of nanoparticles of HAp.
FIGURE 3 Fourier transform‐infrared (FT‐IR) spectrum of fresh
hydroxyapatite (HAp) calcined at 500°C (a); after five runs of
recyclability (b)
The functional groups of particle surface of synthe-
sized HAp can be explored by FT‐IR spectrum. The
spectrum shows bands at 475, 575, 966, 1090–1220 and
3370 cm−1, attributed to stretching modes of phosphate
compared with peaks of recyclable HAp, in terms of posi-
tion and intensity of peaks. As a result, these sites active
(carbonate, phosphate and hydroxyl) on the catalyst are
stable after each run of recyclability.
and O–H functional groups, respectively (Figure 3a).
2−
The stretching band of C=O of the CO3
group at
1660 cm−1 indicates the incorporation of carbonate in
apatite structure that could improve the absorption or
catalytic activity of HAp. To prove that the carbonate,
phosphate and hydroxyl sites on the catalyst are stable
after each run of recyclability, we obtained the FT‐IR
spectrum of HAp after five runs (Figure 3b) and com-
pared with fresh HAp (Figure 3a). The results show the
FT‐IR of recyclable HAp is similar to fresh HAp, and also
there is almost no change after five performance runs
3.2 | Nanostructural examination
Because of high co‐surface energy of their particles, amor-
phous materials could start to crystallize through the low
calcination temperatures, resulting in remarkable poros-
ity and agglomerated particles. The measured Ca/P molar
ratio of 1.70 by elemental analysis of EDX suggested (Ca5)
(PO4)2.82(CO3)0.12(OH)1.3 formula confirming the synthe-
sis of carbonate HAp (Figure 4). EDX results are W/W
%: Ca 37.1%, P 8.9%, O 51.1% and C 2.9%.
The measured crystallite size of HAp by direct TEM
and indirect XRD methods with good consistency shows
a moderate value of about 45–55 nm (Figure 5). The crys-
tallite size via the Scherrer formula (equation 3) can be
determined as:[6,52]
D ¼ Kλ=½W cos ðθÞꢀ
(3)
where K is a constant value of 0.9, λ is the Cu Kα radia-
tion (0.1544 nm), W is the full‐width at half‐maximum,
and θ is the diffraction angle (deg).
It should be considered that the contributions of crys-
tallite size, instrumental effect and micro‐strain єs cause
the peak width of the XRD pattern.[52] For deconvolution
of size and instrumental issues, the more accurate W−H
FIGURE 2 Scanning electron microscopy (SEM) image of
calcined hydroxyapatite (HAp)

MALEKI ET AL.
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FIGURE 4 Energy‐dispersive X‐ray
analysis (EDX) image of hydroxyapatite
(HAp) calcined at 500°C
FIGURE
6
Deconvolution of strain and size effects of
hydroxyapatite (HAp) using the Cauchy approximation by the
Williamson–Hall equation
FIGURE 5 Transmission electron microscopy (TEM) image of
hydroxyapatite (HAp)
method using the Cauchy approximation (equation 4)
was applied:[6,52]
ðW cos θÞ ¼ ðKλ=DÞ þ 4 єs sin θ
(4)
Plotting the W cos θ vs. sin θ, the W−H curve, resulted
in obtaining the crystallite size (D) and єs. Plotting the
related curve for (002), (210), (211), (300) and (310) reflec-
tions of synthesized HAp resulted in D = 49.6 nm and
єs = 4.5 E–4 (Figure 6).
3.3 | Thermal analysis of HAp
FIGURE
7
Thermogravimetric analysis (TGA)/differential
The TGA/DTA analysis of synthesized HAp is shown in
Figure 7. The weight losses occur in four obvious stages.
The first one corresponds to 5% weight loss recorded in
the range of 30–75°C because of OH group presence.
The second and third stages related to the 8% and 18%
weight losses that were recorded at the range of 80–
190°C and 190–415°C due to evaporation of entrapped
thermal analysis (DTA) for dried gel of hydroxyapatite (HAp)
chemisorbed water and apatite phase transformation
from amorphous to the crystalline hexagonal one. The
last region can be attributed to 22.5% weight loss
observed in the range of 415–610°C, due to

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MALEKI ET AL.
decomposition of impurities like carbonates. DTA shows
some endothermic peaks at temperatures of 146.4, 245.3,
587.8, 627.5 and 684.4°C, the two first ones can be
assigned to the adsorbed surface water and the last
three correspond to the below suggested Ca–P phase
transformation reaction (Re. 1)
solvents such as ethanol, water and water/ethanol (2:1,
v/v) for this reaction, with various amounts of HAp cata-
lyst (Table 1, entries 1–5). This investigation revealed that
TABLE 2 Synthesis of 3,4‐disubstituted isoxazole‐5(4H)‐ones
(4a–o) catalyzed by HAp (0.03 g) in water/ethanol (2:1, v/v) at R.T.
m.p. (°C)
Yielda Time
(%)
1=2Ca2P2O7 þ Ca3ðPO4Þ2 þ Ca ðNO3Þ2 þ CaCO3
þ 1=2H2O →Ca5ðPO4Þ3ðOHÞ þ CaO þ 2NO2
Entry Products
4a
(min) Found Lit.
þ CO2 þ 1=2O2
(Re1)
98
20
20
25
140–141 141–142[37]
It should be considered that there are two exothermic
peaks at 272.6°C and 335.2°C relating to the crystalliza-
tion process of amorphous to crystallized apatite phases.
4b
4c
96
91
173–174 173–174[34]
137–138 137–139[48]
3.4 | Performance of HAp nanoparticles
in preparation of 3,4‐disubstituted
isoxazole‐5(4H)‐ones
4d
95
25
199–200 200–201[37]
After preparing and characterizing the catalyst, we used it
in the synthesis of 3,4‐disubstituted isoxazole‐5(4H)‐ones.
For this reason, initially, the reaction of benzaldehyde
(1 mmol), hydroxylamine hydrochloride (1 mmol) and
ethyl acetoacetate (1 mmol) in the presence of HAp was
chosen as a model of reaction. The effects of the amounts
of catalyst and solvents were investigated. The results are
summarized in Table 1. We also screened a variety of
4e
4f
90
87
25
35
220–221 220–221[29]
199–201 198–200[37]
4g
4h
4i
85
95
95
25
25
20
149–150
–
TABLE 1 Optimization of reaction conditions
212–214 210–211[37]
133–135 134–136[36]
Catalyst
Entry (g)
Time Yielda
(min) (%)
4j
90
88
90
25
25
25
143–144 143–145[31]
238–240 239–241[37]
178–179 178–179[39]
Conditions
1
2
3
4
5
6
7
HAp
(0.03 g)
Water/R.T.
20
90
4k
4l
HAp
(0.03 g)
Ethanol/R.T.
20
32
HAp
(0.03 g)
Water/ethanol (2:1, v/v)/ 20
98
R.T.
HAp
(0.02 g)
Water/ethanol (2:1, v/v)/ 20
R.T.
70
4m
89
20
214–216 213–215[37]
HAp
(0.04 g)
Water/ethanol (2:1, v/v)/ 20
R.T.
93
4n
4o
92
91
20
20
169–170 168–170[37]
183–184 182–183[31]
HAp
(0.03 g)
Solvent‐free/R.T.
40
trace
trace
b
–
Water/ethanol (2:1, v/v)/ 20
R.T.
aIsolated yield.
bThis reaction was carried out in the absence of HAp.

MALEKI ET AL.
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the reaction in water/ethanol (2:1, v/v) resulted in the
best reaction time and yield (entry 3). Furthermore, the
reaction using HAp as catalyst under solvent‐free condi-
tions gave a trace yield, even after prolonged reaction
time (entry 6). It was observed that in the absence of
HAp catalyst, the reaction led to only trace amounts
of 4‐benzylidene‐3‐methylisoxazol‐5(4H)‐one (4a) after
20 min at R.T. (entry 7).
proved to be good substrates and reacted smoothly. How-
ever, the aryl aldehydes with the electron‐donating
group at the ortho‐position, such as 2‐methoxy and
2‐hydroxybenzaldehyde, afforded longer times and low
yields probably due to the steric hindrance effects (entries
4c, 4f). Also, the scope of the reaction has been studied
with more dicarbonyl (4m–o). It is observed that the reac-
tion gave good yields of products.
HAp, hydroxyapatite; R.T., room temperature.
The reusability of the catalyst was checked using HAp
recovered from the synthesis of 4‐benzylidene‐3‐
methylisoxazol‐5(4H)‐one (4a). It was observed that the
recovered catalyst could be satisfactorily used for five
runs (98%, 96%, 92%, 89% and 87%).
After optimizing the reaction conditions, different
derivatives of 3,4‐disubstituted isoxazole‐5(4H)‐ones
(4a–o) were prepared for the reaction of hydroxylamine
hydrochloride, β‐ketoester with various aryl aldehydes
in the presence of HAp (0.03 g) in water/ethanol (2:1,
v/v) at R.T. The results are shown in Table 2.
The proposed mechanism for the formation of the prod-
ucts is shown in Scheme 2. β‐Ketoester (activated by Ca+2
)
It is found that aromatic substrates with electron‐
donating functional groups afforded good to high yields
of products. Furthermore, the reaction with π‐excessive
heterocyclic aldehydes also preceded smoothly with high
yields in short reaction times (Table 2, entries 4k–l).
These results show that the electron‐withdrawing groups
are not favored under these conditions, whereas aromatic
aldehydes bearing electron‐donating functional groups
reacted with hydroxylamine hydrochloride to afford oxime
intermediate [A]. Thus, the CO32− or PO43− or HO− groups
on HAp deprotonate the oxime intermediate [A] that is
more susceptible for reaction with aromatic aldehydes.
The reaction proceeds via an intermolecular Knoevenagel
adduct [B] followed by dehydration and ring closure,
which is also catalyzed by HAp.
TABLE 3 Comparison of methods for the synthesis of 3,4‐disub-
stituted isoxazole‐5(4H)‐ones
Time Yield
Compounds
Conditions
(min) (%)
HAp/water:ethanol/R.T.
(present work)
20
98
90
4a
Sodium saccharin/water/ 100
R.T.[31]
TBAP/water/R.T.[32]
115
Citric acid/water/R.T.[35] 480
88
90
89
Sodium silicate/water/R.
T.[36]
150
Sodium sulfide/ethanol/R. 150
T.[38]
80
Ag/SiO2/water/R.T.[42]
2‐HSBA/water/R.T.[48]
Nano‐MMT‐Sn/water/us/
30°C[50]
60
110
40
93
87
92
HAp/water:ethanol/R.T.
(present work)
20
75
96
TBAP/water/R.T.[32]
90
90
87
Citric acid/water/R.T.[35] 300
Sodium benzoate/water/R. 90
T.[37]
4b
Ag/SiO2/water/R.T.[42]
2‐HSBA/water/R.T.[48]
Dowex1‐x8OH/water/R.
T.[49]
60
80
60
90
92
95
Imidazole/water/us/
30°C[51]
25
95
SCHEME 2 The proposed mechanism for the synthesis of 3,4‐
disubstituted isoxazole‐5(4H)‐ones catalyzed by hydroxyapatite
(HAp)
2‐HSBA, 2‐hydroxy‐5‐sulfobenzoic acid; HAp, hydroxyapatite; R.T., room
temperature; TBAP, tetrabutylammonium perchlorate.

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MALEKI ET AL.
[2] M. J. Glimcher, Phil. Trans. Royal Soc. B 1984, 304, 479.
In order to demonstrate the merit of HAp catalyst in
[3] M. Vallet‐Regi, J. M. González‐Calbet, Prog. Solid State Chem.
2004, 32, 1.
comparison with other catalysts used for the same reac-
tion, some of the obtained results are tabulated and
compared in Table 3. The results summarized in Table 3
clearly demonstrate the superiority of the present work
in time of reaction, high yields of the products, and reus-
ability of the nanocatalyst.
[4] A. Carradò, N. Viart, Solid State Sci. 2010, 12, 1047.
[5] R. Castro, K. Van Benthem, (Eds.), “Sintering: Mechanisms of
Convention Nanodensification and Field Assisted Processes”
Springer, Berlin Heidelberg, 2013, p. 35.
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phase of synthesized HAp was studied by SEM. Then,
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size was accurately determined. During the aging step,
2446.
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Ca2+ and NO3 ions react with hydrolyzed TEP
−
Org. Prep. Proced. Int. 2018, 50, 288.
resulting in formation of a complex that is stabilized
in the subsequent drying step. Actually, small gel parti-
cles having high surface energy resulted in a low crys-
tallization temperature of 500°C. The Williamson–Hall
plot was used to separate the effect of crystallite size
and microstrain on reflection broadening, which gave
a crystallite size in relatively good agreement with
TEM. These methods show low crystallite size of about
45–50 nm. Also, we have developed highly efficient,
green, and one‐pot three‐components methods for the
synthesis of 3,4‐disubstituted isoxazole‐5(4H)‐ones by
nanoparticle HAp. It is evident from the results that
the reaction in the presence of 0.03 g of catalyst at R.
T. provided the desired products 4a–o with excellent
yields in 20–35 min in water/ethanol (2:1, v/v). The
merits of the described process are simple work‐up,
short reactions times, mild reaction conditions, and
using water as an ecological solvent.
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The authors wish to thank the Hakim Sabzevari Univer-
sity for financial support of this article.
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ORCID
Behrooz Maleki https://orcid.org/0000-0002-0322-6991
Reza Tayebee https://orcid.org/0000-0003-2907-1091
[26] M. M. Santos, N. Faria, J. Iley, S. J. Coles, M. B. Hursthouse, M.
L. Martins, R. Moreira, Bioorg. Med. Chem. Lett. 2010, 20, 193.
Heshmatollah Alinezhad
7189-2961
https://orcid.org/0000-0002-
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S. Synthesis and characterization of nanocrystalline
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