Polyfluorinated-zinc(II)phthalocyanine complex immobilized on silica: A novel, highly selective and recyclable inorganic-organic hybrid catalyst for the synthesis of biologically important 1,5-benzodiazepines

Article abstract of DOI:10.1016/j.ica.2012.11.012

A novel, efficient and recyclable catalyst was prepared by covalent grafting of polyfluorinated-zinc(II)phthalocyanine complex onto functionalized silica gel. The activity of the catalyst was investigated for the solvent-free synthesis of 1,5-benzodiazepi

Full text of DOI:10.1016/j.ica.2012.11.012

Inorganica Chimica Acta 397 (2013) 21–31
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Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Polyfluorinated–zinc(II)phthalocyanine complex immobilized on silica: A novel,
highly selective and recyclable inorganic–organic hybrid catalyst for the synthesis
of biologically important 1,5-benzodiazepines
⇑
R.K. Sharma , Shikha Gulati, Amit Pandey
Green Chemistry Network Centre, Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 April 2012
Received in revised form 28 August 2012
Accepted 12 November 2012
Available online 1 December 2012
A
novel, efficient and recyclable catalyst was prepared by covalent grafting of polyfluorinated–
zinc(II)phthalocyanine complex onto functionalized silica gel. The activity of the catalyst was investi-
gated for the solvent-free synthesis of 1,5-benzodiazepines at room temperature. The immobilized
catalyst was characterized by elemental analysis (CHN), diffuse reflectance UV–Vis spectroscopy, solid-
state 13C CPMAS and 29Si CPMAS NMR spectroscopy, X-ray diffraction (XRD), scanning electron micros-
copy (SEM), BET surface area analysis, energy dispersive X-ray fluorescence (ED-XRF), Fourier transform
Infrared (FT-IR) and atomic absorption spectroscopy (AAS) techniques. Short reaction time, mild reaction
conditions, high turnover numbers, and easy recovery and reusability of the catalyst make this method a
novel, economic and waste-free chemical process for the synthesis of biologically important 1,5-
benzodiazepines.
Keywords:
Silica
Phthalocyanine
Immobilization
Catalyst
Ó 2012 Elsevier B.V. All rights reserved.
Benzodiazepine
1. Introduction
polyfluorinated compounds are very effective catalysts due to their
highly hydrophobic nature, high stability (thermal and chemical),
The use of low-cost and readily available species as catalyst
plays a significant role for economical feasibility of the chemical
processes. Metallophthalocyanines (MPcs) being thermally stable,
easily accessible and cost-effective, are very attractive from this
viewpoint [1–4]. However, due to their strong tendency towards
aggregation [5] and difficulty in separation from reaction mixture,
immobilization of MPcs on solid supports is carried out to make
catalysts recoverable and recyclable [6–10]. Several types of sup-
port materials and immobilization strategies are used to convert
homogeneous catalysts into the heterogeneous ones [11]. The
covalent immobilization of catalysts on inorganic supports not
only gives good catalyst recycling results but also shows minimal
influence on the catalytic site by the support. Among various inor-
ganic support materials, silica gel is highly preferred since it pos-
sesses high surface area, excellent stability (thermal and
mechanical), ready availability, economic viability, and organic or
organometallic moieties can be robustly anchored on the surface
[12–17].
and no steric strain due to the small size of fluorine atoms [18].
Considering the above advantages, novel polyfluorinated–
zinc(II)phthalocyanine complex has been synthesized and immobi-
lized on silica gel, and used as a catalyst in the synthesis of
1,5-benzodiazepines.
a
Benzodiazepines are very important class of biologically ac-
tive heterocyclic systems. The synthesis of these compounds
has been receiving a great deal of attention in the field of medic-
inal and pharmaceutical chemistry owing to their application as
anticonvulsant, anti-depressant, anti-inflammatory, analgesic,
hypnotic and sedative agents, and are now one of the most
widely prescribed class of psychotropics [19–25]. Generally,
1,5-benzodiazepines are synthesized by condensation reaction
of o-phenylenediamines (OPDAs) with ketones, and due to their
extensive range of activity and importance, this transformation is
catalyzed by a plethora of reagents [26–31]. However, most of
them involved excess amount of catalyst, harsh reaction condi-
tions, prolonged reaction times, toxic and expensive organic sol-
vents, unsatisfactory yields, tedious work-up procedures, low
selectivity, co-occurrence of several side reactions, and need of
chromatography for purification of adducts. So, these methods
are environmentally unsound, especially with regard to large-
scale synthesis. Therefore, there is a growing demand for mild,
economic and environmentally benign catalytic methods which
will allow facile recovery of the catalyst from the reaction media.
In recent years, considerable emphasis has been placed on fluo-
rine chemistry because of major commercial significance of fluori-
nated organic and organometallic compounds in pharmaceuticals,
agrochemicals, materials and polymer industries. In particular,
⇑
Corresponding author. Tel./fax: +91 011 27666250.
E-mail address: rksharmagreenchem@hotmail.com (R.K. Sharma).
0020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2012.11.012

22
R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
Taking into consideration all the aforementioned limitations, and
functionalized silica by covalent grafting method. The resulting inor-
ganic–organic hybrid material was applied as catalyst for the solvent-
free synthesis of biologically important 1,5-benzodiazepines. The use
of recoverable catalyst in combination with solvent-free reaction
conditions leads to enhancement in conversions with several advan-
tages of the eco-friendly approach, termed green chemistry [42].
in continuation of our work on the synthesis of inorganic–
organic hybrid materials, and their applications as metal scavengers,
sensors, and catalysts for various organic transformations
[32–41], herein we report the synthesis of polyfluorinated–zinc(II)
phthalocyanine complex, and its subsequent immobilization on
H2O
(CH3CH2O)3Si(CH2)3NH2
(HO)3Si(CH2)3NH2
Hydrolysis
Si-O
Si-O
Si-O
Si-OH
Si-OH
Si-OH
Condensation
-3H2O
(HO)3Si(CH2)3NH2
Silica
F
Silica
Si (CH2)3NH2
F
F
F
F
O
N
N
N
F
F
F
F
F
F
F
O
F
N
Zn
O
F
N
N
O
F
F
N
N
F
F
F
F
DMAE
(Reflux)
F
F
F
F
F
O
N
N
F
F
F
F
F
Si (CH2)3NH
F
F
O
F
N
Si-O
Si-O
Si-O
Silica
Zn
O
N
F
N
N
O
F
N
N
F
F
F
F
Scheme 1. Preparation of silica-supported zinc phthalocyanine complex (ZnPcOC6F5–APTES@SiO2).

R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
23
methanol/water mixture, and dried under vacuum to give a dark
2. Experimental
green powder. Yield: 75%; melting point: >200 °C; Anal. Calc. for
C
56H12F20N8O4Zn: C, 51.50, H, 0.93, N, 8.58, Zn, 5.01. Found: C,
2.1. General remarks
52.48, H, 1.01, N, 8.56, Zn, 4.98%. IR
m
(cmÀ1): 3422 (aromatic C–
H), 1616 (aromatic C@C), 1460 (aromatic C@N), 1287 (C–O–C),
1108 (C@N), 460 (Zn@N); UV–Vis (N-methyl-2-pyrrolidinone),
kmax(nm): 705.
Scanning electron microscopy (SEM) images were obtained
using a ZEISS EVO 40 instrument. The samples were placed on a
carbon tape and then coated with a thin layer of gold using a sput-
ter coater. Powder X-ray diffraction (XRD) patterns were recorded
on Bruker D8 ADVANCE X-ray diffractometer using graphite
2.3.2. Synthesis of aminopropylated silica gel (APTES@SiO2)
The grafting of APTES on silica gel was performed using a green-
er protocol. One milliliter of APTES was dissolved in 100 mL of dis-
tilled water acidified with acetic acid (pH 4). Then, 2 g of activated
silica gel (dried in oven at 150 °C for 18 h) was added in the silane
solution and stirred for 2 h at room temperature. The product was
filtered off and kept in oven at 150 °C for 4 h. The dried product
was washed consecutively with water, ethanol and acetone to re-
move the un-grafted material, and dried for another 2 h at 120 °C
(Scheme 1).
monochromatized Cu Ka radiation. The UV–Vis diffuse reflectance
spectrum of the catalyst was obtained over the spectral range 300–
800 nm using Perkin Elmer Lambda 35 scanning double beam
spectrometer equipped with a 50 mm integrating sphere. The
surface area was measured with Gemini-V2.00 instrument
(Micromeritics Instrument Corp.). Solid-state 13C and 29Si cross-
polarization magic-angle spinning (CPMAS) NMR spectra were re-
corded on Bruker DSX-300 NMR spectrometer. Elemental analysis
for CHN was performed using Elementar Analysensysteme GmbH
VarioEL V3.00 instrument. The microwave-assisted syntheses and
digestion were carried out in Anton Paar multiwave 3000 micro-
wave reaction system equipped with temperature and pressure
sensor. Energy dispersive X-ray fluorescence (ED-XRF) spectro-
scopic studies were performed on Fischerscope X-ray XAN-FAD
BC. The amount of zinc in the catalyst was determined by Atomic
absorption spectroscopy (AAS) using LABINDIA AA 7000 Atomic
Absorption Spectrometer. All experiments were carried out in trip-
licate. Specord 250 spectrophotometer was used to obtain the elec-
tronic spectra of the complex in N-methyl-2-pyrrolidinone as a
solvent. The Fourier transform infrared (FT-IR) spectra of the com-
pounds were recorded using Perkin-Elmer Spectrum 2000 at room
temperature using KBr pellet technique in the range of 4000–
400 cmÀ1 under the atmospheric conditions with a resolution of
1 cmÀ1. All samples and KBr were dried at 100 °C overnight before
KBr pellets preparation. Melting points were recorded on a Buchi
R-535 apparatus and are uncorrected. 1H NMR spectra were re-
corded on JEOL ECX 400 NMR spectrometer operating at
400 MHz. Chemical shifts (d) were reported relative to TMS. The
products obtained were analyzed and confirmed on an Agilent
gas chromatography (6850 GC) with a quadrupole mass filter
equipped 5975 mass selective detector (MSD) using helium as car-
rier gas (rate 0.9 ml minÀ1).
2.3.3. Synthesis of immobilized zinc complex (ZnPcOC6F5–APTES@SiO2)
A mixture of APTES@SiO2 (5 g) and ZnPcOC6F5 (0.75 mmol)
solution in dimethylaminoethanol was stirred and refluxed for
4 h. After that, the material was filtered, washed with water and
dried in vacuum oven to give a green solid material, ZnPcOC6F5–
APTES@SiO2 (Scheme 1).
2.4. Catalytic studies
A
reaction vessel was charged with o-phenylenediamine
(1.0 mmol), ketone (2.2 mmol) and ZnPcOC6F5–APTES@SiO2 cata-
lyst (30 mg), and the whole reaction mixture was stirred at room
temperature for an appropriate time (20–35 min). After the com-
pletion of reaction, monitored by TLC (ethyl acetate:hexane, 8:2)
and GC, the reaction contents were subjected to multiple ethyl ace-
tate extractions. The catalyst was filtered and washed with ethyl
acetate. The combined organic layers were washed with brine,
and dried over anhydrous Na2SO4 followed by GC–MS analysis.
All products were also characterized by using NMR, elemental
analysis (CHN), mass spectra and melting points, and compared
with literature data (Supplementary material) [26,30,31,53–56].
2.2. Chemical reagents
3-Aminopropyltriethoxy silane (APTES) (98%), silica gel (60–100
mesh), 4-nitrophthalonitrile and pentafluorophenol were procured
from Sigma–Aldrich. N,N-dimethylaminoethanol (DMAE) (98%)
was obtained from Fluka, and used as such in this study. Starting
materials and reagents used in the reactions were obtained from
Spectrochem. Pvt. Ltd., India and used without purification.
2.3. Synthetic procedures
2.3.1. Synthesis of tetrakis-(perfluoro-phenoxy)phthalocyaninato
zinc(II) complex, (ZnPcOC6F5)
The phthalocyanine precursor, i.e., 4-(perfluorophenoxy)pht-
halonitrile was prepared according to the reported protocol [43]
with slight modification (Supplementary material). To prepare tet-
rakis-(perfluoro-phenoxy)phthalocyaninato zinc(II) complex [44],
a mixture of zinc acetate (0.025 mmol, 0.054 g), 4-(perfluorophen-
oxy)phthalonitrile (0.1 mmol, 0.31 g), N,N-dimethylaminoethanol
(DMAE) (5 ml) and DBU (0.05 mmol 0.087 ml) was irradiated in
microwave at 150 °C for 10 min. After cooling to room temperature
the solution was poured into methanol/water (3:1) and centri-
fuged. The precipitated solid was filtered off, washed with
Fig. 1. Diffuse reflectance UV–Vis spectra of (a) SiO2 and (b) ZnPcOC6F5–
APTES@SiO2.

24
R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
R2
R3
H
N
R1
NH2
NH2
R1
O
Catalyst.
R2
R3
N
R2
solvent-free, rt
o-phenylenediamines
Ketones
1,5-benzodiazepines
Scheme 2. Solvent-free synthesis of 1,5-benzodiazepines.
BET surface area measurements were carried out to analyze the
Table 1
grafting reactions. The surface area of the un-functionalized silica
was approximately 235 m2 gÀ1. The surface area of aminopropylat-
ed silica gel (APTES@SiO2) and immobilized complex
(ZnPcOC6F5–APTES@SiO2) was found to be 174 m2 gÀ1 and
166 m2 gÀ1, respectively. Generally, anchoring of organic and orga-
nometallic moieties on the silica surface blocks the access of nitro-
gen molecules, thus reducing the surface area. Therefore, the
reduction in surface area according to the sequence SiO2 >
APTES@SiO2 > ZnPcOC6F5–APTES@SiO2 confirmed the functionali-
zation of SiO2 with 3-aminopropyltriethoxy silane to give
APTES@SiO2, and its modification with ZnPcOC6F5 to yield the cat-
alyst, ZnPcOC6F5–APTES@SiO2. The elemental analysis data of
APTES@SiO2 showed the appearance of nitrogen (1.09%) as well
as the carbon surface content (2.94%), providing an evidence for
the APTES immobilization onto silica gel. The nitrogen loading of
APTES@SiO2 was found to be 0.77 mmol gÀ1. The observed carbon
and nitrogen contents of APTES@SiO2 also showed C/N ratio to be
ꢀ2.69 which is close to the expected value thereby confirming
the APTES grafting onto the surface of silica gel (Table 1). The
ninhydrin test was also performed to detect qualitatively the
existence of free amine groups on APTES@SiO2 [46]. The color of
the material changed from white to blue when the ninhydrin solu-
tion was added, confirming the presence of free amine groups. In
contrast, the test was negative for the silica gel (no color change).
The chemical analyses of ZnPcOC6F5–APTES@SiO2 (Table 1) re-
vealed the presence of organic matter with a C/N ratio roughly sim-
ilar to that of phthalocyanine. The metal loading of ZnPcOC6F5–
Physico-chemical parameters of SiO2, APTES@SiO2 and ZnPcOC6F5–APTES@SiO2
catalyst.
Material
Elemental analysis
BET surface
area (m2 gÀ1
)
%C
%H
%N
SiO2
APTES@SiO2
ZnPcOC6F5–APTES@SiO2
–
2.94
9.98
–
1.64
2.36
–
1.09
1.41
235
174
166
3. Results and discussion
3.1. Characterizations of immobilized zinc complex (ZnPcOC6F5–
APTES@SiO2)
Immobilized zinc complex (ZnPcOC6F5–APTES@SiO2) was pre-
pared by nucleophilic substitution of activated fluorine substituent
of ZnPcOC6F5 with the amino groups of aminopropylated silica gel
(APTES@SiO2) [45]. Thus, the covalent grafting of ZnPcOC6F5 com-
plex on APTES@SiO2 was confirmed by solid-state diffuse-reflec-
tance UV–Vis spectroscopy. The diffuse reflectance UV–Vis
spectrum of silica gel does not have any absorption band in the re-
gion of 300–900 nm. On the other hand, the diffuse reflectance UV–
Vis spectrum of ZnPcOC6F5–APTES@SiO2 (Fig. 1) shows broad
absorption band in the region of 550–800 nm due to ligand
p–
p⁄
electronic transitions which is comparable to those of the un-
grafted complex (Supplementary material), confirming that ZnP-
cOC6F5 complex has been covalently anchored on silica surface
without degradation. The blue shift was observed, indicating in-
APTES@SiO2 was confirmed by AAS and found to be 0.12 mmol gÀ1
.
Further to support the above observation, ZnPcOC6F5–APTES@SiO2-
was subjected to energy dispersive X-ray fluorescence. A well re-
solved peak of zinc in the ED-XRF spectrum (Fig. 2) confirms the
immobilization of ZnPcOC6F5 complex on APTES@SiO2.
creased
p overlap on immobilization of the phthalocyanine com-
plex (see Scheme 2) [13].
Fig. 2. ED-XRF spectrum of ZnPcOC6F5–APTES@SiO2.

R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
25
The FT-IR spectroscopy was employed to examine the covalent
grafting reactions (Supplementary material). The FT-IR spectrum of
silica exhibits the characteristic bands of the silica framework re-
lated to Si–O–Si asymmetric stretching (1087 cmÀ1), Si–O stretch-
ing of Si–OH and Si–OÀ groups on the surface (965 cmÀ1), Si–O–Si
symmetric stretching (800 cmÀ1) and Si–O–Si bending vibrations
(467 cmÀ1) [47–49]. Additionally, the spectrum presents a band
at 1645 cmÀ1 associated with H–O–H bending vibrations of physi-
cally adsorbed water and a broad band centered around 3460 cmÀ1
due to O–H stretching vibrations of hydrogen-bonded surface
silanol groups. The grafting of APTES onto silica was confirmed
by the appearance of new peak at 2925 cmÀ1 in the spectrum of
APTES@SiO2, which is due to the C–H stretching vibration of the
functionalized aminopropyl group. Also, the peak due to silanol
groups present in silica gel has disappeared in APTES@SiO2. Fur-
thermore, a significant reduction of the intensity of the O–H
stretching and bending vibrations bands was observed moving
from silica to APTES@SiO2. The peak around 1645 cmÀ1 attributed
to N–H bending vibration of –NH2 groups was overlapped by the
bending vibration of adsorbed H2O. By comparing the spectra of
APTES@SiO2 and ZnPcOC6F5–APTES@SiO2, it was found that the
absorption at 1645 cmÀ1 was shifted to 1654 cmÀ1, and also the
intensity of the peak has decreased confirming that ZnPcOC6F5
has been covalently anchored onto the surface of APTES@SiO2.
Fig. 3. (a) 13C CP-MAS NMR spectrum of APTES@SiO2 and (b) 29Si CP-MAS NMR spectrum of ZnPcOC6F5–APTES@SiO2.

26
R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
Table 2
Screening of catalyst for the synthesis of 1,5-benzodiazepines.a
Entry
Catalyst
Time (min)
Yield (%)
TONb (TOF)c
1
2
3
4
5
6
7
8
–
120
90
40
20
20
20
20
20
–
–
–
–
–
Zinc acetate
SiO2
15
62
73
81
85
99
ZnPcOC6F5 (0.001 mmol)
ZnPcOC6F5 (0.002 mmol)
ZnPcOC6F5 (0.003 mmol)
ZnPcOC6F5 (0.004 mmol)
ZnPcOC6F5–APTES@SiO2
620 (1865)
365 (1095)
270 (810)
236 (708)
275 (825)
a
Reaction conditions: OPDA (1.0 mmol), acetone (2.2 mmol), catalyst (30 mg,
0.36 mol%), room temperature.
b
TON, number of moles of product per mol of catalyst.
TOF, TON per hour (values in parentheses).
c
Fig. 4. X-ray diffraction patterns of (a) SiO2, (b) APTES@SiO2 and (c) ZnPcOC6F5–
APTES@SiO2.
The preservation of 3-aminopropyl group after functionaliza-
tion of silica gel with APTES was confirmed by solid state 13C
NMR spectroscopy. The 13C CPMAS NMR spectrum of APTES@SiO2
presents three well resolved peaks at 9.3, 22.3 and 42.9 ppm as-
signed to C1, C2, and C3 carbons of the incorporated aminopropyl
group O3SiCH2(1)CH2(2)CH2(3)NH2, respectively (Fig. 3a) which
authenticate the synthesis of APTES@SiO2 [50]. The covalent link-
age between the silanol groups and the organic moiety on the silica
can also be examined by 29Si CPMAS NMR spectroscopy. The solid-
state 29Si NMR spectrum of ZnPcOC6F5–APTES@SiO2 presents four
peaks (Fig. 3b): À57 ppm assigned to Si–OH of C–Si(OSi)2(OH)
group (T2) and À68 ppm assigned to C–Si(OSi)3 group (T3), which
provide direct evidence that the inorganic–organic hybrid sample
consists of a highly condensed siloxane network with an organic
group covalently bonded to the silica. Two other typical peaks cor-
respond to the inorganic polymeric structure of silica: À111 ppm
assigned to Si(OSi)4 group (Q4) and À101 ppm assigned to the free
silanol group of Si(OSi)3OH (Q3) [45].
Fig. 6. Effect of solvent on the yield of 1,5-benzodiazepine (reaction conditions:
OPDA (1.0 mmol), acetone (2.2 mmol), catalyst (30 mg), room temperature).
The structural features of the silica gel before and after func-
tionalization were checked by XRD measurements (Fig. 4). The
broad peak centered around 2h = 23o in the XRD patterns of silica
gel, APTES@SiO2 and ZnPcOC6F5–APTES@SiO2 is assigned to the dif-
fraction peak of amorphous silica, which clearly depicts that there
is no change in the topological structure of silica gel before and
after grafting reactions [51]. Apparently, by functionalizing silica
gel and eventually anchoring ZnPcOC6F5 complex, the intensities
of reflections have decreased significantly confirming the immobi-
lization [52].
The morphology of ZnPcOC6F5–APTES@SiO2 was examined by
SEM. During the preparation of APTES@SiO2 as well as ZnPcOC6F5–
Fig. 5. SEM images of (a) SiO2 and (b) ZnPcOC6F5–APTES@SiO2.

R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
27
had good mechanical stability, and they had not been destroyed
during the whole surface modification reactions.
3.2. Catalytic activity of ZnPcOC6F5–APTES@SiO2 for the synthesis of
1,5-benzodiazepines
Initially, for the optimization of reaction conditions, the reac-
tion of acetone with o-phenylenediamine was carried out as the
model reaction without solvent at room temperature. The reaction
did not occur in absence of catalyst, while it was very slow using
silica as catalyst. Moreover, in presence of ZnPcOC6F5 as catalyst,
we obtained moderate yield of the corresponding product, but
the main disadvantage of this catalyst was its non-reusability.
Hence, among the catalysts studied, ZnPcOC6F5–APTES@SiO2 was
found to be highly active and selective giving the desired product
in excellent yield (Table 2). Due to the various disadvantages of
using organic solvents such as toxicity, flammability and high cost,
there is a pressing need to circumvent the use of solvents com-
pletely in the chemical processes. In addition, solvent-free reac-
tions are usually quantitative and waste free and thus
environmentally benign. Therefore, we have studied this reaction
using various solvents and under solvent-free conditions in the
presence of catalyst. We found that solvent-free conditions were
more suitable and efficient in which a desired product was ob-
tained in excellent yield after 20 min. Inferior results were ob-
tained in the presence of various solvents (Fig. 6). Next, we
optimized the quantity of the catalyst (ZnPcOC6F5–APTES@SiO2)
(Fig. 7) and it was observed that on increasing the amount of cat-
alyst, yield also increased due to the availability of large number of
active sites on the porous surface of catalyst. Hence, in all cases,
Fig. 7. Effect of amount of catalyst on the yield of 1,5-benzodiazepine (reaction
conditions: OPDA (1.0 mmol), acetone (2.2 mmol), catalyst, solvent-free, room
temperature).
APTES@SiO2, the silica gel beads were subjected to rigorous stirring
but it is evident from SEM image (Fig. 5) that no clog between par-
ticles occurred during the grafting procedure, and the particles
maintained regular lumpy shape. It could be seen that the particles
appearance and size of silica gel and ZnPcOC6F5–APTES@SiO2 sam-
ples are very comparable, demonstrating that the particles of silica
Table 3
ZnPcOC6F5–APTES@SiO2 catalyzed synthesis of 1,5-benzodiazepines.a
Entry
1
OPDA
Ketone
Product
Time (min)
20
Yield (%)
99
TONb (TOF)c
275 (825)
NH2
NH2
O
H
N
N
2
20
98
272 (816)
NH2
NH2
O
H
N
N
3
4
25
30
96
91
266 (640)
NH2
O
H
N
NH2
NH2
N
252 (505)
O
H
N
NH2
N
(continued on next page)

28
R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
Table 3 (continued)
Entry
5
OPDA
Ketone
Product
Time (min)
Yield (%)
94
TONb (TOF)c
261 (522)
30
NH2
NH2
O
H
N
N
6
7
25
25
99
94
275 (660)
261 (626)
NH2
H
N
O
Cl
Cl
NH2
NH2
Cl
N
H
N
O
Cl
N
NH2
NH2
8
9
25
30
90
89
250 (600)
247 (494)
H
N
O
Cl
Cl
NH2
NH2
Cl
N
O
O
O
H
N
NH2
NH2
Cl
N
10
35
87
241 (414)
H
N
Cl
NH2
NH2
Cl
N
11
12
25
25
95
93
263 (633)
H
N
H3C
NH2
NH2
N
258 (620)
H
O
N
H3C
NH2
N
13
30
92
255 (511)
NH2
NH2
H
N
O
H3C
N

R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
29
Table 3 (continued)
Entry
14
OPDA
Ketone
Product
Time (min)
35
Yield (%)
88
TONb (TOF)c
244 (419)
NH2
NH2
NH2
NH2
O
H
N
H3C
N
15
35
89
247 (423)
O
H
N
H3C
N
a
b
c
Reaction conditions: OPDA (1.0 mmol), ketone (2.2 mmol), catalyst (30 mg), room temperature.
TON, number of moles of product per mol of catalyst.
TOF, TON per hour.
neat reactions were carried out at room temperature in presence of
30 mg of ZnPcOC6F5–APTES@SiO2 catalyst under solvent-free
conditions (Scheme 2 and Table 3).
In all cases, the reactions were completed within 20–35 min. It is
noteworthy that in unsymmetrical ketone such as 2-butanone, the
ring closure occurred selectively only from one side of the carbon skel-
eton yielding a single product indicating the selectivity of the present
catalytic system as compared to the reported ones. The reaction was
further extended to cyclic ketones (Table 3, entries 4–5) which react
without any significant difference to give the corresponding fused ring
R2
R3
R2
O
H2N
H2N
R1 R1
-2H2O
N
N
R3
R3
R2
Silica
ZnPc
O
R2
R3
Silica
R1
ZnPc
R2
R3
R3
R2
N
N
H
H
R2
R2
R3
R1
N
R1
N
R3
N
H
N
R2
R2
Scheme 3. Plausible reaction mechanism.

30
R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
1,5-benzodiazepines in good yields but after a longer time as com-
pared to the aliphatic ketones (Table 3, entries 1–3). Chloro-(Table
3, entries 6–10) and methyl-substituted benzodiazepines (Table 3, en-
tries 11–15) were also obtained in high yields, which are also of much
interest with regard to biological activity.
In general, 1,5-benzodiazepines are synthesized by condensa-
tion reaction of o-phenylenediamines (OPDAs) with ketones.
Therefore, Lewis acid is required which makes feasible the nucleo-
philic attack of OPDA on carbonyl group by withdrawing electron
density from carbonyl carbon. In this context, polyfluorinated
zinc phthalocyanine having high Lewis acidity due to zinc metal
and electron withdrawing fluorine substituents, is highly
promising. It must be noted that reaction did not occur in absence
of catalyst indicating that Lewis acidity of the catalyst
(ZnPcOC6F5–APTES@SiO2) plays a critical role in this transforma-
tion, and dictates the activity of the catalyst. Also, no product
was formed when zinc acetate was used because it might be the
possibility that zinc coordinates N-atoms of OPDAs and form com-
plex. But, if ZnPcOC6F5–APTES@SiO2 is used, then it has bulky
phthalocyanine ring which does not allow zinc to coordinate to
N-atoms of OPDA. Actually, ZnPcOC6F5–APTES@SiO2 withdraws
electron density of the carbonyl group in order to facilitate the
nucleophilic attack of amino groups of OPDAs to give the interme-
diate diimine. Moreover, the fluorine substituents in polyfluorinat-
ed zinc(II) phthalocyanine make the catalyst highly hydrophobic
which helps in spilling out water formed during the reaction. Final-
ly, 1,3-hydrogen shift occurs to form an isomeric enamine which
cyclizes to afford the 7-membered ring (Scheme 3).
Table 4
Literature precedents of heterogeneous catalysts for solvent-free synthesis of 1,5-benzodiazepines.
Entry
1
Substrate
Ketone
Catalyst
Time (min)
45
Yielda (%)
90
Ref.
Clay KSF–H3PMo12O40
[53]
NH2
O
NH2
NH2
2
PVP–FeCl3
60
92
[30]
O
NH2
NH2
3
4
HPW–SiO2 (HPW-12-tungstophosphoric acid)
100
20
87
86
[54]
[54]
O
Ph
NH2
HPW–SiO2
NH2
O
NH2
NH2
5
6
HPW–SiO2
110
120
84
81
[54]
[55]
O
Ph
NH2
FeAlP-550 (FeAlP-iron aluminophosphate)
NH2
NH2
O
7
8
HBF4–SiO2
HBF4–SiO2
30
35
90
[56]
[56]
Cl
NH2
O
O
NH2
NH2
87b
NH2
a
Isolated yield.
Product is not benzodiazepine.
b

R.K. Sharma et al. / Inorganica Chimica Acta 397 (2013) 21–31
31
Table 5
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4. Conclusion
We have developed an environmentally benign, facile,
efficient and cost-effective procedure for the synthesis of 1,5-
benzodiazepines using polyfluorinated–zinc(II)phthalocyanine
complex grafted onto the functionalized silica gel as catalyst.
Simple procedure, mild reaction conditions, short reaction times,
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the catalyst are the remarkable advantages of present protocol
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The financial assistance from University Grant Commission,
Delhi, India is acknowledged. Due thanks to AIRF, JNU, Delhi, India
for SEM analysis and IISc, Bangalore, India for solid state NMR
measurements.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.ica.2012.11.012.