The magnetic nanostructured natural hydroxyapatite (HAP/Fe3O4 NPs): an efficient, green and recyclable nanocatalyst for the synthesis of biscoumarin derivatives under solvent-free conditions

Article abstract of DOI:10.1007/s11164-019-03788-2

Abstract: The magnetic nanostructured natural hydroxyapatite (HAP/Fe₃O₄ NPs) as a novel magnetic nanocatalyst was synthesized and fully characterized. The excellent catalytic activity of HAP/Fe₃O₄ NPs was investigated in the synthesis of biscoumarin derivatives under mild, green and solvent-free conditions. A series of aromatic (bearing different functional groups), heteroaromatic and aliphatic aldehydes have been converted to biscoumarins with good to excellent isolated yields. The significant advantages offered by the present method in close agreement with green chemistry principles are: catalyst is inexpensive, non-toxic, easy handling and reusable up to six recycle runs, magnetic separation of nanostructured catalyst, simple work-up procedure, short reaction time, high yields of products and using solvent-free conditions. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-019-03788-2

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03788-2
The magnetic nanostructured natural hydroxyapatite
(HAP/Fe3O4 NPs): an efcient, green and recyclable
nanocatalyst for the synthesis of biscoumarin derivatives
under solvent‑free conditions
Batool Akhlaghinia1 · Parvin Sanati1 · Arezou Mohammadinezhad1 ·
Zeinab Zarei1
Received: 10 December 2018 / Accepted: 22 February 2019
© Springer Nature B.V. 2019
Abstract
The magnetic nanostructured natural hydroxyapatite (HAP/Fe3O4 NPs) as a novel
magnetic nanocatalyst was synthesized and fully characterized. The excellent cata-
lytic activity of HAP/Fe3O4 NPs was investigated in the synthesis of biscoumarin
derivatives under mild, green and solvent-free conditions. A series of aromatic
(bearing diferent functional groups), heteroaromatic and aliphatic aldehydes have
been converted to biscoumarins with good to excellent isolated yields. The signif-
cant advantages ofered by the present method in close agreement with green chem-
istry principles are: catalyst is inexpensive, non-toxic, easy handling and reusable
up to six recycle runs, magnetic separation of nanostructured catalyst, simple work-
up procedure, short reaction time, high yields of products and using solvent-free
conditions.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-019-03788-2) contains supplementary material, which is available to authorized users.
* Batool Akhlaghinia
akhlaghinia@um.ac.ir
1
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad,
Mashhad 9177948974, Iran
Vol.:(0123456789)
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B. Akhlaghinia et al.
Graphical abstract
Keywords Magnetic nanostructured natural hydroxyapatite (HAP/Fe3O4 NPs) ·
Biscoumarin derivatives · Aldehyde · 4-hydroxycoumarin
Introduction
Among the heterocyclic compounds which are widely distributed in nature, oxygen
containing moieties occupy an interesting position. Coumarins as the major class
of naturally occurring oxygen heterocycles have long been the subject of numerous
studies from their discovery up to now due to their unique applications in pharmaco-
logic, pharmaceutics, the agricultural and perfume industry [1–4]. Coumarin deriva-
tives exhibit remarkable biological activity such as anti-HIV, antifungal [5], anti-
infammatory [6], anticancer [7], antimicrobial and antioxidants [8, 9]. Despite this
wide range of biological applications, they are largely used as additives in food, opti-
cal brightening agents and fuorescent dyes, medicine, fragrance, cosmetics, elec-
troluminescence [10–17], sensors [18] and used as ligands in Suzuki- Miyaura and
Mizoroki–Heck cross coupling reactions [19]. Therefore, based on the expanding
biological and industrial activities of coumarin derivatives, various catalysts such
as Zr-TMS-TFA-25 [20], ZrOCl2·8H2O/SiO2 [21], Fe3O4@SiO2@Et–PhSO3H [22],
Pd(OAC)2 [23] and Fe3O4@Boehmite–NH2–CoII NPs [24] have been employed for
their synthesis. Among coumarin derivatives, dimeric coumarins are the well-known
family of these compounds. Biscoumarin derivatives, the bridge substituted dimers
of 4-hydroxycoumarin have received increasing attention in synthetic and medicinal
chemistry due to their wide range of biological activities and interesting potential in
therapeutic applications as well [25–29]. It is found that these compounds possess
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The magnetic nanostructured natural hydroxyapatite…
signifcant anticoagulant, insecticidal, antihelminthic, hypnotic, antifungal, and HIV
protease inhibition efects [30–34]. Some biscoumarin derivatives are used as urease
inhibitors [35], agrochemicals [36] and analytical reagents too [37]. Today, a variety
of synthetic approaches have been developed for their synthesis including Knoev-
enagel, Pechmann, Perkin, Reformatsky, and Wittig reactions [38]. Among them,
domino Knoevenagel–Michael reaction between a carbonyl compound and two
equivalents of 4-hydroxycoumarin is the most commonly applied one, in which dif-
ferent types of both acidic and basic catalysts or promoters (such as silica-supported
Preyssler nanoparticles [39], CuO–CeO2 nano-composite [40], basic ionic liquid
tetramethylguanidinium acetate [41], poly(4-vinylpyridine) and 1,4-butanesultone
[42], propane-1,2,3-triyl tris(hydrogen sulfate) [43], silica-supported perchloric acid
nanoparticles [44], RuCl3·nH2O [45], SO3H– functionalized ionic liquids based on
benzimidazolium cations [46], sodium dodecyl sulfate (SDS) [47], tetrabutylam-
monium bromide [48], pentafuoropropionic acid (PFPA) [49], semicarbazide-based
acidic ionic liquid tag [50], cellulose sulfonic acid [51], magnetite-containing sul-
fonated polyacrylamide [52], sulfated titania [53], P4VPy–CuO nanoparticles [54],
protic ionic liquid [Et3NH][HSO4] [55], ionic liquid immobilized on FeNi3 nano-
catalyst [56], zwitterionic liquid (ZIL) coated CuO [57], tris(hydrogensulfato) boron
[58], p-dodecylbenzenesulfonic acid (DBSA) [59]), were employed. Although most
of the reported methods are useful, but a great demand is needed to introduce a
neutral, efcient and economical catalytic system which can catalyze this type of
reaction without drawbacks such as long reaction times, unsatisfactory yields, harsh
reaction conditions, tedious workup and using expensive, hazardous and toxic rea-
gent, solvent or catalyst.
Nowadays, the design and development of efcient green catalysts as one of the
most important felds in organic chemistry has attracted remarkable attention. In this
regard, hydroxyapatite (HAP) represented by a general formula of Ca10(PO4)6(OH)2
(as the main component of bones and teeth), because of it having chemically active
sites (phosphate group as basic sites and Ca+2 and/or P–OH as Lewis and/or BrØn-
sted acid sites [60]) can be employed as an excellent biomaterial for catalyst prepa-
ration. Likewise, compared to synthetic hydroxyapatite, natural hydroxyapatites
have unique properties such as low cost, high specifc surface area, low water solu-
bility, availability, high stability under oxidizing and reducing conditions [61]. On
the other hand, as regards the difcult separation of hydroxyapatite nanoparticles
by conventional approaches (centrifugation and fltration) from the reaction mixture,
using magnetic nanoparticles (MNPs) can cause simple separation of the catalyst
using an external magnet that prevents losing catalyst during the separation process.
Following our continuous interest to introduce new, safe, stable and recyclable
heterogeneous catalyst [62–94], and by considering all the aforementioned reasons
and importance of clean synthetic procedures, herein we extract natural hydroxyapa-
tite from cow bones through two burning processes, and then magnetic nanoparti-
cles were incorporated into the hydroxyapatite scafold (Scheme 1). Then, the cat-
alytic activity of HAP/Fe3O4 as a new, highly efcient and magnetically reusable
nanocatalyst for the synthesis of biscoumarin derivatives via reaction between two
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B. Akhlaghinia et al.
16
Scheme 1 The schematic pathway for the synthesis of the magnetic nanostructured natural hydroxyapa-
tite (HAP/Fe3O4 NPs) (III)
1 3

The magnetic nanostructured natural hydroxyapatite…
molecules of 4-hydroxycoumarin and various aldehydes under solvent-free condi-
tions was studied (Scheme 2).
Results and discussion
In the present study, the magnetic nanostructured natural hydroxyapatite (HAP/
Fe3O4 NPs) (III) was prepared according to our previously reported procedure [61]
(Scheme 1).
Characterization of catalyst
Full characterization of the magnetic natural hydroxyapatite (HAP/Fe3O4 NPs) (III)
was performed by recording Fourier transform infrared spectroscopy (FT-IR), X-ray
powder difraction (XRD), transmission electron microscopy (TEM), energy- dis-
persive X-ray analysis (EDX), vibrating sample magnetometer (VSM) and thermo-
gravimetric analysis (TGA). The obtained results confrmed the successful prepara-
tion of this nanostructured catalyst.
The FT-IR spectra of the bone ash (I), HAP (II) and HAP/Fe3O4 (III) are illus-
trated in Fig. 1a–c. The FT-IR spectrum of bone ash demonstrated a relatively broad
band around 3660–3280 cm−1, which is related to the stretching vibrations of the
hydroxyl groups in the bone ash matrix [95]. Also, a discerned absorption band at
1629 cm−1 was attributed to amide functional groups of the protein constituents in
the organic matrix of bone ash [96]. Furthermore, the observed band at 1471 cm−1
with a shoulder at 1420 cm−1 (due to the stretching vibration of CO32−), confrmed
the presence of the carbonate ions in the bone ash [96]. The absorption bands at
1039, 961, 605 and 562 cm−1 were allocated to the stretching vibration modes
of phosphate groups (Fig. 1a) [96]. In Fig. 1b, the color change of black powder
ash(I) to white powder (II) was shown by disappearance of the broad band around
3660–3280 cm−1 and subsequent replacing by a weak and sharp absorption band
at 3571 cm−1 (due to the hydroxyl stretching vibration) [96]. The FT-IR spectrum
of HAP/Fe3O4 (III) (Fig. 1 c) displayed two broad absorption bands at 3415 cm−1
and 633–565 cm−1 attributed to the presence of hydroxyl groups on the surface of
Scheme 2 Synthesis of biscoumarin derivatives via the condensation reactions of aldehydes with
4-hydroxycoumarin in the presence of the magnetic nanostructured natural hydroxyapatite (HAP/Fe3O4
NPs) (III)
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B. Akhlaghinia et al.
Fig. 1 FT-IR spectrum of a the bone ash (I), b HAP (II), c HAP/Fe3O4 NPs (III), d and 6th reused HAP/
Fe3O4 NPs (III)
the magnetic nanoparticles and the stretching vibration bands of Fe–O bonds [97],
respectively.
The X-ray difraction (XRD) analysis was conducted to investigate the crys-
talline structure of the prepared HAP (II) and HAP/Fe3O4 (III) nanocatalyst.
The attained data are given in Fig. 2. As seen in Fig. 2a, refections observed at
2Ɵ = 26.0°, 32.0°, 33.1°, 34.2°, 40.0°, 46.7° and 49.5° belong to the (002), (211),
(300), (202), (130), (222) and (213) planes, matching well with the characteristic
planes of the hexagonal structure of the natural hydroxyapatite (JCPDS: 24-0033)
[98, 99]. The sharp peak intensities can be ascribed to the phase purity of HAP
nanoparticles. As regards the XRD pattern of HAP/Fe3O4 (III) (Fig. 2b), there
Fig. 2 The XRD patterns of a HAP (II) and b HAP/Fe3O4 NPs (III)
1 3

The magnetic nanostructured natural hydroxyapatite…
are fve additional peaks at 2Ɵ = 35.4°, 43.3°, 53.7°, 57.3° and 62.9° which are
imputed to the (311), (400), (422), (511) and (440) crystal planes, respectively,
due to the existence of the cubic spinel structure of Fe3O4 NPs (JCPDS: 19-0629)
[100]. The crystalline size of particles, which had been estimated using the Deby-
Scherer equation, is 30 nm.
Furthermore, transmission electron microscopy (TEM) of the prepared nano-
catalyst was recorded and is presented in Fig. 3. Investigating the TEM images
revealed that the particle size distribution is about 8–30 nm. Particles are rod-like
in shape [101], which is in good agreement with the results deduced from XRD
analysis. As well, in order to achieve more detailed structure information of the
catalyst, high resolution transmission electron microscopy (HRTEM) was carried
out. As shown in Fig. 3c and d, the dark particles (Fe3O4), (due to the strong
absorption contrast), have been well-dispersed in the HAP matrix.
Energy-dispersive X-ray analysis (EDX) is shown in Fig. 4, presenting all
expected elements containing Ca, P, O and Fe that proves the composition of the
nanocatalyst. In addition, no impurity element was detected in the nanocatalyst
structure.
Fig. 3 TEM images with 120 kV (a, b) and 150 kV (c, d) of HAP/Fe3O4 NPs (III)
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B. Akhlaghinia et al.
Fig. 4 EDX analysis of HAP/Fe3O4 NPs (III)
The magnetic behavior of HAP/Fe3O4 (III) was investigated using a vibrational
sampling magnetometer (VSM) at room temperature, and reported in Fig. 5. As is
evident from the resulting magnetization curves, the saturation magnetization value
of the prepared nanocatalyst reached 5.51 emu/g from 73 emu/g for the Fe3O4 NPs
[102]. This drastic decrease arises from the successful placement of the Fe3O4 NPs
into the HAP matrix. Additionally, the prepared nanocatalyst showed a superma-
gnetic behavior.
In order to acquire information on the thermal stability of HAP/Fe3O4 (III),
thermogravimetric analysis (TGA) of the nanocatalyst was carried out (Fig. 6). It
could be inferred that the TGA thermogram of the prepared nanocatalyst exhib-
ited three major weight-loss steps. The initial stage can be attributed to the physi-
cally absorbed moisture on the catalyst surface (weight loss 0.79% at 32–140 °C),
whereas major weight loss occurred at around 140–450 °C due to the decomposition
Fig. 5 Magnetization curve of HAP/Fe3O4 NPs (III)
1 3

The magnetic nanostructured natural hydroxyapatite…
Fig. 6 TGA thermogram of HAP/Fe3O4 NPs (III)
of the organic segment (the organic components of bone were not removed com-
pletely during heating the bone to produce bone ash) in the structure of III (2.99%).
Finally, the observed weight loss from 450 to 750 °C (0.33%) was assigned the
decomposition of calcium carbonate to calcium oxide that proved the presence of
natural hydroxyapatite [96].
Catalytic synthesis of biscoumarin derivatives
According to our previous study, ZnII/HAP/Fe3O4 was found to be a highly efcient,
robust and magnetically recyclable heterogeneous nanocatalyst in the preparation
of structurally diferent propargylamine derivatives via a one-pot three-component
A3-coupling reaction of terminal alkynes, aldehydes and secondary amines [61]. To
extend the application of the magnetic nanostructured natural hydroxyapatite (HAP/
Fe3O4 NPs) (III) as a reusable catalyst, condensation reactions of aldehydes with
4-hydroxycoumarin were studied towards the synthesis of biscoumarin derivatives
(Scheme 2).
To establish the optimum reaction conditions (solvent, temperature and catalyst
amount), in an initial attempt, the synthesis of 3,3’-(phenylmethylene)-bis-(4-hy-
droxy-2H-chromene-2-one) from the condensation reaction of benzaldehyde with
two equivalents of 4-hydroxycoumarin as the model reaction was studied (Table 1).
Preliminary studies were performed by conducting the model reaction in the pres-
°
ence of 0.005 g of HAP/Fe3O4 NPs (III) at 100 C in diferent solvents (toluene,
EtOH, DMSO, H2O, DMF) and also in solvent-free conditions (Table 1, entries
1–6). When the model reaction was performed in solvent-free conditions, surpris-
ingly, the highest yield was obtained comparatively; other polar solvents gave lower
yields even after long reaction times (Table 1 entry 6). Since the reaction proceeded
without any solvent, optimization was carried out by varying the reaction tempera-
ture (Table 1, entries 7–10). The best yield of the desired product was obtained at
°
90 C while lower temperatures resulted in the product’s longer reaction times and/
or lower yields. Further experiments with variable amounts of catalyst loading and
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B. Akhlaghinia et al.
Table 1 Optimization of reaction conditions for the synthesis of 3,3′-(phenylmethylene)-bis-(4-hydroxy-
2H-chromene-2-one)
Entry
Molar ratio of 4-hydroxy- Catalyst (g)
coumarin: benzaldehyde
Solvent
Tempera- Time (h)
ture (°C)
Isolated
yield (%)
1
2
3
4
5
6
7
8
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.004
0.006
0.007
0.008
0.009
0.008
0.008
0.008
0.008
0.008
–
Toluene
EtOH
DMSO
H2O
DMF
–
–
–
–
–
–
–
–
–
–
–
–
100
100
100
100
100
100
90
85
80
70
90
90
90
90
90
90
90
90
90
4.5
4
3.5
3
1.5
1.5
1.5
2
2.5
3
1.8
1.3
1.1
1
1
1
1
1
1
1
3
2
4
85
60
90
95
75
95
95
80
90
85
95
95
95
95
95
95
95
95
95
95
30
65
40
9
10
11
12
13
14
15
16
17
18
19
20
21
22a
23b
2.1:1
2.2:1
2.3:1
2.4:1
2:1.2
2:1
–
–
–
–
–
–
90
90
90
90
2:1
2:1
0.008
0.008
aReaction was performed in the presence of HAP(II)
bReaction was performed in the presence of Fe3O4NPs
molar ratios of 4-hydroxycoumarin: benzaldehyde demonstrated that the reaction
proceeded very efectively using 0.008 g of catalyst and 2/1 molar ratio of 4-hydrox-
ycoumarin: benzaldehyde (Table 1, entries 11–15 and 16–20). Table 1 clearly shows
°
that, in the absence of catalyst in solvent-free conditions at 90 C, desired product
was produced in only 30% yield after 3 h (Table 1, entry 21). Furthermore, in two
separate fasks, the same model reaction was performed using HAP(II) and Fe3O4
under the optimized reaction conditions to assess the crucial role of HAP/Fe3O4 NPs
(III) in the preparation of 3,3’-(phenylmethylene)-bis-(4-hydroxy-2H-chromene-2-
one) (Table 1, entries 22–23). As shown in Table 1, the yield of desired product was
greater and the reaction time was generally shorter using HAP/Fe3O4 NPs (III) as
catalyst.
Encouraged by the remarkable optimization results (Table 1, entry 14), to prove
the general applicability and scope of the present methodology, our investiga-
tion involves subjecting of a range of structurally diverse aldehydes belonging to
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The magnetic nanostructured natural hydroxyapatite…
the categories aromatic, heteroaromatic, α,β-unsaturated and aliphatic aldehydes
and 4-hydroxycoumarin under the optimized reaction conditions. These results are
listed in Table 2. As shown, the condensation reactions of aromatic aldehydes bear-
ing electron-withdrawing groups were completed within 15–40 min (Table 2, entries
2–6), while, in the case of electron-rich aromatic aldehydes longer reaction times are
needed to achieve the same yields of corresponding biscoumarins (Table 2, entries
7–10). Surprisingly, the heteroaromatic as well as α, β-unsaturated (cinnamalde-
hyde) aldehydes were found to be equally efcient to yield the expected products
in excellent yields (Table 2, entries 11–14). Longer reaction times were needed to
achieve the reasonable yields of the desired products in the profle of aliphatic alde-
hydes (Table 2, entries 15–16).
In the present method, the product purifcation does not need column or thin layer
chromatography. The obtained solid products were just fltered of the reaction mix-
ture, after separating HAP/Fe3O4 NPs (III) by means of an external magnetic feld.
The pure biscoumarins were fnally recrystallized from ethanol. Purity checks were
made with melting points and TLC. Most of the synthesized biscoumarin deriva-
tives were known compounds. The structures of all of them were deduced from their
mass spectrometry and comparison of their melting points with the literature values.
The molecular ion was not evident in some of the mass spectra (J, K, N, P) because
of the very facile cleavage of C–C bond between the aryl/or alkyl and methylene
carbon. Nevertheless, the structure of desired products was described by other use-
ful fragmentation information of each compound. The structure of some selected
products was further confrmed by the FT-IR, 1H NMR, and 13C NMR spectroscopy.
The FT-IR spectra show a broad absorption band around 3435–3026 cm−1 due to
OH stretching frequency. The vibrational modes of C=O and C–O groups appeared
at 1661–1650 and 1348–1345 cm−1 respectively. In addition, resonating signal at
1
11–8 ppm was attributed to the OH proton in HNMR spectra. But OH resonating
signals of A, I, J, and P were broadened or disappeared upon the interaction with
the aqueous DMSO-d6 as a polar and hydrogen bond acceptor solvent [103–105].
The methine proton appeared as a singlet around ~6–4 ppm (except P and N which
appeared as a triplet and doublet, respectively). Moreover, in the 13C NMR spectra,
the signals at 169–163 and 37–33 ppm correspond to carbonyl and methine carbon
atoms. The rest of the protons and carbons were resonating in the expected regions,
which revealed the successful formation of biscoumarin derivatives. All spectro-
scopic and spectrometric data show that only one product is formed in all cases and
no undesirable side products are produced.
The proposed mechanism for the preparation of biscoumarin derivatives based
on the reported pathway in literature [50], involves a Knoevenagel condensation of
4-hydroxycoumarin with the aldehyde followed by a Michael addition with another
molecule of 4-hydroxycoumarin in the presence of HAP/Fe3O4 NPs as catalyst
(Scheme 3). The catalytic activity of HAP/Fe3O4 NPs can be attributed to Lewis acid
sites (Ca2+), BrØnsted acid sites (hydroxyl groups) and basic sites (phosphate ani-
ons) as well. The catalyst is capable of binding with the carbonyl oxygen increasing
the electrophilicity of aldehyde towards nucleophiles. As shown in Scheme 3, phos-
phate anions/or hydroxyl groups on the surface of the catalyst as a hydrogen bond
donors activating the O–H of 4-hydroxycoumarin (as a hydrogen bond acceptor)
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B. Akhlaghinia et al.
Table 2 Synthesis of biscoumarin derivatives catalyzed by HAP/Fe3O4 NPs (III) in solvent-free condi-
tions at 90 °C
Entry
1
R
Product
Time (min)
60
Isolated yield (%)
C6H5
95
2
4-O2N-C6H4
15
95
3
4-NC- C6H4
15
95
4
5
4-F- C6H4
20
30
95
98
4-Cl- C6H4
6
3-Br- C6H4
40
95
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The magnetic nanostructured natural hydroxyapatite…
Table 2 (continued)
Entry
R
Product
Time (min)
75
Isolated yield (%)
98
7
4-CH3- C6H4
8
4-CH3O- C6H4
70
90
9
4-HO-C6H4
80
90
85
10
4-(Me)2NC6H4
100
11
12
2-thienyl
2-furyl
90
90
85
98
13
4-pyridyl
80
95
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B. Akhlaghinia et al.
Table 2 (continued)
Entry
R
Product
Time (min)
Isolated yield (%)
14
CH2=CH2-C6H4
80
90
15
H
110
95
16
(CH2)5CH3
240
85
which leads to formation of II. Nucleophilic addition of II to catalyst-aldehyde com-
plex I followed by loss of H2O generates intermediate III. Further, this intermediate
is activated again by the catalyst and after the second nucleophilic attack of another
activated molecule of 4-hydroxycoumarin (II), compound IV is provided. Finally, V
is formed upon tautomerization of IV as the more stable tautomeric form with high
efciency. Then, the nanostructured catalyst re-enters the catalytic cycle for further
turnovers. However, at the present time there is no experimental evidence for the
one-pot Knoevenagel-Michael addition reaction proceeding in this manner and fur-
ther investigation to elucidate the details of the mechanism are ongoing.
As the long-term durability is one of the important advantages in the feld of het-
erogeneous nanocatalysts, the reusability of HAP/Fe3O4 NPs(III) was investigated
on a model reaction (between benzaldehyde and 4-hydroxycoumarin) under the opti-
mized reaction conditions. To this end, after completion of the reaction which was
monitored by TLC, the magnetic nanocatalyst was separated via an external mag-
netic feld, washed in turn with water (20 mL) and boiled ethyl acetate (20 mL) for
several times to remove the residual of organic compounds, and then dried at 60 °C
for 12 h. Thereafter, a new condensation reaction was done under the optimized
reaction conditions using the recovered nanocatalyst. The results were presented in
Fig. 7. As it is evident from Fig. 7, no signifcant change was observed in the yield
of the desired product during the recycling process. The obtained results clearly
confrmed that the catalytic activity of the as-synthesized magnetic nanostructured
natural hydroxyapatite (HAP/Fe3O4NPs(III)) was preserved during the recovery
process, and the catalyst was stable up to six recycle runs under the optimized reac-
tion conditions.
1 3

The magnetic nanostructured natural hydroxyapatite…
Scheme 3 Probable mechanism for the synthesis of biscoumarin derivatives catalysed by HAP/Fe3O4
NPs
Fig. 7 Synthesis of biscoumarin derivatives in the presence of 6th reused HAP/Fe3O4 NPs (III)
The FT-IR spectrum of the nanostructured catalyst recovered after the sixth run
(Fig. 1d) confrmed no substantial changes in the chemical structure of the func-
tional groups and hydrogen bonding network of the HAP/Fe3O4 NPs(III). These
1 3

B. Akhlaghinia et al.
results arise from the entire preservation of the shape, position and relative intensity
of the indicative absorption bands.
In another variation, the efciency of HAP/Fe3O4 NPs (III) was compared with
that of catalysts reported by others for the synthesis of biscoumarin derivatives. We
have tabulated the results of some commonly homogeneous and heterogeneous cata-
lysts in the literature for the same transformation in Table 3. As Table 3 indicates,
despite the merits of most of the previously reported methods, the newly developed
catalytic system acts better rather than other ones from the aspect of magnetically
separation of eco‐benign recyclable catalyst from the reaction mixture which pro-
vides easy and less time consuming work-up procedure.
Conclusion
In summary, the preparation, characterization and new application of the magnetic
nanostructured natural hydroxyapatite (HAP/Fe3O4 NPs(III)) as a green and mild
magnetically recyclable nanocatalyst in a one-pot three-component condensation
reaction of two molecules of 4-hydroxycoumarin and various aldehydes (aromatic,
heteroaromatic, aliphatic and α,β-unsaturated) under green, mild and solvent-free
conditions were described. The results clearly show that the new methodology for
preparation of biscoumarin derivatives regardless of the nature of the substitution
(electron donating and electron withdrawing) of the aromatic aldehydes can tolerate
a wide range of diferently substituted aldehydes. The present method includes some
important aspects such as relative environmental benignity, avoidance of toxic cata-
lyst and hazardous organic solvents, cleaner reaction profle, use of magnetic sepa-
rable catalyst, easy work-up and product isolation, short reaction time, good pro-
ductivity, recyclability and reusability of the nanostructured catalyst up to six runs,
which make this protocol in accord with green and sustainable chemistry. We feel
that this protocol is an attractive alternative to the currently reported methods for the
synthesis of biscoumarin derivatives.
Experimental
General
The purity determinations of the products and the progress of the reactions were
accomplished by TLC on silica gel polygram STL G/UV 254 plates. The melting
points of products were determined with an Electrothermal Type 9100 melting point
apparatus. The FT-IR spectra were recorded on an Avatar 370 FT-IR Thermo Nico-
let spectrometer and PerkinElmer Spectrum Version 10.03.02. The NMR spectra
were recorded on a 300 MHz Bruker Avance instrument in DMSO-d6 or CDCl3.
Elemental analysis was performed using a Thermo Finnigan Flash EA 1112 Series
instrument. Mass spectra were recorded with a CH7A Varianmat Bremem instru-
ment at 70 eV electron impact ionization, in m/z (rel %). The crystal structure of cat-
alyst was analyzed by XRD using a D8 ADVANCE-Bruker difractometer operated
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The magnetic nanostructured natural hydroxyapatite…
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B. Akhlaghinia et al.
at 40 kV and 30 mA utilizing Cu Kα radiation (λ=0.154 Å). Transmission electron
microscopy (TEM) was performed using a TEM microscope Leo 912 AB micro-
scope (Zeiss, Germany) and Philips CM30 with an accelerating voltage of 120 kV
and 150 kV, respectively. Elemental compositions were determined with an SC7620
energy-dispersive X-ray analysis (EDX) presenting a 133 eV resolution at 20 kV.
Thermogravimetric analyses (TGA) were carried out using a Shimadzu Thermo-
°
gravimetric Analyzer (TG-50) in the temperature range of 25–950 C at a heating
°
rate of 10 C min−1 under air atmosphere. The magnetic property of the catalyst
was measured using a vibrating sample magnetometer (VSM, 7400 Lake Shore and
VSM, Magnetic Danesh Pajoh Inst.). All of the products were isolated as solids
and all yields refer to isolated products after purifcation by recrystallization. HAP/
Fe3O4 NPs were prepared using a method previously reported in the literature [61].
Typical procedure for the synthesis
of 3,3’‑(phenylmethylene)‑bis‑(4‑hydroxy‑2H‑chromene‑2‑one) in the presence
of HAP/Fe3O4 NPs(III)
A glass tube was charged by benzaldehyde (1 mmol, 0.106 g), 4-hydroxycoumarin
(2 mmol, 0.324 g) and HAP/Fe3O4 NPs(III) (0.008 g). Thereafter, the reaction mix-
ture was heated up to 90 °C for a certain time (60 min) under solvent-free conditions.
After completion of the reaction which was monitored by TLC, the reaction mix-
ture was cooled to room temperature by adding cold water (3 mL). The nanocatalyst
was separated by an external magnetic feld, washed in turn with water (20 mL),
boiled ethyl acetate (20 mL) for several times to remove the residual of organic com-
°
pounds before drying at 60 C for 12 h (for using in the subsequent catalytic run).
Afterwards, the resultant mixture was fltered to obtain the solid target product. The
pure 3,3′-(phenylmethylene)-bis-(4-hydroxy-2H-chromene-2-one) was obtained by
recrystallization from ethanol (0.391 g, 95%).
Acknowledgements The authors gratefully acknowledge the partial support of this study by the Ferdowsi
University of Mashhad Research Council (Grant No. 2/47664).
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