Thiourea-functionalized magnetic hydroxyapatite as a recyclable inorganic-organic hybrid nanocatalyst for conjugate hydrocyanation of chalcones with TMSCN

Article abstract of DOI:10.1016/j.catcom.2015.08.016

The recoverable nanomagnetic catalyst was manufactured based on thiourea modified magnetic hydroxyapatite. Magnetic hydroxyapatite (mHAp) as the inorganic-organic hybrid support was fabricated using co-precipitate condition and then modified via the covalently anchoring of 1-(3,5-bis(trifluoromethyl)phenyl-3-propyl)thiourea. The hybrid nano-catalyst has been identified by TEM, SEM, FTIR, BET, TGA, and XRD. This nanocatalyst appeared efficient and robust in the 1,4-addition reaction of TMSCN to α,β-unsaturated aromatic enones in excellent yields (85-96%) under mild reaction condition and simple work-up process. This recoverable organocatalyst has a great potential as an industrially viable and eco-safe catalyst.

Full text of DOI:10.1016/j.catcom.2015.08.016

Catalysis Communications 72 (2015) 6–10
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short communication
Thiourea-functionalized magnetic hydroxyapatite as a recyclable
inorganic–organic hybrid nanocatalyst for conjugate hydrocyanation of
chalcones with TMSCN
a,
b
c
d
Afsaneh Arefi Oskouie ⁎, Salman Taheri , Leila Mamani , Akbar Heydari
a
Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, P.O.Box: 19395-4618 Tehran, Iran
Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
Nanotechnology Department, Agricultural Biotechnology Research Institute of Iran (ABRII), Karaj, Iran
Chemistry Department, Tarbiat Modarres University, Tehran, Iran
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2015
Received in revised form 12 August 2015
Accepted 13 August 2015
Available online 3 September 2015
The recoverable nanomagnetic catalyst was manufactured based on thiourea modified magnetic hydroxyapatite.
Magnetic hydroxyapatite (mHAp) as the inorganic–organic hybrid support was fabricated using co-precipitate con-
dition and then modified via the covalently anchoring of 1-(3,5-bis(trifluoromethyl)phenyl-3-propyl)thiourea. The
hybrid nano-catalyst has been identified by TEM, SEM, FTIR, BET, TGA, and XRD. This nanocatalyst appeared efficient
and robust in the 1,4-addition reaction of TMSCN to α,β-unsaturated aromatic enones in excellent yields (85–96%)
under mild reaction condition and simple work-up process. This recoverable organocatalyst has a great potential as
an industrially viable and eco-safe catalyst.
Keywords:
Chalcones
Conjugate hydrocyanation
Recoverable nanomagnetic catalyst
Thiourea modified magnetic hydroxyapatite
© 2015 Elsevier B.V. All rights reserved.
1
. Introduction
The nucleophilic 1, 4-addition is one of the most interesting reac-
extra, and in some cases the protocols involve the usage of harsh condi-
tions and laborious aqueous work-up leading in the production of the
large amount of unwanted products such as hydrogen cyanide. Further-
more the safety worries, the reaction mixture has become highly col-
ored on reaching reflux. Among different cyanide sources, TMSCN has
been used as a safer and more effectual cyanide anion source compared
to the above cyanide reagents [13].
tions that always has been a significant notice [1]. Michael reaction
has many applications in diverse fields such as coating, synthesis of
bioactive natural products, and toxicity, but there is always the problem
of competition between 1, 4-addition and 1, 2-addition reactions [2,3].
Improvement of organic catalysts for the nucleophilic 1, 4-addition
is still an interesting subject in synthetic chemistry. There are a few
useful methods for hydrocyanation using various cyanation reagents
such as hydrogen cyanide, alkali or earth metal cyanides,
organoaluminum cyanide, organosilicon cyanide, and acetone cyanohy-
drin, which can generate cyanide ion in the presence of a base. Lapworth
procedure used potassium cyanide [4] and Nazarov base catalyzed
hydrocyanation used acetone cyanohydrin as the cyanide source [5].
Recently nanomagnetic catalysis has emerged as a remarkable issue
to create ideal systems for broad biological, medical, and catalytic appli-
cations [14–16]. Indeed, owing to the demands of clean technology,
there are many reports about the synthesis and applying of recyclable
nano-catalysts [17–20]. In spite of these reports, the introduction of
novel green catalysts and reagents has still remained as an interesting
challenge. In the traditional heterogenization (surface immobilization
on inorganic materials) the catalyst recovery was improved, but the
high rigidity of the support containing catalytic centers leads to a
decrease in the disposal catalytic centers for the reactants [21,22].
Therefore, “inorganic–organic hybrid materials” which are achievable
by grafting of flexible organic spacers on the surface, have introduced
as applicable tools to overcome this shortcoming. The delicate advan-
tage of these compounds is the favorable germination of the organic
and inorganic characteristics such as high reactivity and stability
[23–25]. Due to the high stability, surface area, surface manipulation
Some Lewis acid catalysts have been used for example Et
2
AlCN
[8]. Previously, Ellis used
25 mol% of acetone cyanohydrin and 5 mol% of tetramethyl ammoni-
(
1
3 3
Nagata's reagent) [6], Et Al [7], and AlCl
um hydroxide [9] and Hamana applied MW irradiations without any
catalyst [10]. CsF catalyst with water was applied as additive in refluxing
dioxane [11]. Recently Lalitha et al. reported scandium(III) triflate with
tetraethylammonium cyanide as a cyanide source [12]. In most hydro-
genation methods the amount of cyanide source has been applied
4 6 2
ability and low toxicity, hydroxyapatite (HAp) “Ca10(PO ) (OH) ” has
been used as a robust material for drug and protein delivery agent
⁎
Corresponding author.
E-mail address: a.arefi@sbmu.ac.ir (A.A. Oskouie).
[26–29] and catalyst supporting material [30–32]. Thiourea derivatives
http://dx.doi.org/10.1016/j.catcom.2015.08.016
566-7367/© 2015 Elsevier B.V. All rights reserved.
1

A.A. Oskouie et al. / Catalysis Communications 72 (2015) 6–10
7
Scheme 1. a) Synthesis of organosilane I, and b) thiourea functionalized mHAp.
are regarded as typical and fundamental organo-catalytic compounds
and in many kinds of base and hydrogen bond catalyzed reactions has
been used for C–C bond formation [33–34]. In this regards, we wish to
report a green magnetically recoverable thiourea based organocatalyst
for hydrocyanation of chalcone derivatives.
2
washed with Et O. Afterwards, It was further purified by soxhlet extrac-
tion with EtOH and then dried under vacuum for 24 h at 50 °C to give the
thiourea functionalized magnetic nanoparticles at a loading about
0.93 + 0.01 per gram of catalyst (determined by TGA analysis).
2.2. General procedure for the synthesis of beta ketonitrile 3
2
2
2
. Experimental section
1
.1 mmol of TMSCN was added to a mixture of thiourea functional-
.1. Preparation of catalyst
ized mHAp (5.5 mg, 0.5 mol%) and 1 mmol a chalcone in 4 mL of H O
2
and allowed to stir at 50 °C. The reaction progress was monitored by
TLC. At the end of the reaction, the nanocatalyst was separated from
the reaction mixture by an external magnet. Then the resulting suspen-
sion was concentrated on a rotary evaporator. The product was obtain-
.1.1. Synthesis of organosilane I
N′-(3,5-bis-trifluoromethylphenyl)
isothiocyanate
and
trimethylsilyloxypropyl amine in 1:1 mol ratio was refluxed in
dry EtOH for 2 h under Ar atmosphere. After evaporation of the
2
ed via purification of the residue by recrystallization on EtOH/H O (4:1)
solvent and washing with 100 mL Et
um at 100 °C to give 1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-
2
O, the solid was dried under vacu-
to afford the pure products. For testing the recovery of catalyst, the
separated catalyst was washed with hot EtOH and also acetone or
Et O to remove the residual product, and dried to reuse in the subse-
2
1
(
trimethoxysilyl)propyl)thiourea (organosilane I). HNMR (500 MHz,
MeOD):8.16 (s, 2H), 7.61 (s, 1H), 3.55 (s, 9H), 3.3 (t, 2H), 1.73 (m,
quent runs. All isolated products gave satisfactory spectral data com-
pared with those reported in literature.
2
H), .68 (t, J = 6.0 Hz, 2H).
2
.1.2. Synthesis of thiourea functionalized mHAp
3. Results and discussion
1
g of mHAp which was prepared according to the previously report-
ed method was pre-activated by heating under vacuum for 48 h at 120
C [35]. Then the activated magnetic HAp was suspended in a mixture of
00 mL of dry toluene containing organosilane I (3 mmol, 1.35 g). The
mixture was refluxed under Ar atmosphere at 100 °C for 24 h. The re-
sulted solid was separated by an external magnetic device and then
To achieve the desired organocatalyst, we synthesized a magnetically
recoverable organocatalyst based on thiourea using magnetic hydroxyap-
atite as a robust supporting material according to the procedure shown in
Scheme 1. Afterwards, to achieve the organosilane I, the equimolar
amount of N′-(3,5-bistrifluoromethylphenyl) isothiocyanate was reacted
°
1
Fig. 1. a) The isotherm plot, and b) VSM curve of mHAp and functionalized mHAp nanoparticles.

8
A.A. Oskouie et al. / Catalysis Communications 72 (2015) 6–10
Fig. 2. a) TEM, SEM, and c) EDX micrographs of thiourea functionalized mHAp.
with trimethylsilyloxy propyl amine in dry EtOH (Scheme 1a), and
onto the surface of mHAp. The synthetic powder showed a type (IV)
nitrogen adsorption–desorption isotherm (Fig. 1a). The synthesized
core-shell catalyst possesses sufficient superparamagnetic characteris-
tic for practical applications. Magnetic hysteresis measurements were
done in an applied magnetic field at r.t, with the field sweeping from
−8000 to +8000 Oe using a vibrating sample magnetometer (VSM)
as a scientific instrument for measuring magnetic properties. As
shown in Fig. 1b, the M (H) hysteresis loop for the samples was
completely reversible. The magnetic saturation values of the mHAp
1
13
was confirmed by FTIR, HNMR and CNMR. Then the synthesized
organosilane I was grafted onto the surface of mHAp to synthesize
thiourea functionalized mHAp as a magnetic thiourea-based inorganic–
organic hybrid material (Scheme 1b).
The nanoparticles were characterized by different techniques such
as FT-IR, TGA, VSM, TEM and SEM. In the FT-IR spectra characteristic ab-
sorption bands due to the bending vibration of O–P–O group in the HAp
−
1
shell were observed at 581 and 617 cm
and the stretching of P–O
−
1
bond appeared at 1063 cm . The C_S and C–N stretching bands of
thiourea group appeared at 1546 and 1314 cm , respectively. Also,
and thiourea functionalized mHAp Nanocrystallites are 7.2 and
−
1
−1
4.5 emu·g
at r.t, respectively. Decreased magnetic saturation of
the bending vibration modes of O–Si–O and thiourea functional group
mHAp thiourea functionalized NPs is attributed to the influence of the
grafted organic moiety. Both particles show high permeability in mag-
netization and their magnetization is sufficient for magnetic separation
with a conventional magnet.
were observed at 677 cm− and 1270 cm , respectively. The surface
1
−1
area of the mHAp and thiourea functionalized mHAp was determined
2
−1
utilization BET analysis showed reduction from 224 m ·g
8
to
2
−1
9 m ·g which revealed the success of the immobilization of thiourea
Quantitative determination of the thiourea-based functionality load-
ing was performed by using TGA analysis. TGA analysis of the catalyst
showed a first peak due to desorption of water (centered at 97 °C).
This was followed by a second decrease from 337 °C to 592 °C, corre-
sponding to the loss of the organic functional group. With the knowl-
edge of the thermal decomposition of the mHAp and thiourea
functionalized mHAp, it was concluded that the loading of the thiourea
moiety on the surface was about 0.93 + 0.01 mmol per gram of catalyst.
The SEM, EDX, and TEM images of thiourea functionalized mHAp nano-
particles were shown in Fig. 2.
Table 1
Optimization of the model reaction condition.
Entry
Catalyst
Solvent
mol%
Time(h)
Yield%
1
2
3
4
5
6
7
8
–
H
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
OH
OH
OH
OH
OH
OH
–
24
24
24
24
24
1
0
0
0
3
PW12
O
40
10
10
5
50
0.5
0.5
1
Oxalic acid
Guanidine hydrochloride
mHAp
Thiourea functionalized mHAp
Thiourea functionalized mHAp
Thiourea functionalized mHAp
0
10
86
90
90
To evaluate the capability of thiourea functionalized mHAp, nucleo-
philic 1,4-addition of TMSCN to α,β-unsaturated aromatic enones was
selected as a model reaction. The reaction generally involves the nucle-
ophilic addition of activated cyanide ion 2 to chalcone 1 to form
H
H
2
O
O
6
3
2
Table 2
Efficient synthesis ofβ-ketonitriles.
Entry
Ar
Ph
4-MePh
Ph
Ph
Ph
4-Br–Ph
R
1
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
H
H
OMe
Br
Ph
H
Cl
H
NO
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
92
85
96
89
90
91
92
85
89
1-Naphtyl
4-Cl–Ph
Ph
2
10
4-NO
2
-Ph
3j
a
Isolated yield.

A.A. Oskouie et al. / Catalysis Communications 72 (2015) 6–10
9
Fig. 3. The reusability test of the catalyst.
cyanohydrin trimethylsilyl ether which undergoes in situ desilylation
by thiourea functionalized mHAp (Scheme 1). The 1, 4-addition reac-
tions take place smoothly leading to the corresponding β-keto nitriles
biocompatibility. We found that thiourea functionalized mHAp can be ap-
plied as a novel and simple magnetic separable heterogeneous
organocatalyst for selective and highly efficient 1, 4-addition reaction of
chalcones and related enones with TMSCN. Based on these observations,
it can be concluded that the operational simplicity, practicability, easy ap-
proachability of reactive centre and environmentally benefits are the
worthy advantages of this green and cost-effective catalyst. The intro-
duced thiourea functionalized mHAp is in particular highly stable and
can be reused in ten successive runs with no significant structural change
and loss of catalytic activity. This method proposes several advantages
such as high yields, simple work-up condition, high selectivity and
straightforward starting from easily accessible starting materials, which
makes it a useful and attractive strategy for the preparation of beta-
ketonitriles.
3
in excellent to good yields. Initially we set out to investigate solvent,
amount of catalyst, and time effects in the reaction of chalcone 1a and
TMSCN 2 as a simple model substrate (Table 1). The results showed
that the presence of a catalyst is required to achieve the products.
The effect of solvent was studied using various solvents, with
MeOH and H O providing the highest yields and short reaction
2
times. With respect to the green chemistry goals and the mol% of cat-
alyst, time and solvent, the best optimized condition is: thiourea
functionalized mHAp (0.5 mol%), H
2
O as solvent (4 ml) at 50 °C for
6
h (Table 1, Entry 7). As shown in Table 2, in this method we have
seen only the desired product 1, 4-adduct and the 1, 2-adduct was
not seen. The products were satisfactorily characterized by its
1
13
HNMR, CNMR and melting points.
Acknowledgements
With regard to the success of the above reaction, various
chalcones were subjected to this reaction (Table 2). The reactions
proceed in the presence of thiourea functionalized mHAp under op-
timal condition. Through this protocol the 1,4-addition reaction of
TMSCN to α,β-unsaturated aromatic enones was accomplished in
excellent yields (85–96%) under mild reaction condition and simple
work-up process. Notably, no undesirable side reactions (1, 2-
addition) were observed under this reaction condition. Spectral
analysis of the β-ketonitrile products clearly indicated the formation
of 3a-j.
We gratefully acknowledge the financial support from the Depart-
ment of Basic Science, Faculty of Paramedical Sciences, Shahid Beheshti
University of Medical Sciences.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.catcom.2015.08.016.
We have also tried to evaluate the recyclability of the nanocatalyst at
least ten times. To this purpose, the separated catalyst was thoroughly
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