Tandem selective reduction of nitroarenes catalyzed by palladium nanoclusters

Article abstract of DOI:10.1039/c9gc03957k

We report a catalytic tandem reduction of nitroarenes by sodium borohydride (NaBH₄) in aqueous solution under ambient conditions, which can selectively produce five categories of nitrogen-containing compounds: anilines, N-aryl hydroxylamines, azoxy-, azo- and hydrazo-compounds. The catalyst is in situ-generated ultrasmall palladium nanoclusters (Pd NCs, diameter of 1.3 ± 0.3 nm) from the reduction of Pd(OAc)₂ by NaBH₄. These highly active Pd NCs are stabilized by surface-coordinated nitroarenes, which inhibit the further growth and aggregation of Pd NCs. By controlling the concentration of Pd(OAc)₂ (0.1-0.5 mol% of nitroarene) and NaBH₄, the water/ethanol solvent ratio and the tandem reaction sequence, each of the five categories of N-containing compounds can be obtained with excellent yields (up to 98%) in less than 30 min at room temperature. This tunable catalytic tandem reaction works efficiently with a broad range of nitroarene substrates and offers a green and sustainable method for the rapid and large-scale production of valuable N-containing chemicals.

Full text of DOI:10.1039/c9gc03957k

View Article Online
View Journal
Green
Chemistry
Cutting-edge research for a greener sustainable future
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Z. Yan, X. Xie, Q.
Song, F. Ma, X. Sui, Z. Huo and M. Ma, Green Chem., 2020, DOI: 10.1039/C9GC03957K.
Volume 20
This is an Accepted Manuscript, which has been through the
Number
May 2018
Pages 1919-2160
9
7
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Cutting-edge research for a greener sustainable future
rsc.li/greenchem
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1463-9262
PAPER
Paul T. Anastas et al.
The Green ChemisTREE: 20 years after taking root with the 12
principles
rsc.li/greenchem

Please do not adjust margins
Page 1 of 8
Green Chemistry
View Article Online
DOI: 10.1039/C9GC03957K
Journal Name
ARTICLE
Tandem Selective Reduction of Nitroarenes Catalyzed by
Palladium Nanoclusters
Ziqiang Yan#, Xiaoyu Xie#, Qun Song, Fulei Ma, Xinyu Sui, Ziyu Huo and Mingming Ma*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We report a catalytic tandem reduction of nitroarenes by sodium borohydride (NaBH4) in aqueous solution at ambient
conditions, which can selectively produce five categories of nitrogen-containing compounds: anilines, N-aryl
hydroxylamines, azoxy-, azo- and hydrazo- compounds. The catalyst is the in situ-generated ultrasmall palladium
nanoclusters (Pd NCs, diameter of 1.3±0.3 nm) from the reduction of Pd(OAc)2 by NaBH4. These highly active Pd NCs are
stabilized by the surface-coordinated nitroarenes, which inhibit the further growth and aggregation of Pd NCs. By
controlling the concentration of Pd(OAc)2 (0.1-0.5 mol% of nitroarene) and NaBH4, the water/ethanol solvent ratio and the
tandem reaction sequence, each of the five categories of N-containing compounds can be obtained with excellent yields
(up to 98%) in less than 30 min at room temperature. This tunable catalytic tandem reaction works efficiently with a broad
range of nitroarene substrates, which offers a green and sustainable method for rapid and large-scale production of
www.rsc.org/
valuable
N-containing
chemicals.
Since the reduction of nitroarenes is typically a tandem
reaction, selectivity has also become an urgent issue. Most of
nitro-reduction methods are developed to produce aniline, the
Introduction
The selective reduction of nitroarenes can produce different
N-containing compounds, such as anilines, hydroxylamines,
nitroso-, azoxy-, azo- and hydrazo- compounds.1 Many of these
N-containing compounds are vital intermediates for the
synthesis of organic dyes, food additives, agrochemicals,
pharmaceuticals and functional materials2-11. Conventional
reduction of nitroarenes are achieved by metal reduction at
acidic conditions, which generates large amounts of by-
products and waste acids. To overcome these issues, catalytic
reduction of nitroarenes has been developed with transition
metal catalysts in various hydrogenation systems12-19. Many
efficient catalysts based on Fe20, Co21, Ni22-24, Pd25-27, Pt28-30
,
Ru31-33, Ag34, 35 or Au36-40 have been developed for selective
reduction of nitroarenes to desired N-containing compounds.
However, the applications of these catalytic reactions are
limited because of 1) the usage of large amounts of expensive
noble-metal catalysts; 2) the employment of toxic and/or
hazardous reagents; 3) the request of harsh reaction
conditions and tedious work-up process. Therefore, the
development of green and sustainable catalytic reduction of
nitroarenes represents a challenging task for both catalysis and
organic synthesis.
Scheme 1. Synthetic methods for partial reduction of nitroarenes.
fully reduced product. As shown in Scheme 1, only a few
reports are available for the selective synthesis of partially
reduced products by nitroarene reduction, such as
hydroxylamine, azoxy- and azo- aromatic compounds. For
instance, Garcia and Cao used Au catalysts to reduce
nitroarenes into azo- compounds36, 39, which requires high
reaction temperature, and pressured hydrogen as the reducing
agent. Konakahara used InX3/Et3SiH reduction system to
selectively produce four partially reduced products from
nitroarene41. Su presented a photocatalytic strategy for the
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for
Physical Sciences at the Microscale, University of Science and Technology of China,
Hefei, Anhui 230026, China
*E-mail: mma@ustc.edu.cn. # Yan and Xie contribute to this work equally.
Electronic Supplementary Information (ESI) available: details of reaction conditions
and characterization data. See DOI: 10.1039/x0xx00000x
synthesis of azoxy- and azo- compounds under visible light
27
irradiation42. Gu used Pd26,
and Pt29 nanoparticles to
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 8
ARTICLE
Journal Name
catalytically reduce nitroarenes to azo- compounds, which nitrotoluene was dissolved in 10 mL water/EtOH mixture.
View Article Online
needs high reaction temperature, pressured hydrogen and NaBH4 solid was added to the mixture asDrOeId: u10c.i1n0g39a/gCe9nGtC.0T3h9e57nK,
corrosive strong base. Although significant progress has been Pd(OAc)2 was dissolved in a minimum amount of CH2Cl2 and
made toward the selective catalytic reduction of nitroarenes, added to the mixture. The reaction conditions were optimized
these reactions usually need harsh reaction conditions (such as by changing the concentration of Pd(OAc)2 and NaBH4, the
high pressure, high temperature, corrosive or toxic reagents) ratio of water and ethanol as the solvent, and the reaction
and long reaction time.
time and sequence. Table 1 shows the yield of the
Recently, Pd nanoclusters (Pd NCs) with diameter less than 2 corresponding hydroxylamine, aniline, azoxy-, azo-, and
nm have attracted much attentions.43-46 Owing to the quantum hydrazo- compounds at different reaction conditions.
size effect, these ultrasmall Pd NCs show distinct catalytic According to the result, the reduction reaction is significantly
properties as compared to larger Pd nanoparticles.43 However, solvent-directed: the reduction of 1a to hydroxylamine (2a)
these ultrasmall Pd NCs are quite unstable, which have to be gave almost no conversion in EtOH (entry 1); whereas, 60%
46
stabilized by either thiolate ligands45, or being caged in a conversion was achieved in a Vwater : VEtOH = 1:3 mixture (entry
porous structure, such as metal-organic frameworks.43, 44 Since 2), which indicates that the ratio of water and EtOH exerts
sulfur is generally a poison to many noble-metal catalysts, the crucial impact on the reaction. To improve the conversion of
thiolate ligands would significantly reduce the catalytic activity 1a to 2a, the ratio of water was further increased. When the
of ultrasmall Pd NCs.
volume ratio of water and EtOH was 2:3, 1a was completely
Herein, we report a catalytic tandem reduction approach to converted and afforded 2a in a yield of 85% in 10 min (entry
conveniently and selectively convert nitroarenes into five 3). Surprisingly, when the reaction time was shortened to 5
categories of products: anilines, hydroxylamines, azoxy-, azo- min, 2a was obtained with a higher yield of 97% (entry 4),
and hydrazo- compounds. With NaBH4 as the reducing agent, which could be because of the minimized oxidation of 2a.
the selective reduction of nitroarene is catalyzed by in situ Further increasing the percentage of water (Vwater : VEtOH = 1:1)
generated ultrasmall Pd NCs from Pd(OAc)2. Without using any decrease the yield of 2a, and a small amount of 4,4'-
additional ligands, these ultrasmall Pd NCs (diameter of dimethylazoxybenzene (3a) was discovered (entry 5). When 2a
1.3±0.3 nm) are stabilized by surface-coordinating nitroarenes in solution is exposed to air, 2a can be slowly oxidized to 3a
and well-dispersed in the reaction solution. By controlling the (entry 6). To speed up the oxidation, we use O2 to oxidize 2a.
concentration of Pd(OAc)2 (0.1 or 0.5 mol% of nitroarene) and When the 2a solution is stirred under O2 atmosphere for 3
NaBH4, water/ethanol solvent ratio and reaction sequence, min, pure 3a was conveniently obtained with 92% yield (entry
each of the five reduction products can be acquired with 7) as a precipitate by filtration and washing.
excellent yields (up to 98%) in less than 30 min at room
temperature.
In the mixture of 3a product and Pd NCs catalyst, additional
reducing agent NaBH4 (3 mmol.) and solvent MeOH was
added. 3a can be dissolved with the help of MeOH and rapidly
reduced to give 4,4'-dimethylhydrazobenzene (4a) (entry 8).
Since hydrazobenzene is easily oxidized to form azobenzene
under air during the work-up process, 4a was obtained in a
slightly lower isolate yield (85%) and the corresponding
Results and discussion
The catalytic reduction of nitroarenes was studied using p-
nitrotoluene (1a) as the model substrate. Briefly, 1 mmol
a
z
o
b
e
n
z
e
n
e
5
a
w
a
s
Table 1. Optimization of reaction conditions[a]
.
NHOH
NO2
O-
N+
Pd(OAc)2
NaBH4 (2 equiv.)
H
N
N
N
H
H2O/EtOH, RT
4a
3a
1a
2a
NH2
N
N
5a
6a
Entry H2O/EtOH
(ml/ml)
Pd(OAc)2
(mol %)
Total
Conv.
(%)
Selectivity[%]b
time
(min)
20
20
10
5
5
8
8
20
25
2a
3a
4a
5a
6a
1
0/10.0
2.5/7.5
4.0/6.0
4.0/6.0
5.0/5.0
4.0/6.0
4.0/6.0
4.0/6.0
4.0/6.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
10
60
trace
50
85
97
85
50
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2
3
4
5
trace
-
-
100
100
100
100
100
100
100
10
-
trace
40
92
-
-
-
-
-
85
-
6[c]
7[d]
8[e]
9[f]
trace
trace
14
-
-
-
97
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 8
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
10
11
7.5/2.5
7.5/2.5
0.1
0.5
5
5
100
100
50
-
10
-
-
-
-
-
37
98
View Article Online
DOI: 10.1039/C9GC03957K
[a] Condition: 1a (1.0 mmol), Pd(OAc)2 (0.1 or 0.5 mol%), NaBH4 (2.0 mmol) in solvent(10 ml), RT. [b] all the yields are isolation yields. [c] Under air. [d] O2 is bubbled
into solution for 3 min. [e] NaBH4 (3.0 mmol) and MeOH (10 ml) were added and reacted for 12 min. 4a is easily oxidized to 5a during purification. [f] O2 is bubbled into
solution to oxidize 4a to 5a.
obtained in 14% yield. Inspired by this rapid oxidation process, was added into the mixture containing nitroarene and NaBH4,
5a was conveniently obtained in 97% yield by the oxidation of the colour of the solution quickly turned into brown, indicating
46
4a in the reaction system by using O2 (entry 9).
the formation of Pd NCs.45,
However, during the whole
When the percentage of water was further increased to reaction process, there was no formation of Pd black
Vwater : VEtOH = 3:1, the Pd-catalytic reduction of 1a is faster, precipitate. We hypothesize that the nitro group of
with 100% conversion achieved in 5 min, but the selectivity is nitroarenes can coordinate to the surface of new-born Pd NCs
poor (entry 10). 2a, 3a and 6a (p-methylaniline) were obtained and inhibit their further growth (Figure 1a). To probe this
with 50%, 10% and 37% yield, respectively. However, when the hypothesis, we took the high-resolution transmission electron
amount of Pd(OAc)2 was increased to 0.5 mol% of 1a, the fully microscopy (HR-TEM) image of the brown colour reaction
reduced product 6a can be obtained with excellent yield (98%) mixture (Figure 1b), which showed crystalline nanoclusters
in 5 min (entry11).
with the diameter around 1-2 nm. The well-resolved lattice
After the optimization of reduction conditions, we have fringe of 0.21 nm corresponds to the Pd (111) fringe.47 In
achieved the selective reduction 1a to N-aryl hydroxylamine another TEM image, a large number of well-separated Pd NCs
with solvent ratio of Vwater : VEtOH = 2:3. Then N-aryl were observed (Figure 1c). The statistical analysis result of
hydroxylamine can be oxidized by O2 to form azoxy compound, these Pd NCs shows the average diameter is 1.3±0.3 nm
followed for the Pd-catalyzed reduction of azoxy compound to (Figure 1d), which indicates a quite uniform size distribution.
hydrazo compound, and finally oxidized by O2 to form azo When we used 4-nitrobenzoic acid as the reactant, the in-situ
compound. The conversion from nitroarenes to the final azo generated Pd NCs with 4-nitrobenzoic acid as surface ligands
compound can be achieved in 25 min with 97% yield at the can be easily precipitated by adjusting the solution to acidic
presence of only 0.1 mol% of in-situ generated Pd NCs as the (pH≈2). These dark brown color solid could be washed by
catalyst. Surprisingly, the activity of Pd NCs is well preserved water to remove excess 4-nitrobenzoic acid, then dissolved in
during the two oxidation steps using O2 as the oxidant. To ethanol to give a brown-color clear solution (Figure 1e, insert
prepare the fully reduced product: aniline, we just need to picture). This solution was studied by using dynamic light
change the solvent ratio to Vwater : VEtOH = 3:1 and increase the scattering (DLS, Figure 1e), which also confirmed the uniform
usage of Pd(OAc)2 to 0.5 mol% of nitroarene. With this more size distribution of Pd NCs in solution. The measured average
polar solvent mixture and higher concentration of Pd NCs, the hydrodynamic diameter of Pd NCs was 6.5 nm, which is bigger
nitroarene would be quickly and completely reduced to than the diameter measured by TEM. This is because the
aniline.
diameter on TEM shows only the palladium core of Pd NCs.
Pd-based nanomaterials have been utilized as catalysts for The hydrodynamic diameter is the size of palladium core plus
the reduction of nitroarenes. 26, 27 In the pioneer works by Gu, the 4-nitrobenzoic acid ligand layer and also the solvating layer,
worm-like aggregates of Pd nanoparticles were prepared which should be significantly bigger. We also measured the
separately and then added to the reaction mixture. These UV-vis spectrum of the Pd NCs solution and compared with
large aggregates would form black precipitate, which hinders that of the
Pd(OAc)2 (0.1 mol%)
NaBH4 (2.0 equiv.)
H
their catalytic activity. In our case, when the Pd(OAc)2/CH2Cl2
solution
NO2
N
OH
R
R
H2O/EtOH, RT
1
2
H
H
H
H
N
N
N
N
OH
OH
OH
OH
H3CO
2d
2b
(7 min, 89%)
(5 min, 88%)
2c
(8 min, 84%)
2a
(5 min, 90%)
H
N
H
H
H
N
N
N
OH
OH
OH
OH
H2N
H3CO
F
NC
O
2g
O
2e
(3 min, 84%)
2h
(5 min, 86%)
(3 min, 88%)
2f
(3 min, 91%)
OH
HN
H
H
H
N
N
Br
N
OH
OH
OH
Br
Cl
2j
(4 min, 86%)
2i
(4 min, 89%)
2k
(4 min, 87%)
Figure 1. Characterization of Pd NCs. a) In-situ formation of Pd NCs. b) High-
resolution TEM image of Pd NCs showing the crystalline structure of Pd NCs. c) A
typical TEM image and d) size distribution of Pd NCs. e) Picture (insert) and the
hydrodynamic diameter of Pd NCs in an ethanol solution.
2l
(4 min, 88%)
Scheme 2. Synthesis of hydroxylamines 2. Reaction condition: nitroarene (1.0
mmol), Pd(OAc)2 (0.1 mol%), NaBH4 (2.0 mmol), water/EtOH (4 ml/6 ml), stirring
at RT for indicated time in the parentheses. all the yields are isolation yields.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 8
ARTICLE
Journal Name
All the yields are Isolation yields. [a] Stirring at RT for 10 min. Then O2 is
4-nitrobenzoic acid ligand (Figure S1). By adjusting the
concentrations, the two spectra coincide with each other in
the <300 nm wavelength range. However, in the 300-500 nm
range, the absorption of Pd NCs solution is much higher than
that of 4-nitrobenzoic acid solution, which agrees well with the
reported absorption spectrum of ultrasmall Pd NCs.44 With
these characterization data, we have demonstrated the in situ
formation of uniform Pd NCs in the reaction solution, which
are stabilized by the surface coordinated nitroarenes.
View Article Online
bubbled into the solution for 5 min.
DOI: 10.1039/C9GC03957K
1) Pd(OAc)2 (0.1 mol%)
NaBH4 (2.0 equiv.)
H2O/EtOH, RT
R
H
NO2
N
N
R
R
H
2) O2
3) NaBH4 (3.0 equiv.)
MeOH, RT
4
1
H
N
N
H
H
H
N
N
N
H
N
H
With these optimized reaction conditions in hand, we have
explored the substrate scope of this one-pot reduction method.
We firstly examined the synthesis of N-aryl hydroxylamine
derivatives from nitroaromatic compounds (Scheme 2). We
found that the substituted position (para-, meta- and ortho-)
of alkyl group had little effect on the reaction (2a-2c). Both
electron-donating groups (such as methoxy group, 2d) and
electron-withdrawing groups (cyano, ester and amide groups,
2e-2g) are also well-tolerated in the reduction reaction, and
provide expected products with high yield (84-91%). In
addition,
F-, Cl- and Br- substituents are also adequately tolerated,
which were efficiently converted to the corresponding
products (2h, 2i, 2j and 2k) in high yields (86-89%), with no
dehalogenation products. However, I- substituent on aromatic
ring would be reduced to H. We have also tried 1-nitro-
naphthalene, which can also be rapidly reduced to the
corresponding hydroxylamine with a high yield of 88% (2l). It is
worthy noted that the hydroxylamine products with electro-
withdrawing groups on the aromatic ring (2e-2g) are more
resistant to air oxidation than those with electro-donating
groups (2a-2d). The dimeric azoxy- compounds can slowly
formed from the oxidation of 2a-2d by air, which slowly turned
from white solid to yellow color.
4b
(20 min, 86%)
4c
(25 min, 75%)
4a
(20 min, 85%)
O
O
CN
H
N
N
H
OCH3
H2N
NH2
H
N
N
H
H
N
N
H
H3CO
NC
4d
(16 min,88%)
4e
4f
(16 min, 85%)
(16 min, 87 %)
Br
H
N
N
H
O
O
CH3
Br
Cl
H
H
Br
H3C
N
N
N
N
H
H
Br
Cl
4g (20 min,92%)
4h
(20 min, 90%)
4i
(20 min, 85%)
Scheme 4. Synthesis of hydrazo- compounds 4. Reaction condition:
nitroarene (1.0 mmol), Pd(OAc)2 (0.1 mol%), NaBH4 (2.0 mmol),
water/EtOH (4 ml/6 ml), stirring at RT for 5-10 min, then input O2 for 5 min,
then NaBH4 (3.0 mmol) and MeOH (10 ml) were added, stirring at RT for 5-
15 min. The total reaction time is indicated in the parentheses. All the
yields are isolation yields.
We next investigated the scope of controllable conversion of
various nitroarenes into azoxy-compounds (Scheme 3). After
the fast reduction of nitroarenes to N-aryl hydroxylamines,
without isolation, the N-aryl hydroxylamines 2 are rapidly
oxidized by O2 to form corresponding azoxybenzenes 3, which
precipitate out as a solid after poured into a large amount of
water. The alkyl group substituted position (para-, meta- and
ortho-) has little effect on the reaction (3a-3c). Electron-
donating groups (3d-3f), electron-withdrawing groups (3h) and
halogen groups (3i-3l) are also well-tolerated in the reactions,
and provide expected products with high yield (85-90%).
Particularly, 4-nitrothioanisole is a highly challenging substrate
for Pd-catalyst, since the thiolether may coordinate with Pd
and inactivate the catalyst. However, the desired azoxy-
compounds (3g) was successfully obtained in good yield (86%).
It is likely that the coordinating affinity of thioether to Pd
catalyst is reduced by the electro-withdrawing nitro and azoxy
groups.
To dissolve the azoxy- products, additional 10 mL MeOH was
added to the 10 mL water/EtOH (2:3) solution. Then, 3 mmol
NaBH4 solid was added. The azoxy products 3 are catalytically
reduced to form hydrazo- products (Scheme 4). The alkyl
substitution at the para-, meta- position (4a-b) shows little
effect on the reaction. At ortho- position (4c), the yield (75%)
was lower than the para- and meta- analog (~85%), which
could be due to the steric hindering of the two ortho alkyl
groups. Electron-withdrawing groups (4d), electron-donating
groups (4e-3f), and halogen groups (4g-4i) are also well-
tolerated in the reactions, and provide expected products with
high yield (85-92%). Particularly, it is noteworthy that hydrazo-
compounds with electro-withdrawing groups are quite stable
under air at room temperature.
1) Pd(OAc)2 (0.1 mol%)
NaBH4 (2.0 equiv.)
H2O/EtOH, RT
R
NO2
N
N+
O-
R
R
2) O2
3
1
N
N
N
N+
O-
N+
O-
N+
O-
a
3a
3d
(8 min, 92%)
3c
(15 min,86%)
3b
(8 min, 90%)
OCH3
OH
H3CO
N
N
N+
O-
OCH3
H3CO
N+
O-
N
N+
HO
O-
(10 min, 89%)
3f
(10 min, 88%)
3e
(10 min, 90%)
F
S
CN
N
N
N
N+
O-
N+
O-
N+
O-
F
S
NC
3g
(10 min, 86%)
3i
, (9 min, 84%)
3h
(6 min, 85%)
Br
Cl
CH3
N
N
Br
H3C
N
N+
O-
N+
O-
N+
O-
Br
Br
Cl
3k
3l
(8 min, 87%)
3j
(8 min, 86 %)
(8 min, 88%)
Scheme 3. Synthesis of azoxy- compounds 3. Reaction condition:
nitroarene (1.0 mmol), Pd(OAc)2 (0.1 mol%), NaBH4 (2.0 mmol),
water/EtOH (4 ml/6 ml), stirring at RT for 5 min. Then O2 is bubbled into the
solution for 3-5 min. The total reaction time is indicated in the parentheses.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 8
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
1) Pd(OAc)2 (0.1 mol%)
NaBH4 (2.0 equiv.)
H2O/EtOH, RT
These results revealed above prompted us to test the
selective preparation of azo-aromatic compounds by oxidizing
the hydrazo- compounds using O2, as summarized in Scheme 5.
The azo-aromatic compounds are readily obtained after 10-
min oxidation by O2, which precipitate out as a solid after
poured into a large amount of water. Again, the alkyl group
substituted position (para-, meta- and ortho-) has little effect
on the reaction (5a-5c). Both electron-donating, electron-
withdrawing groups such as methoxy, hydroxymethyl,
methanethiol, cyano, ester and halogen, are well tolerated,
with good to excellent yields (83-97%). In addition, the azo-
compound containing two naphthalene ring was also obtained
in a good yield of 80% (5n), which was rarely reported in the
literature. Previous reports use palladium26, 27 and platinum29
nanosticks to catalyze the reduction of nitroarene to azo-
products, which request stoichiometric strong bases (KOH),
high temperature (~100℃) and long reaction time (several
hours). In contrast, we can achieve this conversion rapidly (less
than 30 min) under very mild condition (room temperature, no
need of acid or base as additives).
View Article Online
DOI:N10.1039/RC9GC03957K
NO2
N
R
R
2) O2
3) NaBH4 (3.0 equiv.)
MeOH, RT
5
1
4) O2
N
N
N
N
N
N
5b
5e
5a
5d
(25 min, 94%)
5c
5f
(25 min, 97%)
(30 min, 83%)
OCH3
H3CO
N
N
N
N
N
OCH3
N
H3CO
(25 min, 93%)
(30 min, 93%)
S
(30 min, 94 %)
CN
OH
N
N
N
N
N
N
HO
NC
S
5g
(25 min, 90 %)
O
5i
(20 min, 92%)
5h
5k
(30 min, 87 %)
F
Cl
OCH3
N
N
N
N
N
N
H3CO
Cl
F
(25 min, 90 %)
5l
(25 min, 92%)
5j
(20 min, 93 %)
O
Br
CH3
Br
Finally, we have examined the scope of reduction of
nitroarenes into anilines, as showed in Scheme 6. By increasing
the solvent polarity (changing the Vwater : VEtOH ratio from 2:3
to 3:1) and increasing the usage of Pd(OAc)2 from 0.1 mol% to
0.5 mol%, nitroarenes can be quickly and completely reduced
to aniline in less than 10 min at room temperature. Hydroxyl-
amines can be detected as the intermediate. In most of tested
N
N
N
Br
N
N
N
Br
H3C
5m
(25 min, 90%)
5n
5o
(25 min, 85%)
(25 min, 80 %)
Scheme 5. Synthesis of azo- compounds 5. Reaction condition: nitroarene
(1.0 mmol), Pd(OAc)2 (0.1 mol%), NaBH4 (2.0 mmol), water/EtOH (4 ml/6
ml), stirring at RT for 5 min. Then O2 is bubbled into the solution for 3-5
min. Then NaBH4 (3.0 mmol) and MeOH (10 ml) were added, stirring at RT
for 5-10 min. Finally, O2 is bubbled into the solution for 5-10 min. The total
entries, the aniline products can be obtained as pure reaction time is indicated in the parentheses. All the yields are isolation
yields.
compound just by extraction with dichloromethane or ethyl
acetate, without using column separation. This reaction
Pd(OAc)2 (0.5 mol%)
NO2
NH2
condition is highly efficient for the synthesis of aniline
derivatives, regardless of the presence of electronic-donating
(6a-6d) or
NaBH4 (2.0 equiv.)
H2O/EtOH, RT
R
R
6
1
NH2
NH2
NH2
NH2
HO
H3CO
6c
(7 min, 96%)
NH2
6a
6e
6d
(5 min, 98%)
NH2
(5 min, 90%)
NH2
6b
(5 min, 90%)
NH2
H3CO
H2N
NC
O
6h
O
O
(8 min, 88%)
NH2
6f
6g
(3 min, 95%)
NH2
(3 min, 90%)
NH2
(4 min, 92%)
NH2
OH
B
HO
O
Cl
Br
6j
(5 min, 93%)
6i
(5 min, 96%)
6k
(8 min, 90%)
6l
(9 min, 88%)
Scheme 6. Synthesis of anilines 6. Reaction condition: nitroarene (1.0
mmol), Pd(OAc)2 (0.5 mol%), NaBH4 (2.0 mmol), water/EtOH (7.5 ml/2.5
ml), stirring at RT for indicated time in the parentheses. All the yields are
isolation yields.
electron-withdrawing groups (6f-6h). From the sterically
hindered
2,6-dimethylnitrobenzene
substrate,
2,6-
dimethylani-line (6e) was obtained with a good yield (88%).
Halogen-substituted nitrobenzenes, which may undergo
dehalogenation25 during the reduction of nitro groups, were
well preserved in the corresponding chloro- or bromoanilines
(6i, 6j) exmaples. Moreover, 4-chloroaniline is a crucial
ingredient for the synthesis of an antimalarial drug, paludrine48.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 6 of 8
ARTICLE
Journal Name
Lactone with nitro- group was also examined, providing the reduction of nitroarene to aniline with hydroxylamine as the
View Article Online
DOI: 10.1039/C9GC03957K
expected 6-aminophthalide in 90% yield (6k). 6K is one key detectable intermediate. During the tandem reactions, Pd NCs
intermediate for the synthesis of inhibitors of B-RAF, a are stabilized by either the nitroarenes or the formed azoxy- or
serine/threonine kinase49. In addition, the highly active
boronate –B(OH)2 group is also well preserved during the
selective reduction of nitro group, which provides the
corresponding amino-phenylboronic acid compound (6l). The
successful preservation of halogen and –B(OH)2 groups in
these reduction reactions also suggests that the surface of Pd
NCs is preferred coordinated by the nitro group, rather than
the halogen and –B(OH)2 groups.
To further verify the effectiveness of the present reduction
system, a 50 mmol scale reduction of 1a (6.85 gram) was
carried out. The nitroarene 1a could afford separately the
corresponding N-aryl hydroxylamines, azoxy-, hydrazo-, azo-
derivatives and anlines in 88%, 90%, 82%, 92%, 94% yield,
respectively (Scheme S1-S5), implying the potential application
for large scale synthesis of valuable N-containing chemicals.
We also tested the recyclability of the Pd NC catalysts. The Pd
NCs can be easily recycled by centrifuge and reused up to five
cycles. To evaluate catalytic activity of the recycled Pd NCs, the
hydrogenation reaction of 1a converted toward 3a was
performed (see SI, Table S1). During the centrifuge of Pd NCs,
the size of Pd NCs increased from 1-2 nm to 3-5 nm because of
aggregation (Figure S2), and the catalytic activity of Pd NCs
slightly decreased. However, we can still get good yields (~
90%) by extend the reaction times (from 8 min to 15 min) and
change the solvent ratios (from water/EtOH = 4:6 to
water/EtOH = 5:5), as shown in Table S1.
a
z
o
-
c
o
m
p
o
u
n
d
s
.
Conclusions
In conclusion, we have developed an efficient synthesis
method to selectively produce five categories of N-containing
compounds by the catalytic tandem reduction of nitroarenes
with NaBH4 as the convenient reducing agent, in aqueous
solution at room temperature. These tandem reactions are
catalyzed by the in-situ generated Pd NCs from the low-cost
Pd(OAc)2 precursor reduced by NaBH4. The in situ generated
Pd NCs are surface coordinated by nitroarenes, which prevent
the further growth and aggregation of Pd NCs. Therefore,
these separated ultrasmall Pd NCs show much higher catalytic
activity than those aggregated or substrate-supported Pd
nanomaterials. The latter catalysts usually require higher
temperature, longer reaction period, and/or higher catalysts
concentration to achieve the reduction of nitroarenes.26,
27
Besides the high catalytic activity and broad scope of
substrates, our Pd NCs catalysis system also exhibits many
environment-friendly and energy-efficient features, including
the usage of aqueous solvents, short reaction period at room
temperature to reduce energy input, and simple separation
process with minimum usage of column separation. The Pd
NCs can also be reused for up to 5 times with well retained
activity. These features enable this green and sustainable
reaction attractive for large-scale preparation of valuable N-
containing chemicals.
R
NO2
NHOH
NO
R
N
Ox.
coupling
Red.
O
R
Red.
N
N
N
R
R
Pd NCs
Pd NCs
Azo
Ox. Red.
Conflicts of interest
There are no conflicts of interest to declare.
R
R
Hydroxyl
amine
R
Nitro
Azoxy
Red.
Pd NCs
Pd NCs
H
R
NH2
N
N
R

H
Pd NCs
Acknowledgements
Hydrazo
Aniline
This work was supported by the National Natural Science
Foundation of China (21722406, 21975240) and by the
Fundamental Research Funds for the Central Universities
(WK2060190102).
Scheme 7. Proposed pathways for the reduction of nitroarenes to the
corresponding fully and partially reduced N-containing products.
Based on previous mechanistic studies39, 50, 51 for nitro group
reduction, a plausible pathway of our Pd NCs catalytic system
is described in Scheme 7. With a low catalyst concentration
(0.1 mol% Pd(OAc)2), hydroxylamine is formed by reduction of
nitroarene, which can be readily oxidized under aerobic
atmosphere to form nitroso intermediate and coupled to give
azoxy-compound.29 Azoxy-compound can be catalytically
reduced to form azo- compound, and further reduced to
hydrazo- compound. Hydrazo- compound are easily oxidized to
azo- compound under air, especially for the hydrazo-
compounds with electron-donating groups. We have also
observed that hydrazo compounds cannot be reduced to
aniline in our conditions. To produce aniline, a higher
concentration of catalyst (0.5 mol% Pd(OAc)2) and a more
polar solvent mixture are required, which enable the quick
Notes and references
1.
2.
3.
4.
5.
6.
N. Ono, The Nitro Group in Organic Synthesis, John
Wiley-VCH, 2003.
A. M. Tafesh and J. Weiguny, Chem. Rev., 1996, 96,
2035-2052.
R. S. Downing, P. J. Kunkeler and H. vanBekkum,
Catal. Today, 1997, 37, 121-136.
V. M. Dembitsky, T. A. Gloriozova and V. V. Poroikov,
Nat Prod Bioprospect, 2017, 7, 151-169.
H. Mutlu, C. M. Geiselhart and C. Barner-Kowollik,
Mater. Horiz., 2018, 5, 162-183.
C. Luo, O. Borodin, X. Ji, S. Hou, K. J. Gaskell, X. L. Fan,
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Green Chemistry
Please do not adjust margins
Journal Name
J. Chen, T. Deng, R. X. Wang, J. J. Jiang and C. S. Wang, 31.
ARTICLE
R. V. Jagadeesh, G. Wienhofer, F. A. Westerhaus, A. E.
Proc. Natl. Acad. Sci. , 2018, 115, 2004-2009.
T. E. Muller, K. C. Hultzsch, M. Yus, F. Foubelo and M.
Tada, Chem. Rev., 2008, 108, 3795-3892.
Surkus, H. Junge, K. Junge and M. Beller,VCiehweAmrtic.EleuOrn.liJn.e,
DOI: 10.1039/C9GC03957K
7.
8.
2011, 17, 14375-14379.
32.
T. Schabel, C. Belger and B. Plietker, Org. Lett., 2013,
15, 2858-2861.
J. Sheng, Y. Wang, X. Su, R. He and C. Chen,
Angewandte Chemie-International Edition, 2017, 56, 33.
4824-4828.
X. L. Yi and C. J. Xi, Org Lett, 2015, 17, 5836-5839.
S. Wang, P. Shao, G. X. Du and C. J. Xi, J Org Chem, 34.
2016, 81, 6672-6676.
D. V. Jawale, E. Gravel, C. Boudet, N. Shah, V.
Geertsen, H. Y. Li, I. N. N. Namboothiri and E. Doris,
Chem. Commun., 2015, 51, 1739-1742.
K. Layek, M. L. Kantam, M. Shirai, D. Nishio-Hamane,
T. Sasaki and H. Maheswaran, Green Chem., 2012, 14,
3164-3174.
J. Liu, J. S. Cui, F. Vilela, J. He, M. Zeller, A. D. Hunter
and Z. T. Xu, Chem. Commun., 2015, 51, 12197-
12200.
A. Grirrane, A. Corma and H. Garcia, Science, 2008,
322, 1661-1664.
L. He, L. C. Wang, H. Sun, J. Ni, Y. Cao, H. Y. He and K.
N. Ean, Angew. Chem. Int. Edit., 2009, 48, 9538-9541.
H. Y. Zhu, X. B. Ke, X. Z. Yang, S. Sarina and H. W. Liu,
Angew. Chem. Int. Edit., 2010, 49, 9657-9661.
X. Liu, H. Q. Li, S. Ye, Y. M. Liu, H. Y. He and Y. Cao,
Angew. Chem. Int. Edit., 2014, 53, 7624-7628.
S. Fountoulaki, V. Daikopoulou, P. L. Gkizis, I.
Tamiolakis, G. S. Armatas and I. N. Lykakis, ACS Catal.,
2014, 4, 3504-3511.
9.
10.
11.
12.
13.
14.
S. Wang, X. W. Zhang, C. Y. Cao, C. Chen and C. J. Xi,
Green Chem., 2017, 19, 4515-4519.
35.
S. J. Liu, Y. H. Wang, J. Y. Jiang and Z. L. Jin, Green
Chem., 2009, 11, 1397-1400.
U. Sharma, P. Kumar, N. Kumar, V. Kumar and B. 36.
Singh, Adv. Synth. Catal., 2010, 352, 1834-1840.
R. V. Jagadeesh, G. Wienhofer, F. A. Westerhaus, A. E. 37.
Surkus, M. M. Pohl, H. Junge, K. Junge and M. Beller,
Chem. Commun., 2011, 47, 10972-10974.
38.
15.
16.
D. Cantillo, M. Baghbanzadeh and C. O. Kappe,
Angew. Chem. Int. Edit., 2012, 51, 10190-10193.
F. A. Westerhaus, R. V. Jagadeesh, G. Wienhofer, M.
39.
M. Pohl, J. Radnik, A. E. Surkus, J. Rabeah, K. Junge, H. 40.
Junge, M. Nielsen, A. Bruckner and M. Beller, Nat.
Chem., 2013, 5, 537-543.
17.
N. Sakai, K. Fujii, S. Nabeshima, R. Ikeda and T.
Konakahara, Chem. Commun., 2010, 46, 3173-3175.
Y. T. Dai, C. Li, Y. B. Shen, T. B. Lim, J. Xu, Y. W. Li, H.
Niemantsverdriet, F. Besenbacher, N. Lock and R. Su,
Nat. Comm., 2018, 9, 60.
F. R. Fortea-Perez, M. Mon, J. Ferrando-Soria, M.
Boronat, A. Leyva-Perez, A. Corma, J. M. Herrera, D.
Osadchii, J. Gascon, D. Armentano and E. Pardo, Nat
Mater, 2017, 16, 760-+.
18.
19.
20.
C. J. Li, Y. Uozumi and A. Moores, Green Chem., 2013, 44.
15, 2141-2148.
X. L. Li, T. W. Goh, C. X. Xiao, A. L. D. Stanton, Y. C. Pei,
P. K. Jain and W. Y. Huang, Chemnanomat, 2016, 2,
810-815.
M. Cargnello, N. L. Wieder, P. Canton, T. Montini, G.
Giambastiani, A. Benedetti, R. J. Gorte and P.
Fornasiero, Chem Mater, 2011, 23, 3961-3969.
I. Quiros, M. Yamada, K. Kubo, J. Mizutani, M.
Kurihara and H. Nishihara, Langmuir, 2002, 18, 1413-
1418.
21.
22.
23.
Z. K. Zhao, H. L. Yang, Y. Li and X. W. Guo, Green
Chem., 2014, 16, 1274-1281.
45.
L. C. Liu, P. Concepcion and A. Corma, J Catal, 2019,
369, 312-323.
T. T. Hou, Y. H. Wang, J. Zhang, M. R. Li, J. M. Lu, M. 46.
Heggen, C. Sievers and F. Wang, J Catal, 2017, 353,
107-115.
24.
M. N. Pahalagedara, L. R. Pahalagedara, J. K. He, R. 47.
Miao, B. Gottlieb, D. Rathnayake and S. L. Suib, J
Catal, 2016, 336, 41-48.
X. Y. Li, Y. F. Cao, K. Luo, Y. Z. Sun, J. R. Xiong, L. C.
Wang, Z. Liu, J. Li, J. Y. Ma, J. Ge, H. Xiao and R. N.
Zare, Nat Catal, 2019, 2, 718-725.
25.
26.
27.
28.
29.
R. J. Rahaim and R. E. Maleczka, Org. Lett., 2005, 7, 48.
5087-5090.
L. Hu, X. Q. Cao, L. Y. Shi, F. Q. Qi, Z. Q. Guo, J. M. Lu 49.
and H. W. Gu, Org. Lett., 2011, 13, 5640-5643.
J. Q. Wang, L. Hu, X. Q. Cao, J. M. Lu, X. M. Li and H.
W. Gu, Rsc Adv., 2013, 3, 4899-4902.
Y. Takenaka, T. Kiyosu, J. C. Choi, T. Sakakura and H. 50.
Yasuda, Green Chem., 2009, 11, 1385-1390.
L. Hu, X. Q. Cao, L. Chen, J. W. Zheng, J. M. Lu, X. H. 51.
Sun and H. W. Gu, Chem. Commun., 2012, 48, 3445-
3447.
J. K. Baird and S. L. Hoffman, Clin. Infect. Dis. , 2004,
39, 1336-1345.
I. Niculescu-Duvaz, E. Roman, S. R. Whittaker, F.
Friedlos, R. Kirk, I. J. Scanlon, L. C. Davies, D.
Niculescu-Duvaz, R. Marais and C. J. Springer, J. Med.
Chem., 2006, 49, 407-416.
A. Corma, P. Concepcion and P. Serna, Angew. Chem.
Int. Edit., 2007, 46, 7266-7269.
I. T. Papadas, S. Fountoulaki, I. N. Lykakis and G. S.
Armatas, Chem.Eur. J., 2016, 22, 4600-4607.
30.
E. H. Boymans, P. T. Witte and D. Vogt, Catal. Sci.
Technol., 2015, 5, 176-183.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 8 of 8
View Article Online
DOI: 10.1039/C9GC03957K
Journal Name
ARTICLE
TOC
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 8
Please do not adjust margins