Selective Reduction of Azines to Benzyl Hydrazones with Sodium Borohydride Catalyzed by Mesoporous Silica-Supported Silver Nanoparticles: A Catalytic Route towards Pyrazole Synthesis

Article abstract of DOI:10.1002/adsc.201700442

The catalytic activity of supported silver nanoparticles on mesoporous silica was studied, for the selective reduction of azines into benzyl hydrazones using sodium borohydride as mild reducing agent. Different sizes of silver nanoparticles supported on mesoporous silica (Ag/HMS) were successfully prepared by two methods, i.e., wet impregnation followed by reduction with hydrogen at 350 °C and in situ deposition/reduction with a mixture of amines (ethanolamine and ethylenediamine). The Ag/HMS (amines) catalyst was found to promote the selective 1,2-reduction of aryl-substituted azines, compared to the corresponding 1,4-reduction that occurs in general reduction processes. This catalytic transfer hydrogenation process found to be clean, fast and quantitative (>99% yields and selectivity) towards benzyl hydrazone synthesis under mild conditions. Of great importance is that under the present catalytic conditions reducible functional groups remain intact. Formal kinetics, support the in situ formation of silver hydride species being responsible for the reduction process. The presence of protic polar methanol enhanced the catalytic activity of Ag/HMS. Based on the recycling studies the catalytic system Ag/HMS-NaBH₄ was found to catalyze the selective reduction of azines nine times without significant loss of its activity. Finally, a one-pot reaction between the in situ produced benzyl hydrazones and a series of nitrostyrenes readily provided the regioselective synthesis of 1,3,5-subtituted pyrazoles, highlighting a useful synthetic application of the catalytic protocol. (Figure presented.).

Full text of DOI:10.1002/adsc.201700442

Title: Selective reduction of azines to benzyl hydrazones with NaBH4
catalyzed by mesoporous silica supported silver nanoparticles: A
catalytic route towards pyrazole synthesis
Authors: Ioannis Lykakis, Charistoudi Evangelia, Michael Kallitsakis,
Ioannis Charisteidis, and Kostas S. Triantafyllidis
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700442
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Selective reduction of azines to benzyl hydrazones with NaBH4
catalyzed by mesoporous silica supported silver nanoparticles:
A catalytic route towards pyrazole synthesis
Evangelia Charistoudi,a Michael G. Kallitsakis,a Ioannis Charisteidis,a Kostas S.
Triantafyllidis,a,b and Ioannis N. Lykakisa,*
a
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
Fax: +30-2310997871; Phone: +302310997871; e-mail: lykakis@chem.auth.gr
Chemical Process and Energy Resources Institute, CERTH, 6th km. Charilaou-Thermi rd., 57001 Thessaloniki, Greece
b
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The catalytic activity of supported silver
nanoparticles on mesoporous silica was studied, for the
selective reduction of azines into benzyl hydrazones using
sodium borohydride as mild reducing agent. Different sizes
of silver nanoparticles supported on mesoporous silica
(Ag/HMS) were successfully prepared by two methods, i.e.
wet impregnation followed by reduction with hydrogen at
350oC and in situ deposition/reduction with a mixture of
amines (ethanolamine and ethylenediamine). The Ag/HMS
(amines) catalyst was found to promote the selective 1,2-
reduction of aryl-substituted azines, compared to the
corresponding 1,4-reduction that occurs in general
reduction processes. This catalytic transfer hydrogenation
process found to be clear, fast and quantitative (>99%
yields and selectivity) towards benzyl hydrazones synthesis
under mild conditions.
Of great importance is that under the present catalytic
conditions reducible functional groups remain intact.
Formal kinetics, support the in situ formation of silver-
hydride species being responsible for the reduction
process. The presence of protic polar methanol enhanced
the catalytic activity of Ag/HMS. Based on the recycling
studies the catalytic system Ag/HMS-NaBH4 was found to
catalyze the selective reduction of azines nine times
without significant loss of its activity. Finally, one-pot
reaction between the in situ produced benzyl hydrazones
and a series of nitrostyrenes readily provided the
regioselective synthesis of 1,3,5,-subtituted pyrazoles,
highlighting a useful synthetic application of the catalytic
protocol.
Keywords: Silver nanoparticles; heterogeneous catalysis;
selective reduction; mesoporous silica; azines; pyrazoles
Heterogeneous catalytic hydrogenation is a
powerful tool for achieving controlled reduction of
many types of organic compounds under mild
conditions.[13-15] Moreover, heterogeneous reductive
processes catalyzed by supported metal nanoparticles
(i.e. Au, Cu, Ag) has received considerable attention
during the past decade.[16] In particular, apart from the
homogeneous catalysis,[17] significant protocols for
the reduction of aromatic heterocyclic compounds
such as quinolines, including heterogeneous catalytic
systems have been developed.[18-21] Among these
processes, the regioselective reduction of quinolines
into 1,2,3,4-tetrahydroquinolines catalyzed by
AuNPs[22] and AuNPore[23] respectively using
organosilanes as hydrogen source, or catalyzed by
Pd0HAP[24] in the presence of 1 atm of H2, are
distinguished. On the other hand, regarding the
reduction of acyclic conjugated imines or 1-azadiene
analogues, there are only handful of examples to
display the regioselective reduction of the C=N bond,
catalyzed by Re-oxo complexes or AuNPores in the
Introduction
Azines (aldazines and ketazines) constitute of
readily prepared and stable compounds with
interesting chemical properties that undergo a wide
variety of chemical processes.[1,2] These acyclic 1,3-
heterodienes were found to display a diverse range of
pharmacological and biological activities.[3-6] Their
basic synthesis includes the reaction of two molecules
of identical carbonyl compounds (symmetrical
azines) or two different carbonyl compounds
(unsymmetrical azines)with hydrazine.[1] Recently,
they have attracted interest as precursors for the
synthesis
oxadiazoles,[8]
heterocycles.[10-11] Furthermore,
of
1,4-dihydropyridines,[7]
pyrazoles[9]
and
1,3,4-
various
aldazines
as
conjugated dienes have been applied in [1,3]-
cycloadditions with electron deficient unsaturated
molecules to afford 1,5-diazabicyclo[ 3.3.0]octanes
via the so-called criss-cross reaction.[12]
presence
of
boron/aluminum
hydrides
or
1
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
hydrosilanes.[25-30] To our knowledge, there is no
study developed on the selective reduction of azines
to the corresponding benzyl hydrazones catalyzed by
silver nanoparticles (AgNPs), however, only two
reports are recorded using magnesium in methanol,
and palladium on carbon in the presence of ethanolic
HCl, leading to the formation of the fully reduction
product 1,2-dibenzyl hydrazine (Scheme 1, a).[31]
Also, the common reduction processes under NaBH4
and LiAlH4 leads to the formation of 1,2-benzyl
hydrazo compounds through a 1,4-reduction pathway
(Scheme 1, d). So far, synthetic methodologies
including the nucleophilic substitution of benzyl
chlorides with hydrazine hydrate/ benzaldehyde
addition, and the activation of nitrous oxide by
organomagnesium halide, are mainly exhibited to
access benzyl hydrazones (Scheme 1, b and c).[32]
Given the crucial importance of this type of
transformation, the exploration of new, efficient, and
general heterogeneous catalytic system that can
promote regioselective hydrogenation of azines under
mild conditions remains of a great challenge.
As a continuation of our interest in the
heterogeneous catalyzed reduction transformations by
supported gold and silver nanoparticles,[33] we
introduce herein – for the first time- the Ag/HMS-
NaBH4 as an efficient and highly active catalytic
system for the selective 1,2-reduction of azines to the
corresponding benzyl hydrazones, under mild
conditions. Recently, silver nanoparticles supported
on alumina were reported for the hydrogenation of
imines to the corresponding amines, although, high
temperature and pressure were required (Scheme
1).[34] In the combination of catalytic and synthetic
point of view, the present selective heterogeneous
reduction provides an alternative route towards the
synthesis of benzyl hydrazones which offers
advantages such as:selectivity, recyclability,clean
chemical synthesis,high isolated yields, use of more
stable precursorsavoiding harsh conditions and acidic
additives.The catalytic results are interpreted on the
basis of kinetic analysis, as well as on the product
characterization by LC-MS and NMR spectroscopy.
Scheme 1. Synthetic procedures towards hydrazones.
Results and Discussion
The
N2
adsorption-desorption
isotherms
determined at -196oC and the corresponding pore size
distribution curves (from BJH analysis of N2
adsorption data) for the parent HMS mesoporous
silica and representative Ag/HMS catalysts are shown
in Fig. 1. The surface area (BET method), total pore
volume and average pore diameter of HMS and the
Ag/HMS catalysts are given in Table 1. The
adsorption isotherm of the parent HMS silica is of
type IV according to the IUPAC classification typical
for such type of mesoporous materials.[35] It possesses
high surface area and total pore volume of 727 m2/g
and 1.066 cc/g respectively, which are mainly
attributed to mesopores of 3.3 nm average diameter.
The structure of HMS comprises of a 3-dimensional
network of wormhole-type mesopores,[36] which can
be also seen in the TEM image in Fig. 2a. Loading of
silver onto the HMS silica resulted in the decrease of
surface area and pore volume, depending however
strongly on the catalyst preparation method. In order
to identify these effects on silica’s porosity
characteristics, the measured surface area of the
Ag/HMS catalysts was normalized to the weight of
their silica content. As can been seen from the data
summarized in Table 1, the wet impregnation method
followed by reduction of silver at 350oC under H2
flow induced a minor decrease in surface area
(<15%) even at the high Ag content of 30 or 50wt.%.
The pore volume was also high, except in the case of
the 50% Ag/HMS(w.i.) catalyst, while the pore size
of the HMS silica remained also intact. These data
clearly show that the wet impregnation method does
not alter/destroy the mesoporous structure of HMS,
but causes some blockage of the pores. On the other
hand, the amines-reduced Ag/HMS catalysts,
Ag/HMS (amines), exhibited a substantial reduction
of their surface area and pore volume, which is
mainly attributed to the partial destruction of the
HMS mesoporous structure, as can be verified by the
change in the shape of the N2 sorption isotherms
compared to that of the parent HMS or the
Ag/HMS(w.i.) catalysts (Fig. 1). The isotherms of the
Ag/HMS(amines)
catalysts
reveal
a
meso/macroporous structure with larger pore sizes,
i.e. > 10 nm (Table 1). These changes of the HMS
silica mesostructure and the reorganization to a
meso/macropore structure, were induced by the
highly alkaline environment (pH> 13) of the
ethylenediamine-ethanolamine
solution
during
catalyst preparation and silver reduction in
combination with the relatively high temperatures (i.e.
70-120oC) applied for the evaporation of the solvents.
Furthermore, the increase of Ag loading had an
additional effect via pore blockage, thus resulting in
overall relatively low surface area and pore volume.
2
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
800
Table 1. Physicochemical characteristics of HMS
mesoporous silica and the 10, 30 and 50% Ag/HMS
catalysts prepared by the wet impregnation/H2 reduction
method (w.i.) or the amines reduction method (amines).
(a)
HMS
50% Ag/HMS (w.i.)
700
600
500
400
300
200
100
0
10% Ag/HMS (amines)
50% Ag/HMS (amines)
Specific
Total pore
volume[c]
(cm3/g)
Average
pore size[d]
(nm)
Ag crystal
size[e] (nm)
Catalyst[a]
surface
area[b] (m2/g)
727
HMS
10% Ag/HMS
(w.i.)
1.066
3.3
-
3.3
637 (708)[f]
0.913
1.065
32
30% Ag/HMS
(w.i.)
3.2
3.3
467 (668)
49
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
50% Ag/HMS
(w.i.)
P/Po
315 (630)
382 (424)
0.506
1.313
54
15
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
(b)
HMS
10% Ag/HMS
(amines)
13[g]
24[g]
10[g]
50% Ag/HMS (w.i.)
10% Ag/HMS (amines)
50% Ag/HMS (amines)
30% Ag/HMS
(amines)
129 (184)
76 (152)
0.875
0.284
25
33
50% Ag/HMS
(amines)
[a]
10%, 30% and 50% refer to the nominal Ag loading
(wt.%) of the catalysts; the actual Ag loading was
measured by ICP-AES and it was similar (± 5%) to the
nominal loading. [b]Determined by the multi point BET
method. [c]Total pore volume at P/Po=0.99. [d]Determined
from the pore size distribution curves of BJH analysis
based on N2 adsorption data. [e]Estimated by Scherrer
equation using the XRD data of the reflection at 2θ=38ο.
[f]Normalized value based on silica’s weight. [g]The
catalysts contain also macroporous structure.
1
10
100
1000
10000
Pore diameter (Angstrom)
Figure 1. (a) Nitrogen adsorption/desorption isotherms at -
196oC, and (b) pore size distribution curves (BJH analysis
of adsorption data) of HMS mesoporous silica and
representative Ag/HMS catalysts.
Indeed, as can be seen in the TEM image of 10%
Ag/HMS(amines), reduction of silver with amines
leads to the formation of more uniform nearly
spherical nanoparticles with average size of 5-20 nm
(mostly below 10 nm), homogeneously dispersed on
the silica surface (Fig. 2a). On the other hand, the Ag
nanoparticles on 10% Ag/HMS(w.i.) were
significantly larger, c.a. 20 nm and larger, forming
also aggregates with sizes of up to 200 nm (Fig. 2b).
At higher Ag loadings, the Ag particles in the
amines-reduced catalysts retain their spherical
morphology and small size of ca. 10-20 nm, but
larger monolithic particles (of ca. 50-100 nm)
become more abundant, as can be seen in the TEM
image of the 30% Ag/HMS(amines) catalyst in Fig.
2c. The SEM images of the catalysts (Fig. 3)
provided information of the Ag particles morphology
and dispersion at the micrometer scale. In the case of
50% Ag/HMS (w.i.), silver appears as relatively large
condensed phases of up to 2 μm fused with silica,
while in 50% Ag/HMS (amines) more discrete
spherical Ag particles of less than 0.1 μm in size are
homogenously dispersed on the HMS silica particles.
The formation of Ag crystalline phase was
verified by XRD measurements and the obtained
patterns of the Ag/HMS catalysts as shown in Figure
S1, in the Supplementary materials. The
characteristic peaks of metallic silver were clearly
identified at 2θ of 38o, 44o and 64o. The Ag crystal
sizes were estimated by the Scherrer equation using
the data of the peak at 2θ 38o, and the derived data is
presented in Table 1. It can be clearly seen that the
crystal size increases progressively with Ag loading
for both preparation methods, with the amines
method offering smaller sizes (almost half) to those
obtained with impregnation/H2 reduction. It is
however, interesting to note, that for such high Ag
loadings, the high surface area HMS silica favored
the formation of relatively small crystals, i.e. at the
very high 50 wt.% Ag content, the crystal size was
only 33 nm for the amines-reduced catalysts and 54
nm for the impregnated catalysts. When comparing
the two methods, it appears that the silver oxalate and
silver-ethylenediane complexes that are formed prior
to reduction of Ag(II) to Ag(0) offer protection to
silver thus limiting the formation of larger crystals.
This effect also inhibits the aggregation of the
primary crystals towards larger polycrystalline
particles, as was verified by the TEM and SEM
measurements.
3
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
(a)
formed via the 1,4-reduction process. In subsequent
experiments, a series of silver catalysts, were tested
for the title reaction and the results were summarized
in Table 1. Using the AgOTf and the AgNO3, low to
moderate yields were measured in the presence of
NaBH4 (2 mol-excess based on the 1) as the reducing
agent (Table 2, entries 1 and 2).
100 nm
Table 2. Evaluation of supported Ag-catalysts and silver
salts in the catalytic reduction of azine (1).
(b)
(c)
Entry
Catalyst[a]
Time (min)
Conversion (%)[b]
1a (%)[c]
1
2
AgOTf
AgNO3
60
60
63
62
63
21[d]
100 nm
100 nm
100% Ag
(amines)
(dp<45 μm)
10% Ag/HMS
(w.i.)
10% Ag/HMS
(amines)
30% Ag/HMS
(w.i.)
30% Ag/HMS
(amines)
50% Ag/HMS
(w.i.)
50% Ag/HMS
(amines)
3
60
19
19
Figure 2. Transmission electron microscopy (TEM)
images of the (a) 10% Αg/HMS (αmines), (b) 10%
Ag/HMS (w.i.) and (c) 30% Ag/HMS (amines).
4
5
6
7
30
10
30
10
60
41
>99
97
41
99
97
98
68
97
>99
68
10 μm
5 μm
8
9
20
60
60
>99
17
-
[e]
10
11
-
-
HMS
(calcined)
-
[a]3 mg of each catalyst was used (3% mol, based on the
azine amount 0.1 mmol).[b] Based on the consumption of 1,
determined by 1H NMR. [c] Relative yield of 1a determined
by 1H NMR. [d]The corresponding (E)-1,2-bis(4-
methylbenzyl)diazene1b was observed in 41% relative
yield.[e]1b was observed as the only product.
(a)
(b)
Figure 3. Scanning electron microscopy (SEM) images of
the (a) 50% Ag/HMS (w.i.) and (b) 50% Αg/HMS
(amines).
In exploratory experiments, the reduction of azine,
The selective reduction of azine 1 to the
corresponding hydrazone 1a was achieved over
supported silver nanoparticles on the mesoporous
silica (Ag/HMS) using NaBH4 and MeOH as the
reaction solvent. Specifically, supported silver
catalysts (2 mg) was placed in a 4 mL glass reactor,
followed by the addition of methanol (2 mL),
substrate (0.2 mmol) and hydride compound (0.4
mmol), and the reaction was vigorous stirred for
appropriate time (Table 2). To our delight, 10%
Ag/HMS (amines) provide fast, quantitative, and
clean reduction without the requirement of any
chromatographic purification of the product 1a as
white solid, in high isolated yield of 98% (Table 2,
entry 5). No significant amount of the corresponding
1b or (1,2-bis(4-methylbenzyl)hydrazine, 1c, was
detected under the present catalytic conditions.
Meanwhile, 10% Ag/HMS (w.i.), 30% Ag/HMS
(amines), 30% Ag/HMS (w.i.), 50% Ag/HMS
(amines) and 50% Ag/HMS (w.i.), were proved
efficient catalysts, affording hydrazone 1a in
moderated to excellent yields (41%-99%), within
short reaction time 10-60 min (Table 2, entries 4, 6-9).
In comparison, yields dramatically decreased when
unsupported silver particles were used, 100% Ag
1
to the corresponding hydrazone, (E)-1-(4-
methylbenzyl)-2-(4-methylbenzylidene)hydrazine 1a,
was selected as the model reaction to study the
reactivity and selectivity of the commercial supported
gold and the present synthesized silver catalysts. In
particular, the commercially available Au/TiO2,
Au/Al2O3 and Au/ZnO nanoparticles, and as prepared
100% Ag (amines) (dp<45 μm), 10% Ag/HMS
(amines), 10% Ag/HMS (w.i.), 30% Ag/HMS
(amines), 30% Ag/HMS (w.i.), 50% Ag/HMS
(amines), 50% Ag/HMS (w.i.), and the salts such as
AuCl3, AgNO3, AgOTf were employed for the
possible reduction of arylazines. Initially, we
investigated the possible reduction of azine 1 over
Au/TiO2 using hydrosilanes (TMDS and DMPS) as
hydrogen donor molecules, however, the desired
hydrazone 1a was produced in low yields even if four
(4) equivalents of TMDS or PhMe2SiH were used
(Table S1). Further examinations with Au/Al2O3 and
Au/ZnO or AuCl3 did not improve the conversion of 1
to 1a (Table S1). It is worth noting that under gold-
catalyzed reductions, the corresponding azo-
compound, (E)-1,2-bis(4-methylbenzyl)diazene (1b,
Table S1), was formed in significant amount; which
4
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
(amines) (dp<45 μm) (Table 2, entry 3). In the
absence of silver catalyst no conversion of 1 to 1a
was observed even after prolong reaction time;
however the 1b derivative was formed and
determined by 1H NMR (Table 2, entry 10).
Moreover, in the presence of the HMS no reduction
process was occurred (Table 2, entry 11). These
results indicate that the enhanced dispersion of Ag
nanoparticles on the surface of HMS mesoporous
silica offers a very reactive and selective catalytic
system for the present reaction. In addition, in the
Ag/HMS heterogeneous catalytic system, the well
formed AgNPs (≥20nm) on the surface of silica
minimizes the extent of potential reaction on the
interface between silver nanoparicles and silica, as
well as the corresponding homogeneous reduction
process that mainly leads to the unfavourable 1,4-
reduction product 1b (Table 2, entry 10). Thus we
assume that the present reduction proceeds mainly on
the AgNPs which appears to favour the 1,2-selective
reduction, forming exclusively the 1a (Table 2,
entries 4-9). This hypothesis is also based on the
reaction in the presence of unsupported AgNPs, in
which 1a was observed as the only reduction product
(Table 2, entry 3); however, further mechanistic and
product selectivity studies are still in progress.
In all cases, high yields of the product 1a were
measured (Figure S2). This result suggests that a
protic solvent is necessary for the efficient reduction
of azines under the present reaction conditions, by
means of a possible protonation process of the C=N
group and/or the possible enhancement of the
borohydride reagent solubility; however further
mechanistic studies are required. It is worth noting
that the solubility of the tested azines increased in
THF, thus a mixture of MeOH/THF= 1/1 was
selected as the reaction solvent system for our
subsequent experiments.
Moreover, catalyst 10% Ag/HMS (amines) might
also be applicable for the selective reduction of azine
in the presence of different reducing agents, and for
this reason a series of hydrosilanes and common
hydride compounds were used (Table 3). Of
particular note, 1 was reduced into hydrazone 1a in
the presence 2 mol-excess of NaBH4 and NH3BH3 in
quantitative yields, however, the later one required
longer reaction time, 60 min (Table 3, entry 2). In
addtion, lower amount of NaBH4 leads to no reaction
completion (see Table S3). It is interesting that, in the
presence of 4 mol-excess of hydrazine hydrate
(NH2NH2•H2O),
the
(E)-(4-methylbenzylidene)
hydrazine (4-MeC6H4CH2=NNH2) was observed by
1H NMR in 65% relative yield (Table 3, entry 3). In
general, hydrosilanes such as TMDS and DMPS
afforded lower conversions and selectivity of 1a
(Table 3, entries 4 and 5). On the otherhand, in the
presence of NaH, NaBH3CN or BH3-THF hydrides,
no reduction of 1 was observed, however, in the
presence of LiBH4 1a was formed in 73% yield
(Table 3, entries 6-9). Even if LiAlH4 was used in
THF, the corresponding 1b was formed in only 13%
relative yield, accompanying with a significant
amount of 63% relative yield, of the corresponding
further reduced product 1,2-bis(4-methylbenzyl)
hydrazine (1c) as shown in Table 3, entry 10.
Table 3. Evaluation of hydrogen donor molecules in the
reduction of azine 1 catalyzed by 10% Ag/HMS (amines).
Reducing agent/
Mol-excess[b]
Entry[a]
Conversion[b]
1a[c]
1b[c]
1c[c]
1
2
-
-
-
-
-
-
-
-
-
NaBH4 / 2
99%
98%
65%
8%
75%
-
99%
98%
-
NH3BH3 / 2
-
.
[d]
3
To compare the catalytic activity of the present
synthesized Ag/HMS catalysts, we studied the
reduction of 1, with (x%) Ag/HMS (x = 10%, 30%,
50%) catalysts in presence of NaBH4 and the
equimolar mixture of methanol/THF as solvent (Fig.
4). In all cases, the (x%) Ag/HMS materials afforded
excellent selectivity and yields (>99%) to 1a, within
30 min. The observed selectivity to 1a, found to be
highly related to the silver loading amount as well as
to the Ag particle size. Thus, among them, the 10%
Ag/HMS (amines) and 30% Ag/HMS (amines)
catalysts, with an average of AgNPs size below 20
nm, showed the best catalytic activity in terms of the
conversion and selectivity of 1a (Fig. 4). The kinetic
values were determined by monitoring the
NH2NH2 H2O / 4
-
-
4
TMDS / 2
DMPS / 4
NaH / 4
8%
-
5
62%
13%
6
-
-
7
LiBH4 / 2
73%
-
73%
-
8
NaBH3CN / 2
BH3THF / 2
LiAlH4 / 2
-
-
-
-
-
9
-
10
[a]
76%
13%
63%
3 mg of the catalyst was used (3% mol, based on the 1
amount 0.1 mmol). [b]Based on the consumption of 1,
1
[c]
determined by H NMR.
Relative yield determined by
1H NMR. [d](E)-(4-methylbenzylidene)hydrazine (4-
MeC6H4CH2=NNH2)was formed as the only product.
1
consumption of 1 with H NMR, by integrating the
Among the solvents studied, high conversion of 1 to
1a was observed using methanol and less with EtOH,
however, in non protic polar solvents such as THF,
CH3CN, DCE, toluene and 1,4-dioxane, lower yields
appropriate proton signals. Then, a formal kinetic
analysis of the present synthesized catalysts (10%
Ag/HMS, 30% Ag/HMS and 50% Ag/HMS) for the
reduction of
1
was performed (Figure S2).
1
were observed by H NMR (Table S2). To elucidate
Considering that the concentration of the in situ
formed silver-hydride species ([Ag]-H) remains
constant at initial times (t < 10min) and assuming a
if the protic solvent is necessary for this catalytic
process, the reduction of 1 also occurred in a solvent
mixture of THF/MeOH with the ratios of 9/1 and 1/1.
5
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
pseudo-first order dependence of the reaction rate on
the azine concentration, eq. 1 can be applied.
ln(x)= -kt
(1)
where, k is the rate constant and x is the
consumption of the azine 1 at reaction time t.
According to eq. 1, a plot of the -ln(x) versus time
should provide a linear curve with slope equal to the
rate constant kx. Faster relative reaction rate
constants were measured in both cases, with the
present of 10% Ag/HMS (amines) and 30% Ag/HMS
(amines), with a ratio of k10/k30≈ 0.8, respectively
(Figure S2). In contrast, lower reaction rate constants
were measured in the reductions using even 50%
Ag/HMS (amines) catalyst, with ratio of k10/ k50≈ 1.7
(Figure S2). These results indicate that the kinetic
activity of the present catalysts towards reduction of
1 is remarkably affected by the size of the silver
nanoparticles and less by its loading amount. These
findings are in good agreement with previous studies,
which suggest that supported silver particles with
small sizes in the range of 4-7 nm are the more active
species for the Ar–NO2 reduction.[33b]
Figure 5. Recycling study of the 10% Ag/HMS (amines)
catalyst (Experimental conditions: 0.1mmol of azine 1, 9
mg of catalyst, 0.2mmol of NaBH4, 1 mL of methanol, room
temperature, t= 60min).
Because of the heterogeneity of the present system,
the 10% Ag/HMS (amines) catalyst can be easily
separated from the reaction mixture by simple
filtration. Thus, the stability of the catalyst was
examined, on repeating catalytic experiments, where
the catalyst was separated from the reaction mixture,
washed with methanol and reused for the next
catalytic run without further activation. As shown in
Fig. 5, the catalyst can be used at least nine times
without significant loss of its catalytic activity and
selectivity to 1a production. Additionally, after
stirring slurry of 10% Ag/HMS and NaBH4 in
methanol for 1h, we observed that the supernatant
solution is inefficient in promoting reduction of 1.
Indeed, ICP-MS analysis revealed that the silver
content in the supernatant is low (~30 ppb).[37] The
used 10% Ag/HMS (amines) catalyst was also
characterized in order to identify any changes of the
morphology and texture. In the TEM images of
Figure S4, it can be clearly seen that the good
dispersion Ag nanoparticles has been retained (as
compared to that of the fresh catalyst shown in the
TEM image of Fig. 2); however, larger aggregates of
ca. up to 80 nm have been formed in the used catalyst,
thus exhibiting a wider Ag size distribution of ca. 20
to 80 nm. Still, however, this slight aggregation of the
Ag nanoparticles had a negligible effect on the
reactivity and selectivity of the catalyst. With regard
to the textural properties of HMS silica, the
wormhole-like mesopore structure can be clearly
identified in the TEM image of the used 10%
Ag/HMS (amines) catalyst (Fig. S4). The retention of
the porous characteristics of the used catalyst was
also verified by N2 sorption measurements. The SEM
images of the fresh and used catalysts were similar
(Figure S5), thus verifying the stability of the HMS
silica particle morphology, under the reaction
conditions tested. [38]
Figure 4. Kinetic profile of Ag/HMS catalysts towards the
selective reduction of azine (1) to hydrazone (1a) in the
presence of 2 mol-excess of NaBH4.
Based on these encouraging results, the 10%
Ag/HMS (amines) catalyst was further tested for
possible larger-scale production of hydrazones from
azines. For this reason, 3 mmol of azine 1 were
oxidized in the presence of 10% Ag/HMS (3 mg)
with 5 mol-excess of NaBH4 in 10 mL MeOH. After
6
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
completion of the reaction (~20 min based on TLC
analysis), the mixture was filtered upon silica gel,
washed with ethanol and purified by column
chromatography to afford the 1a in 89% isolated
yield. This result corresponds to a high turnover
number (TON) of 960, as measured from the ratio of
product 1a (mmol) / supported AgNPs (mmol), and
high turnover frequency (TOF) value of 2880 h-1.
Having
established
that
10%
Ag/HMS
(amines)/NaBH4 was the most efficient catalytic
system for the reduction of 1, we extended our
studies to various structurally different substituted
azines 2-17. The results were summarized in Scheme
2. Remarkably, this reduction protocol is been
characterized by a broad functional group tolerance.
In general, azines (1-17) converted to the
corresponding hydrazones (1a-17a) with excellent
yields (>75%), high selectivity (>99%) and in short
reaction time (5-20 min). It is worth noting that the
kinetic activity of azines 1-17 is remarkably affected
by the nature of the X-substituent group, in which the
reduction proceeds faster as the electron-withdrawing
ability of the substituent group increases. For
example, the reduction of 7, 8, 9, 10, and 11 (which
contains Cl, Br and 4-CF3 moieties on the aromatic
rings) proceeds faster than the corresponding
reduction of 2 (H), in the presence of 0.2 mmol of
NaBH4. On the contrary, azines 3-6, 12 and 13, that
contains electron-donating groups MeO- and -OH, as
well as heterocyclic azines 14 and 15, were reduced
with slower reaction rates and larger amounts of
NaBH4 were required (3-4 mol-excess). Notably, in
the case of azine (12), allyl group was tolerated under
the reaction conditions and did not undergo C=C
reduction. Subsequently, we applied this catalytic
system to study the possible reduction of more
sterical azine, such as (1E,2E)-1,2-bis(1-(p-
tolyl)ethylidene)hydrazine (16); thus, 4 mol-excess of
NaBH4 within 20 min affording the hydrazone 16a in
very good yield (Scheme 2). In the case of the hetero-
azine (17), which bears an electron reach ring (3,4-
diMeO) and an electron poor ring (4-Cl-), two
hydrazones 17a and 17a΄ were formed in a ratio of ca.
2/1, respectively. In detail, the -C=N- double bond
next to the electron poor ring (4-Cl) underwent
reduction to a greater extent compared to the other
Scheme 2. Selective 1,2-reduction of aryl azines to benzyl
hydrazonescatalyzed by 10% Ag/HMS (amines) in the
presence of NaBH4.
Finally, the general applicability of the present
Ag/HMS/NaBH4 catalytic system in organic
synthesis was verified by performing 1,3-dipolar
cycloaddition reaction between the in situ formed
benzyl hydrazones (or azomethine imines) and the
external addition of various nitrostyrenes[39] (Scheme
3).It is important to note that hydrazones are
particularly unstable in air and are easily hydrolyzed
into the corresponding benzaldehydes. Thus, the
reactions were performed at room temperature in a
one-pot manner. In details, after the first 1,2-selective
heterogeneous reduction step (Ag/HMS/NaBH4), the
produced hydrazone was isolated with a simple
filtration through celite (to withhold the catalyst), and
after solvent evaporation, an oxygen saturated
methanolic solution of the nitrostyrene was added,
and the reaction mixture was stirred at room
temperature for appropriate time. This catalytic-
synthetic route proved versatile to the formation of
several 1,3,5-substituted pyrazoles (22-33) in
moderate to high isolated yields, values in
parentheses (Scheme 3).[40]
1
one, as revealed by H NMR (Figure S3). This result
is consistent with previous assumption support that
the azines substituted with electron withdrawing
groups were reduced within a faster manner than
corresponding with electron rich moieties.
7
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
NH3BH3,
1,1,3,3-tetramethyldisiloxane
(TMDS),
PhMe2SiH (DMPS), LiBH4, NaH, NaBH3CN, BH3THF
solution, LiAlH4, organic solvents and solvents (i.e.
ethylene diamine, ethanolamine), AgNO3 and absolute
ethanol (99.8%) were purchased from Sigma-Aldrich.
Tetraethyl orthosilicate (TEOS) and dodecylamine
(CH3(CH2)11NH2) for the synthesis of mesoporous silica
HMS were also purchased from Sigma-Aldrich.
Preparation of catalysts
The HMS mesoporous silica used as support of silver was
synthesized based on previously reported methods.[35] In a
typical synthesis, dodecylamine (DDA) which was used as
the mesostructure directing agent (template), was dissolved
in ethanol followed by addition of water (water/ethanol =
80:20, v/v). TEOS, used as the silica source, was then
added slowly and the mixture was stirred for 30 min at
room temperature followed by hydrothermal aging in
sealed PP bottles, in a shaker bath, at 65oC for 24 hrs. The
white product was filtered, washed with water and dried at
room temperature and at 90◦C for 3 h. The reaction mole
stoichiometry was 1 TEOS:0.23DDA:9.0EtOH:95 H2O.
The removal of the organic template of the dried as-
synthesized samples was performed by calcination at
600oC for 4 h in air.
Scheme 3. One-pot synthesis of 1,3,5-substituted
pyrazolesfrom the in situ formed hydrazones and the
external nitrostyrenes.
The metallic silver (Ag0) supported catalysts were prepared
by two methods i.e., wet impregnation followed by
reduction with H2 at 350oC and in situ deposition/reduction
with amines followed by calcination in air. (a) In a typical
wet impregnation experiment, for the preparation ofthe 10,
30 and 50 wt. % Ag /HMS (w.i.) catalysts, appropriate
amount of AgNO3 was dissolved in deionized water
followed by HMS silica addition, under continuous stirring
at room temperature. The suspension was further stirred for
2 hrs and then the water was gradually evaporated by
increasing the temperature under vacuum. The received
powder was dried at 100oC in air and was then reduced
under H2 flow (50cc/min) at 350°C for 2 hrs, in order to
remove the nitrates and reduce silver. (b) In the case of the
method using amines as reductants, the precursor silver
compound was as-synthesized silver oxalate (from AgNO3
and oxalic acid), which was solubilized in aqueous solution
of ethylenediamine (65 vol.%). The amount of silver
oxalate was adjusted so that the final silver loading of the
catalysts to be 10, 30 or 50 wt.% Ag/HMS (amines), as in
the case of the impregnated catalysts. Aqueous solution of
ethanolamine was then added to the ethylene diamine
solution, followed by addition of HMS silica under
continuous stirring at room temperature. The molar ratio of
ethylenediamine and ethanolamine to Ag was equal to 3
and 0.5 respectively. The suspension formed was further
left under stirring at room temperature for 1 h, after which
the temperature was gradually raised up to 120 °C under
vacuum in order to induce the reduction of silver (occurred
at about 70-80oC) and evaporate water and most of the
amines. The collected paste was dried at 100oC in air and
was then calcined at 350°C for 3 h, to remove the residual
organic compounds. Self-supported metallic silver powder
(100%Ag) was also prepared, following the above method
without the use of HMS silica..
Conclusion
In summary, we have established -for the first time-
that mesoporous silica supported silver nanoparticles
(Ag/HMS) can catalyze the selective, fast and
quantitative
1,2-reduction
of
azinesto
the
corresponding benzyl hydrazones, using NaBH4 as
reducing agent. Catalysts prepared using amines as
reductant, shows better activity compared to the
typical wet impregnation ones. The catalyst 10%
Ag/HMS (amines) was found to be the most active,
catalyzed the reduction of a series of substituted
azines to the corresponding hydrazo compounds,
even at a larger-scale reaction. Recycling studies
showed that this catalytic system can be used at least
nine times. Kinetic analysis indicated that the azine
reduction is remarkably affected by the size of the
silver nanoparticles, with those of smaller than 20nm
being the most active. It was suggested that the
reaction mechanism occurs via the formation of
intermediate silver hydride [Ag]-H species. The
present Ag/HMS/NaBH4 catalytic system represents
an expeditious approach towards the production of
pyrazoles,through the coupling between the in situ
formed hydrazones and a molecule of nitrostyrenes in
excellent yields. This catalytic/synthetic route,
making the present reaction potentially useful in
organic synthesis and the basis for development of
new catalytic procedures for other key organic
transformations.
Physicochemical characterization
The Ag content of the catalysts was determined by
inductive coupled plasma-atomic emission spectroscopy
(ICP-AES) using
a
Plasma 400 (Perkin Elmer)
spectrometer, equipped with a Cetac6000AT+ ultrasonic
nebulizer. Nitrogen adsorption/desorption experiments at -
196oC were performed for the determination of surface
area (multi-point BET method), total pore volume (at P/Po
= 0.99), and pore size distribution (BJH method using
adsorption data) of the HMS silica and the respective Ag-
loaded catalysts using an Automatic Volumetric Sorption
Analyzer (Autosorb-1MP, Quantachrome). Prior to N2
sorption the samples were outgassed at 150oC for 16 h
under 6.6x10-9 mbar vacuum. Powder X-ray diffraction
Experimental Section
General
The aromatic aldehydes and ketones used as substrates for
the synthesis of the azines were of high purity and
commercially available from Sigma-Aldrich. NaBH4,
8
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
(XRD) experiments were conducted on a Shimadzu XRD
7000 diffractometer using a CuKα X-ray radiation
operating at 45 kV and 100 mA; counts were accumulated
in the range of 10-80o 2θ every 0.02o (2θ) with counting
time 2 sec per step. The Scherrer equation was used to
estimate the crystal size of Ag. Transmission electron
microscopy (TEM) experiments were carried out in a
JEOL 2011 high resolution transmission electron
microscope operating at 200 kV, with a point resolution of
0.23 nm and Cs=1.0 mm. Samples were prepared by gently
grinding the catalyst in high-purity ethanol using an agate
pestle and mortar. A drop of the suspension was
subsequently deposited onto a lacey carbon-film supported
on a Cu grid and allowed to evaporate under ambient
conditions. Scanning Electron Microscopy (SEM)
experiments were performed on a JEOL 6300 microscope.
The back-scattered electron images were used to clearly
identify the Ag particles on the silica support.
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Acknowledgements
Financial support by the Greek Ministry of Education
(ARISTEIA-2691) is kindly acknowledged. I.N.L. and M.G.K.
acknowledged the sponsorship of the COST action
CM1201.M.G.K. acknowledges the “IKY Fellowships of
excellence for postgraduate studies in Greece
- Siemens
program” for financial support. We thanks the Unit of ICP-MS of
the Aristotle University of Thessaloniki and Prof. D.
Lambropoulou for the assistance with the ICP-MS analysis, Prof.
Pantelis Trikalitis for the TEM and SEM experiments (Inorganic
Chemistry Laborator, University of Crete and Prof. G. E.
Kostakis (University of Sussex, UK) for valuable comments and
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10.1002/adsc.201700442
Advanced Synthesis & Catalysis
FULL PAPER
Selective reduction of azines to benzyl hydrazones
with NaBH4 catalyzed by mesoporous silica
supported silver nanoparticles: A catalytic route
towards pyrazole synthesis
Adv. Synth. Catal.Year, Volume, Page – Page
Evangelia Charistoudi,a Michael G. Kallitsakis,a
Ioannis Charisteidis,a Kostas S. Triantafyllidis,a,b
and Ioannis N. Lykakisa,*
11
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