Waste to wealth: conversion of nano-magnetic eggshell (Fe3O4@Eggshell) to Fe3O4@Ca(HSO4)2: cheap, green and environment-friendly solid acid catalyst

Article abstract of DOI:10.1002/aoc.4308

Eggshell is a hazardous waste by European Union regulations, so that discarded thousands of tons per year. To convert waste (eggshell) to wealth (catalyst), nano-magnetic eggshell was prepared based on the nano-Fe₃O₄, and then the eg

Full text of DOI:10.1002/aoc.4308

Received: 17 October 2017
DOI: 10.1002/aoc.4308
Revised: 3 December 2017
Accepted: 4 December 2017
F U L L P A P E R
Waste to wealth: conversion of nano‐magnetic eggshell
(Fe3O4@Eggshell) to Fe3O4@Ca(HSO4)2: cheap, green and
environment‐friendly solid acid catalyst
Ardeshir Khazaei1
| Negin Sarmasti1 | Jaber Yousefi Seyf2
1 Faculty of Chemistry, Bu‐Ali Sina
University, Hamedan 6517838683, Iran
2 Department of Chemical Engineering,
Hamedan University of Technology,
Hamedan, Iran
Eggshell is a hazardous waste by European Union regulations, so that discarded
thousands of tons per year. To convert waste (eggshell) to wealth (catalyst),
nano‐magnetic eggshell was prepared based on the nano‐Fe3O4, and then the egg-
shell was converted to Ca(HSO4)2 with organic acid, namely, chlorosulfonic acid.
Based on the back titration, 5.18 mmol SO4H group was loaded per gram of the
nano‐structure. Using this method eggshell was converted to cheap, green and
environment‐friendly solid acid catalyst. The prepared catalyst (nano‐
Fe3O4@Ca(HSO4)2) was characterized by Fourier transform infrared spectroscopy
(FT‐IR), X‐ray diffraction (XRD), energy dispersive X‐ray spectroscopy (EDX), field
emission scanning electron microscopy (FE‐SEM), transmission electron micros-
copy (TEM), vibrating sample magnetometer (VSM), and thermal gravimetric
analysis (TGA). The activity of eggshell waste‐derived catalysts was successfully
evaluated in the synthesis of value‐added products, namely indazolo[1,2‐b]‐
phthalazinetrione derivatives as a benchmark multicomponent reaction. In addi-
tion, design of experiments shows that increase in amount of catalyst (and temper-
ature), boost the reaction yield, especially with steeper slope at higher temperature.
Correspondence
Ardeshir Khazaei, Faculty of Chemistry,
Bu‐Ali Sina University, Hamedan,
6517838683, Iran.
Email: khazaei_1326@yahoo.com
Funding information
Research Affairs Office of Bu‐Ali Sina
University, Grant/Award Number:
32‐1716
KEYWORDS
environment‐friendly solid acid catalyst, Fe3O4@Eggshell, Fe3O4@Ca(HSO4)2, Waste to wealth
1 | INTRODUCTION
are formed in one‐pot reaction).[12,13] So, MCRs provide a
number of advantages over conventional sequential multi-
Based on the number of participating starting materials,
the reaction in the organic chemistry can be fall in three
main categories, namely: one‐component reactions
(1CR), two‐component reactions (2CR), and one‐pot reac-
tions.[1] Prototypical examples of MCRs are Mannich
3CR,[2] Strecker 3CR,[3,4] Passerini 3CR,[5] Ugi 3CR,[6]
Pauson‐Khand 3CR,[7] Leusen 3CR,[8] Gewald 3CR,[9]
Hantzsch 3CR,[10] Staudinger 3CR.[11] MCRs cover by def-
inition topics such as atom economic, effectiveness, eco‐
friendly, high convergence, reduction of intermediate
steps, reducing time and energy, and a high bond‐
forming‐index (BFI) (several non‐hydrogen atom bonds
step synthesis towards complex and valuable molecules.
One of this MCRs is the synthesis of indazolo[1,2‐b]‐
phthalazinetrione derivatives which are important struc-
tural motif which possess anticonvulsant,[14] cardio-
tonic,[15] and vasorelaxant[16] activities. Although various
catalyst such as Caffeine‐H2SO4,[17] Succinimidinium
Hydrogen Sulfate,[18] β‐Cyclodextrin,[19] encapsulated
phosphotungstic acid nanoparticles,[20] [Et3N‐SO3H]
Cl),[21] β‐Cyclodextrine‐SO3H,[22] Fe3O4@SiO2‐imid‐
PMAn,[23] N,N‐diethyl‐N‐sulfoethanaminium hydrogen
sulfate,[24] succinimidinium N‐sulfonic acid hydrogen sul-
fate,[25] 3‐sulfonic acid 1‐imidazolopyridinium hydrogen
Appl Organometal Chem. 2018;e4308.
wileyonlinelibrary.com/journal/aoc
Copyright © 2018 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4308

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KHAZAEI ET AL.
sulfate,[26] Ca2CuO3/CaCu2O3/CaO,[27] dodecylphosphonic
acid (DPA),[27] [Simp]3PW12O40, Silica sulfuric acid,[28] alu-
their contributions were measured with Energy dispersive
X‐ray analysis (EDXA) (Oxford Instrument). Vibrating
sample magnetometer (VSM), model (MDKB), was used
to determine the magnetic property of catalyst.
mina sulfuric acid,[28] N‐halosulfonamides,[29] H2SO4,
[30]
Fe3O4@GO‐Pr‐SO3H,[30] have been used in the synthesis
of indazolo[1,2‐b]‐phthalazinetrione derivatives, but most
of them are jeopardized due to the relative toxicity of cata-
lyst, use of organic solvents, uneconomical, high reaction
temperature, moderate yield, and others. With regards to
these issues, there have recently been a drift towards the
use of eggshell wastes as catalyst. High quantities of this
solid residue are still disposed as waste in landfills without
any pretreatment. Eggshell based catalyst has been used in
the synthesis of biodiesel, hydrogen/syngas, waste water
treatment, and added‐value compound.[31] In addition,
recently unmodified eggshell[32–39] or modified eggshell
such as eggshell/Fe3O4,[40] eggshell membrane/noble metal
nanoparticles,[41,42] eggshell/Pd,[43] Pd‐Ag/Al2O3 egg-
shell,[44] eggshell/Cu(OH)2[45] has been used in the MCRs.
Calcination and loading of noble metal nano‐particles are
only the modifications which have been reported to con-
vert the eggshell to effective catalyst, so that it is felt that
modification/conversion of eggshell is needed. In addition,
the eggshell should be easily separated from the reaction
media. Bearing this in mind, nano‐Fe3O4@eggshell was
converted to nano‐Fe3O4@Ca(HSO4)2 as a cheap green
and environment‐friendly solid acid catalyst was synthe-
sized from eggshell and used in the synthesis of
indazolo[1,2‐b]‐phthalazinetrione derivatives.
2.2 | Preparation of Fe3O4 Nanoparticles
The co‐precipitation approach was used to synthesize the
magnetic (Fe3O4) nanoparticles.[46] First 11.3 gr
FeCl3.6H2O and 5.6 gr FeCl2.4H2O were dissolved in deion-
ized water at the 80 °C (600 rpm). After complete dissolu-
tion of the FeCl3.6H2O and FeCl2.4H2O, 25 mL ammonia
(28 wt%) was added all at once to the solution. The resulting
black solution was vigorously stirred for 2 hours at 80 °C
and under N2 atmosphere. Then the precipitated magnetic
nanoparticles were separated from the solution using a
magnet. Nanoparticles were washed several times with
water and then with acetone, so that a stable black mag-
netic dispersion was obtained which was dried in an oven.
2.3 | Preparation of eggshell powder
Eggshells were collected at home and washed with warm
tap, and then the adhering membrane was separated
manually. The eggshells were boiled in distilled water
for 2 h and then washed with distilled water. After the
drying of eggshells in an oven (120 °C for 2 h), the size
of the eggshell was reduced using a cutting mill. Eggshells
contain organic impurities that should be removed before
use, so that 100 ml CH2Cl2 was added to the powder and
ultrasound for 2 h. Finally the powder was separated
using filtration and dried in an oven.
2 | EXPERIMENTAL SECTION
2.1 | General Remarks
Ferric chloride hexahydrate (FeCl3·6H2O), ammonia
(28%), ferrous chloride tetrahydrate (FeCl2·4H2O),
Phthalhydrazide, different aldehyde, dimedone, ethanol,
chloroform, acetone, and chlorosulfonic acid were supplied
by Merck company. The reaction progress was monitored
using TLC (silica gel SIL G/UV 254 plates), and the prod-
2.4 | Preparation of Fe3O4@eggshell
1 g of the eggshell powder was added to the 100 ml water
and stirred for 10 min. at room temperature, and then
0.5 g from as‐synthesized nano‐Fe3O4 was added to the
mixture. The mixture was dispersed for 15 min. using
ultrasound and stirred for 2 h at 60 °C. There are two kind
of intermolecular interactions between Fe3O4 and CaCO3,
which are electrostatic, electrostatic‐electrodynamics,
and electrodynamics.[47] The intermolecular interactions
are strong enough to prevent separation of eggshell from
the Fe3O4, so that experimental results confirm this.
Finally the nano Fe3O4@eggshell was filtered and dried
in an oven.
1
ucts were identified using H,13C NMR, IR together with
melting point technique. The corresponding spectral data
have been given Supporting information. The 1H, 13C
NMR (500 MHz) was recorded on a Bruker Avance
DPX‐400 FT‐NMR spectrometer (δ in ppm). Büchi B‐545
apparatus with open capillary tubes and Perkin Elmer
PE‐1600‐FTIR were used to determine the melting point
and Infrared spectrum of products, respectively. Thermal
gravimetric analysis (TGA) of the catalyst under a nitrogen
atmosphere used to determine changes in physical and
chemical properties. Field emission scanning electron
microscopy (FESEM), Transmission electron microscopy
(TEM) images were recorded with SIGMA VP‐500 (ZEISS),
Zeiss‐EM10C‐100 KV, respectively. Elemental analysis and
2.5 | Preparation of Fe3O4@Ca(HSO4)2
1 g Fe3O4@eggshell was dispersed in 100 ml in dried
CH2Cl2 for 15 min (mixture A). Then 0.66 ml
chlorosulfonic acid mixed with 20 ml dried CH2Cl2, and

KHAZAEI ET AL.
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added gently to the mixture A (with stirring) at 0 °C
controlled temperature (Mixture B). The temperature of
mixture B should be at 0 °C until all gases have been
exhausted. Then the mixture B was stirred for 24 h at
room temperature. Finally Fe3O4@Ca(HSO4)2 was sepa-
rated using a magnet, washed several times with dried
CH2Cl2 and dried in an oven. The reaction between
eggshell (CaCO3) and ClSO3H is as ClSO3H
+CaCO3→CaCl2+Ca(HSO4)2+CO2. The exhausted gas
during chlorosulfonic acid addition confirm the genera-
tion of CO2.
FIGURE 1 IR spectra of Fe3O4, eggshell, Fe3O4@eggshell, and
the final catalyst
2.6 | General procedure for the synthesis
of indazolo[1,2‐b]‐phthalazinetrione
derivatives
3.2 | Infrared (IR)
The IR technique was used to identify the presence of
SO4H functional group of the as‐synthesized catalyst
surface. Figure 1 shows the IR spectra of nano‐Fe3O4,
First 1 mmol aldehyde, 1 mmol phthalhydrazide, and
0.8 mmol dimedone, together with 0.05 g as‐synthesized
catalyst was added to a test tube at 110 °C, and solvent
free condition. The progress of the reaction was moni-
tored by thin layer chromatography (TLC), and after the
completion of the reaction, the mixture was dissolved in
20 ml hot chloroform, and the catalyst was separated
using a super magnet. After the evaporation of chloro-
form, product washed with 10 ml ethanol and 10 ml
water, and then dried in an oven.
eggshell,
nano‐Fe3O4@eggshell,
and
nano‐
Fe3O4@Ca(HSO4)2. The IR spectrum of the
Fe3O4@eggshell is a mix of the Fe3O4 and eggshell spectra,
so that the wave numbers related to the eggshell are shown
by vertical magenta dotted rectangles. The wave number
of 1151 cm‐1 is related to the symmetric stretching of
S=O in the –SO4H group. Broad spectrum in 3000‐
3600 cm‐1 indicate the acidic OH of the –SO4H group.
These findings confirm the conversion of eggshell (CaCO3)
on the Fe3O4 surface to Ca(HSO4)2. The First, and second
layers in the as‐synthesized catalyst are Fe3O4, Ca(HSO4)2
groups, respectively. FTIR of the nano‐Fe3O4@Ca(HSO4)2
in the Figure 1 shows that some wave numbers (868, 1411,
and 2522 cm‐1) in the eggshell (represented with pink dot-
ted rectangles) exist in the final catalyst, which implies no
complete reaction between CaCO3 and ClSO3H. This can
be attributed to limited diffusion of ClSO3H to the CaCO3
3 | RESULTS AND DISCUSSION
In the present work, the eggshell was converted to
Ca(HSO4)2 with organic acid, namely chlorosulfonic acid.
Ca(HSO4)2 has been used as a green solid acid catalyst in
conversion of alcohols into N‐substituted amides.[48]
Based on the back titration, 5.18 mmol SO4H group was
loaded per gram of the nano‐structure. Using this method
eggshell was converted to cheap, green and environment‐
friendly solid acid catalyst. The catalytic activity of the as‐
synthesized catalyst was evaluated in the synthesis of
indazolo[1,2‐b]‐phthalazinetrione derivatives.
3.1 | Characterization of the catalyst
To characterize the as‐synthesized catalyst, different tech-
niques were used in the present work, which includes:
Infrared (IR) spectroscopy, Thermal gravimetric analysis
(TGA), Vibrating sample magnetometer (VSM), Energy
dispersive X‐ray analysis (EDXA), Field emission scan-
ning electron microscopy (FESEM), and Transmission
electron microscopy (TEM) images.
FIGURE 2 Magnetization pattern of the nano‐Fe3O4, and nano‐
Fe3O4@Ca(HSO4)2 MNPs

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KHAZAEI ET AL.
particles,[49] with a critical radius (in a radius above the
critical radius, the diffusion is zero).
3.4 | Field Emission Scanning Electron
Microscopy (FESEM) and Transmission
electron microscopy (TEM)
These techniques are useful in the analysis of shape, size
and the morphology of the nono‐particles, and especially
to identify the core/shell structure of the nano‐particles.
The FESEM and TEM images of the as‐synthesized
nano‐Fe3O4@Ca(HSO4)2 are given in the Figure 3. As
one can see from FESEM and TEM images, the geometric
shape of the synthesized particles is spherical. The TEM
image shows an explicit core/shell structure for and the
nano‐Fe3O4@Ca(HSO4)2 nanoparticles. As it is shown in
the Figure 3 d), the as‐synthesized catalyst has two
explicit layers on the core. These layers are attributed to
the unreacted eggshell and the Ca(HSO4)2, so that the
thickness of SO4H layer is less than eggshell layer, and
the density of eggshell layer is less than Fe3O4 cores.
The mean and the standard deviation of the nanoparticles
are 11.3, and 8.7 (nm), respectively. In addition, cumula-
tive size distribution (cumulative probability) of the
nano‐particles together with the fitted function and nor-
mal probability plot are given in the Figure 4 a), and b).
Cumulative probability shows that approximately 80%,
and 90% of the as‐synthesized catalyst has 15, and
3.3 | Vibrating Sample Magnetometer
(VSM)
To obtain the saturation magnetization pattern of the
magnetic nano‐particles (MNPs) VSM technique was
used. Figure 2 shows the saturation magnetization of
nano‐Fe3O4, and nano‐ Fe3O4@Ca(HSO4)2 MNPs. The
saturation magnetizations are 55, and 14 emu/g for
nano‐Fe3O4 and nano‐Fe3O4@Ca(HSO4)2 MNPs.
The amount of nano‐Fe3O4@Ca(HSO4)2 saturation
magnetization is lower than the nano‐Fe3O4. This
reduced magnetization is attributed to the non‐magnetic,
unreacted CaCO3, Ca(HSO4)2 layers in the core/shell
structure of the as‐synthesized catalyst. Non‐magnetic
materials weaker the magnetization because of the
quenching of surface moments.[50] Although the magni-
tude of saturation magnetization of the catalyst is lower
than the nano‐Fe3O4 (14 emu/g versus 55 emu/g), but this
value is enough, so that the catalyst can be easily sepa-
rated from the reaction mixture using a super magnet.
FIGURE 3 Field Emission Scanning Electron Microscopy (FESEM) and Transmission electron microscopy (TEM) of the as‐synthesized
nano‐Fe3O4@Ca(HSO4)2 MNPs

KHAZAEI ET AL.
5 of 11
FIGURE 5 The energy‐dispersive X‐ray spectroscopy (EDX) of
Fe3O4@Ca(HSO4)2 MNPs
the pH dose not changed. The catalyst was separated
and washed with deionized water. Then, two drops phe-
nolphthalein was added to the mixture and was tittered
with 0.6 ml HCl (0.1 N). Thus, based on back titration
method, 1 g of catalyst has 5.18 mmol of SO4H group.
The result of EDX analysis and back titration method is
in good agreement with each other. In other hand, the
surface density of SO4H groups in the as‐synthesized cat-
alyst is higher toward the many cases of SO3H based
reported catalyst in the literature.
3.6 | X‐ray Diffraction (XRD)
FIGURE 4 Cumulative probability and normal probability plot of
as‐synthesized MNPs
This technique is used to identify the size, purity, and
crystallinity nature of the as‐synthesized catalyst, so that
the Scherrer's equation (D=(Kλ)/(βcosθ)) was used to cal-
culate the size of the MNPs from XRD pattern (Figure 6).
In the Scherrer's equation K, λ, β, and θ stand for dimen-
sionless shape factor, X‐ray wavelength, full width at half
maximum (FWHM) of the diffraction peak, and Bragg dif-
fraction angle in radian, respectively. To calculate the
MNPs size, based on the TEM images (Figure 3) it
20 nm, respectively. Normal probability plot of nano‐par-
ticle diameter is given in Figure 4 b). The line looks pretty
straight, so normality seems a reasonable assumption.
One can use a normal probability plot to assess visually
whether the data in x come from a population with a nor-
mal distribution.
3.5 | Energy‐dispersive X‐ray spectroscopy
(EDX)
Further information about the elemental analysis and
contribution of each element can be obtained using
EDX. The elemental analysis of the as‐synthesized cata-
lyst is given in Figure 5. EDX shows that the catalyst has
O, C, Fe, S, and Ca with mass percent of 31.5, 29.7, 24.3,
9.4, and 5.1, respectively. The mass percent of S shows
that loading of SO4H group on the Fe3O4@eggshell is
about 5.875 mmol/g. In addition, the amount of SO4H
group was determined using back titration method. First,
0.027 g of as‐synthesized catalyst was added to the 30 ml
water and stirred for 1 hour, then 2 ml NaOH (0.1 N)
was added to the mixture and stirred up to point that
FIGURE 6 XRD pattern of nano‐ Fe3O4, nano‐Fe3O4@eggshell,
and nano‐Fe3O4@Ca(HSO4)2

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KHAZAEI ET AL.
assumed that the nanoparticles have spherical shape, so
that, the K value is set to 0.9. In addition, the averaged
value of Cu K‐Alpha is used for λ (0.154184 nm). β and
θ are determined from XRD peaks. To determine the dis-
tance between the layer (d‐spacing or interplaner spacing)
in the crystalline structure of as‐synthesized catalyst, the
Bragg equation (dhkl=λ/2sinθ) was used. The size and d‐
spacing of MNPs at a different diffraction angle is given
in the Table 1. The average value of MNPs size and d‐
spacing are 25.89 nm, and 0.36 nm, respectively. The dif-
ference in the size of nanoparticles based on the TEM
and XRD is related to the small area (cannot represent
the whole particles) in the TEM image.
FIGURE 7 Thermal gravimetric analysis (TGA) and differential
thermal analysis (DTA) of the nano‐Fe3O4@Ca(HSO4)2
3.7 | Thermal gravimetric analysis (TGA)
and differential thermal analysis (DTA)
3.8 | Evaluation of the catalytic activity of
nano‐Fe3O4@Ca(HSO4)2
In order to explain the effect of the heat on the catalyst,
TGA and DTA were used. The sample was heated from
room temperature (25 °C) to 800 °C. The result of this
study is shown in the Figure 7; four losses are observed.
The first loss located between 25 °C and 100 °C which
attributed to the loss of solvents and water (4.5%). The
second between 100 °C and 450 °C correspond to the loss
of SO3H group (13.4%). The third between 450 °C and
630 °C likely corresponds to the loss of organic matter
in the eggshell (17.22%). Finally, the region D between
630 °C and 800 °C corresponds to the unreacted carbon
dioxide (as explained in FTIR) loss (12.88%). The TGA/
DTA pattern confirms the core/shell structure of the as‐
synthesize MNPs.
To further investigate thermal stability of the as‐syn-
thesized catalyst, it was heated at 300 °C for 3 hours in
an oven. The IR spectra of the catalyst before and after
the heating is shown in the Figure 8, so that SO4H group
peaks have not changed significantly, which implies the
thermal stability of the catalyst. IR spectra and TGA result
are consistent with each other from thermal stability
point of view.
3.8.1 | Effect of Solvent on the Reaction
To investigate the effect of solvent on the reaction time
and yield, six experiments (benchmark reaction=reaction
between benzaldehydes, phthalhydrazide, and dimedone)
were carried out in solvent free condition, ethyl acetate,
dimethylformamide, water, n‐hexane, and ethanol as sol-
vent (in the presence of Fe3O4@Ca(HSO4)2 as the cata-
lyst). Time and yield of the benchmark reaction are
given in the Table 2 so that the lowest time and the
highest yield are achieved in the solvent free condition.
It should be noted that the benzaldehyde is a liquid at
the reaction condition, so acts as the solvent and a reac-
tive agent in the reaction. Accordingly, solvent free condi-
tion was used to further analysis and optimization of the
reaction condition.
3.8.2 | Optimization of reaction condition
Although, the design of experiments (DOE) as a system-
atic method has been used in numerous papers, but there
TABLE 1 X‐ray diffraction (XRD) data for nano‐ Fe3O4@Ca(HSO4)2 particles
Peak width [FWHM]
(radian)
interplanar spacing
of the crystal (nm)
Entry
2θ
9.4
Size (nm)
1
0.0146
10
20
78
18
18
10
26
0.94
0.35
0.30
0.25
0.16
0.15
0.36
2
25.5
29.5
35.7
57.3
62.9
0.0069
0.0017
0.0075
0.0079
0.0136
3
4
5
6
mean

KHAZAEI ET AL.
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settings of factors, and requires more runs for the same
precision as DOE. So, to find the true optimal point of
the reaction condition, namely, the amount of catalyst,
and temperature, DOE method was used in the present
study. In addition, there are various methods in DOE
approach, so that the response surface method (RSM) is
one of the best methodologies. Among the RSMs, Central
Composite Design (CCD), and Box‐Benken Design (BBD)
are the most popular. Accordingly, CCD with three
groups of design points of two‐level factorial, axial points,
and center points were used. Briefly, the amount of cata-
lyst (X1) and temperature (X2) was used as the vital factors
which can affect the yield (response) of the reaction. The
temperature range was located between 30 °C and
110 °C, and the minimum and maximum amount of cata-
lyst were set at 0.01, and 0.05, respectively. In coded scale
(with efficient CPU time), maximum, middle, and mini-
mum of a factor are shown with +1, 0, and ‐1, respec-
tively. Table 3 shows the designed experiment by CCD
(base on coded and actual scale), which should be carried
out in the laboratory to obtain the reaction yield. To inves-
tigate the effect of the factors, reaction between benzalde-
hyde, phthalhydrazide, and dimedone was used as a
benchmark reaction. To cancel out the effect of time on
the reaction yield, all of the reactions given in the
Table 3 were stopped after 6 minutes. The yields of the
reactions as the dependent variable are given in the
Table 3.
FIGURE 8 IR spectra of the as‐synthesized catalyst before and
after the heating at 300 °C
TABLE 2 Effect of various solvents on the reaction time and yield
(in the presence of catalyst)
Yield a (%)
Time
Entry
Solvent
(min)
60 °C
1
2
3
4
5
6
‐‐‐
12
110
150
130
175
90
85
52
55
43
35
50
EtOAc
DMF
H2O
n‐Hexane
EtOH
aIsolated yield.
These data together with regression method are used
to find the best polynomial, and its coefficients that could
well predict the reaction yield. The relation between vital
factors and dependent variable can be described using a
polynomial model:
are so many researchers who use from one‐factor‐at‐a‐
time (OFAT). OFAT methods have disadvantages which
include: cannot estimate interactions, can miss optimal
TABLE 3 Levels of the experimental variables and the corresponding reaction yields using the CCD method
Independent variables
dependent variable
Yield
X1 (amount of catalyst)
X2 (temperature)
Coded levels
Runs
Coded levels
Actual levels
Actual levels
1
‐1
‐1
0
0.0100
0.0100
0.0275
0.0500
0.0500
0.0100
0.0275
0.0500
0.0275
0.0275
0.0275
0
‐1
+1
+1
‐1
+1
0
70.00
30.00
110.00
110.00
30.00
110.00
70.00
70.00
70.00
70.00
30.00
62
52
74
76
56
62
66
71
68
65
53
2
3
4
+1
+1
‐1
0
5
6
7
8
+1
0
0
9
0
10
11
0
0
0
‐1

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KHAZAEI ET AL.
Y ¼ β0 þ β1x1 þ β2x2 þ ⋯ þ βkxk þ β12x1x2
þ β13x1x3 þ ⋯ þ βk−1;kxk−1xk þ β11x12 þ β22x22
þ ⋯ þ βkkx2k þ ε
(1)
where β0,…,βkk stand for the coefficient of the model. x,
and y explain the factors, and dependent variable, respec-
tively. Using linear optimization technique vector of β can
be calculated as:
À
Á
−1
β ¼ XTX XTY
(2)
The obtained coefficient after optimization and poly-
nomial model are as bellow:
Y ¼ 37:367 þ 152:302×X1 þ 0:466×X2
þ 3:125×X1×X2−2434:21×X1 −2:483×10−3×T2 (3)
2
The analysis of variance (ANOVA) shows that a qua-
dratic model could well predict the experimental reaction
yield. ANOVA is given in the Table 4, so that the p‐value
(probability) of the model is 0.0008. Small probability
values call for rejection of the null hypothesis, so that
the obtained model is significant from a statistical point
of view. In addition, the p‐value of factors (amount of cat-
alyst and temperature) are given in Table 4. The p‐value
of X12 term is larger than 0.05 (threshold criterion), so this
term should be removed from the model. Although, the
value of the coefficient of determination (R2) implies that
model could well fit to the experimental data, but the pre-
dictive power of the model must be evaluated. Accord-
ingly, predicted R2 was calculated (0.7606) based on
leaving out the i_th run. Predicted R2 shows that the
obtained quadratic model could well predict the experi-
mental reaction yields.
FIGURE 9 Contour and 3 dimensional (3D) of reaction yield
versus temperature, and the amount of the catalyst
Figure 9 shows the effect of the amount of catalyst and
temperature of the reaction yield, so that increase in
amount of catalyst and temperature leads to increase the
reaction yield. The catalyst boosts the reaction yield with
steeper positive slope, which results from the activation
of the catalyst at higher temperatures.
TABLE 4 Analysis of variance (ANOVA) for the response surface
Expression 3 was used to find the optimum reaction
condition. Using the optimization technique, the optimal
values for the amount of catalyst and temperature were
obtained at 0.05, and 110 °C, respectively, which are the
maximum values of the factors used. To investigate the
predictive power of the model, an experiment was carried
out in the optimal condition and stopped after 4 minutes,
so that the experimental yield was 75%. The predicted
yield using the expression 3 at optimal condition is
77.34%, with 3.12% deviation from experimental yield.
Accordingly, the result of the model is in good agreement
with the experimental results. It should be noted that, the
model must be used in the range of the factors that have
been used to obtain the model.
quadratic model of the yield
Source
p‐value.>F
Model (yield)
0.0008
0.0026
0.0001
0.0530
0.4695
0.0242
0.9698
0.7606
0.3345
X1
X2
X1X2
2
X1
2
X2
R2
Predicted R2
Lack of fit

KHAZAEI ET AL.
9 of 11
Table 5 are the purification yields, and doesn’t mean the
reaction yields.
3.10 | Proposed mechanism
To figure out the plausible mechanism of the reaction,
three different experiments was carried out, so that benz-
aldehyde, dimedone, and phthalhydrazide separately
were mixed with the as‐synthesized catalyst. The IR spec-
tra of the mixtures show that the catalyst only interacts
with benzaldehyde, so that the wave number of carbonyl
group shifts from 1703 cm‐1 to 1687 cm‐1. This indicates
that the ‐SO3H group on the surface of the eggshell is
the initiator of the reaction. Accordingly, and based on
the literature reported mechanism,[18,19,22] the possible
mechanism is shown in the Figure 11.
FIGURE 10 Synthesis of indazolo[1,2‐b]‐phthalazinetrione
derivatives in the presence of nano‐Fe3O4@Ca(HSO4)2 catalyst
In other hand, to probe the effect of catalyst, an exper-
iment was carried out in the optimal condition with and
without the catalyst. The reaction yield without the cata-
lyst was 55% up to 30 minutes, but using the catalyst,
87% yield was obtained after 6 minutes.
3.9 | Synthesis of indazolo[1,2‐b]‐
phthalazinetrione derivatives at optimum
condition
3.11 | Retrieval of the catalyst
In another investigation, the recyclability of the as‐syn-
thesized catalyst was studied. For this purpose, after the
completion of the reaction, product mixture was dissolved
in 20 ml hot chloroform and the catalyst was separated
using a super magnet. Then the catalyst dried in an oven
and used for the next cycle, so that the catalyst activity
does not significantly decrease. Figure 12 shows the yield
of the reaction versus cycles. It should be noted that, for
the fair compare the catalyst activity at different cycles,
the reaction was stopped after 6 minutes. Some tech-
niques such as IR, EDX, and SEM were used to demon-
strate possible changes before and after using of the
catalyst, which are given in the supplementary material.
The results (IR, EDX, and SEM) indicate that the changes
It was assumed that the optimum condition for all the
indazolo[1,2‐b]‐phthalazinetrione derivatives are the
same as obtained from the benchmark reaction. So, the
reaction between different aldehydes, phthalhydrazide,
and dimedone were carried out by using the as‐synthe-
sized catalyst at optimum condition (0.05, and 110 °C).
Figure 10 shows the general procedure for the synthesis
of indazolo[1,2‐b]‐phthalazinetrione derivatives. Different
substitute on the benzaldehyde include electron with-
drawing and electron donating groups was tested with
low reaction time, and medium to high yield with com-
pare to literature data.[18,20–29,51–53] Given data in the
TABLE 5 Reaction time, yield, and melting point of the synthesized indazolo[1,2‐b]‐phthalazinetrione derivatives in the presence of as‐
synthesized catalyst
Compound
R
Time (min.)
Yielda (%)
Melting point (°C)
References
[21]
1
H
6
7
5
4
5
6
6
8
2
3
87
79
74
78
78
82
83
85
76
75
209‐211
271‐273
228‐230
265‐267
264‐265
218‐220
226‐229
254‐257
266‐267
183‐185
[54]
2
3‐NO2
3‐F
[55]
3
[29]
4
2,3‐Cl2
2‐Cl
[26]
5
[30,54]
[54]
6
2,4‐Cl2
4‐Me
4‐Br
7
[54]
8
[54]
9
4‐Cl
[26,27]
10
2‐OH
aYield refers to the purified product using cooling crystallization up to 6 °C.
R=substituent in the benzaldehyde

10 of 11
KHAZAEI ET AL.
catalyst. Because of the massive amount of eggshell waste,
this type of reaction convert the waste to wealth, so that it
used for production of value‐added of indazolo[1,2‐b]‐
phthalazinetrione derivatives. Thermal analysis shows
that it can withstand the temperature up to 300 °C, which
imply the thermal stability of the as‐synthesized catalyst.
The as‐synthesized catalyst can be used in any reaction
that requires the acid catalyst. In addition, the design of
experiments was used to find the optimum reaction con-
dition, so that increase in the amount of catalyst (and
temperature), especially at higher temperature boosts
the reaction yield. Hope this work motivates the
researcher interest for further investigations in order to
widen the possible conversion of this waste to convert it
to green and environment‐friendly catalyst.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge partial support of this
work by the Research Affairs Office of Bu‐Ali Sina Uni-
versity (Grant number 32‐1716 entitled development of
chemical methods, reagents and molecules), Center of
Excellence in Development of Chemical Method
(CEDCM), Hamedan, I. R. Iran.
ORCID
FIGURE 11 The plausible mechanism in the synthesis of
indazolo[1,2‐b]‐phthalazinetrione using Fe3O4@Ca(HSO4)2 as a
solid acid catalyst
Ardeshir Khazaei http://orcid.org/0000-0001-7990-2266
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