Selective hydrogenation of nitroaromatics to: N -arylhydroxylamines in a micropacked bed reactor with passivated catalyst

Article abstract of DOI:10.1039/d0ra05715k

In this contribution, a protocol was established for the selective catalytic hydrogenation of nitroarenes to the corresponding N-arylhydroxylamines. The reduction of 1-(4-chlorophenyl)-3-((2-nitrobenzyl)oxy)-1H-pyrazole, an intermediate in the synthesis of the antifungal reagent pyraclostrobin that includes carbon-chlorine bonds, benzyl groups, carbon-carbon double bonds and other structures that are easily reduced, was chosen as the model reaction for catalyst evaluation and condition optimization. Extensive passivant evaluation showed that RANEY-nickel treated with ammonia/DMSO (1 : 10, v/v) afforded the optimal result, especially with a particle size of 400-500 mesh. To combine the modified catalyst with continuous-flow reaction technology, the reaction was conducted at room temperature, rendering the desired product with a conversion rate of 99.4% and a selectivity of 99.8%. The regeneration of catalytic activity was also studied, and an in-column strategy was developed by pumping the passivate liquid overnight. Finally, the generality of the method was explored, and 7 substrates were developed, most of which showed a good conversion rate and selectivity, indicating that the method has a certain degree of generality.

Full text of DOI:10.1039/d0ra05715k

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Selective hydrogenation of nitroaromatics to N-
arylhydroxylamines in a micropacked bed reactor
with passivated catalyst†
Cite this: RSC Adv., 2020, 10, 28585
c
a
Feng Xu,a Jian-Li Chen,a Zhi-Jiang Jiang,
Peng-Fei Cheng,a Zhi-Qun Yu
*
ab
*
and Wei-Ke Su
In this contribution, a protocol was established for the selective catalytic hydrogenation of nitroarenes to
the corresponding N-arylhydroxylamines. The reduction of 1-(4-chlorophenyl)-3-((2-nitrobenzyl)oxy)-
1H-pyrazole, an intermediate in the synthesis of the antifungal reagent pyraclostrobin that includes
carbon–chlorine bonds, benzyl groups, carbon–carbon double bonds and other structures that are
easily reduced, was chosen as the model reaction for catalyst evaluation and condition optimization.
Extensive passivant evaluation showed that RANEY®-nickel treated with ammonia/DMSO (1 : 10, v/v)
afforded the optimal result, especially with a particle size of 400–500 mesh. To combine the modified
catalyst with continuous-flow reaction technology, the reaction was conducted at room temperature,
rendering the desired product with a conversion rate of 99.4% and a selectivity of 99.8%. The
regeneration of catalytic activity was also studied, and an in-column strategy was developed by pumping
the passivate liquid overnight. Finally, the generality of the method was explored, and 7 substrates were
developed, most of which showed a good conversion rate and selectivity, indicating that the method has
a certain degree of generality.
Received 30th June 2020
Accepted 27th July 2020
DOI: 10.1039/d0ra05715k
rsc.li/rsc-advances
(c) hydroxylamine-reduction (Scheme 1). Unfortunately,
condensation can occur between the nitrone and hydroxyl-
Introduction
amine intermediates, affording unexpected azoxy and azo side
products (Scheme 1).3b Furthermore, the reduction of hydrox-
ylamine can be achieved via similar conditions, which leads to
over-reduction becoming a prevailing side reaction. Thus,
removing in situ generated N-arylhydroxylamines promptly from
the complex environment may further enhance the
performance.
Selective catalytic hydrogenation of nitroarenes is one of the
most promising methods for producing N-arylhydroxylamines,
and it is frequently used in pharmaceuticals, agrochemicals,
and materials.1 Excellent results have been achieved during the
past few decades by utilizing nely optimized conditions,2
including catalytic hydrogenation3 (with Pt/C/DMSO/H2,3a
RANEY®-Ni/NH4VO3/H2,3b Pt/SiO2/DMSO/nBuNH2/H2,3c Pd/SIO-
2H2,3d RuCNT/N2H4$H2O3e) and electro-reduction.4 However,
these processes are not necessarily environmentally benign,
cost-efficient, and complex post-processing (due to the use of
additives) and severe side reactions still bother the eld due to
the lability of the hydroxylamine group.
During the past few decades, continuous-ow reactors have
attracted considerable attention from both academic and
industrial communities.5 The advantages of continuous-ow
reactors in terms of mass and heat transfer accompanied with
low back-mixing have shown a unique advantage in process
enhancement, where excellent examples can be found in the
form of nitration and diazotization.6 The technique has also
unveiled promising application in the eld of catalytic hydro-
genation,7 especially combined with heterogeneous catalysis.8
Recently, Jensen and co-workers reported a catalytic hydroge-
nation of nitroarenes employing a micropacked bed reactor
(mPBR).9 Although the formation of N-arylhydroxylamines was
not discussed in this case, this excellent result aroused our
interest to cut down sequential hydrogenation at the middle
point of the reaction, affording hydroxylamine selectively.
Fortunately, a similar strategy has been successfully proved
by pumping the substrate through a packed-bed of zinc
powder.10 Encouraged by this result, we commenced our
Mechanistically, the reduction of nitroarenes can be divided
into three steps: (a) nitro-reduction, (b) nitrone-reduction, and
aNational Engineering Research Center for Process Development of Active
Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta
Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou
310014, People's Republic of China. E-mail: yzq@zjut.edu.cn; pharmlab@zjut.edu.cn
bKey Laboratory for Green Pharmaceutical Technologies and Related Equipment of
Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, People's Republic of China
cSchool of Biological and Chemical Engineering, Ningbo Tech University, Ningbo,
315100, People's Republic of China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra05715k
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 28585–28594 | 28585

View Article Online
RSC Advances
Paper
Scheme 1 General scheme for the catalytic hydrogenation of nitroarene.
exploration of selective hydrogenation under continuous-ow
conditions using RANEY®-nickel as a catalyst. Our initial
strategy speeded up feeding-rate imaging, indicating that the
desired N-arylhydroxylamine could be ushed out before the
over-reduction. However, no selectivity was observed even when
the conversion rate dropped to 20%. Thus, our focus turned to
manipulate the activity of N-arylhydroxylamine and inhibit the
excessive reduction of hydroxylamine by combining the modi-
ed catalyst with continuous-ow. For concern of additive
residue accumulation, a stable catalyst may be more suitable for
a continuous-ow reaction rather than adding passivants into
a feeding solution. Herein, we unveil a convenient protocol for
selectively catalytic hydrogenation to N-arylhydroxylamines
using the continuous-ow technique with a recyclable mPBR.
The strategy described in this paper is low cost, environmentally
friendly, and the reaction proceeds directly to the next step
without post-treatment.
Catalysts evaluation
The initial evaluation of the catalyst performance was conducted
in an autoclave. The data obtained for the normal RANEY®-Ni
showed no selectivity toward the desire product N-(2-((1-(4-
chlorophenyl)-1H-pyrazol-3-yl)oxy)phenyl)hydroxylamine (HA-1)
for 6 h of HPLC tracking, and only 2-(((1-(4-chlorophenyl)-1H-
pyrazol-3-yl)oxy)methyl)aniline (AM-1) was obtained (Table 1,
entry 1). Then, the catalyst was treated with various passivants,
and their performance is summarized in Table 1. Firstly, DMSO-
treated catalyst was tested, which showed a promising selectivity
toward hydroxylamine (Table 1, entry 3). However, the low
conversion can hardly satisfy the kinetic requirement for the
continuous-ow reactor. A similar result was observed by using
diphenyl sulde as passivant (Table 1, entry 5). When amine was
employed as passivant, the reaction proceeded with a high
conversion and extremely poor selectivity (Table 1, entries 6–7). It
is noteworthy that a rapid accumulation of N-arylhydroxylamine
was observed in the rst 2 min of the reaction using an ammonia-
treated catalyst. However, the immediate quenching failed to
afford any satisfying result due to the rapid hydroxylamine-
reduction. To balance the selectivity and conversion, a mixture
of DMSO and aqueous ammonia was employed as passivant.
Fortunately, this strategy showed a promising result (Table 1,
entry 9). Subsequent optimization showed that ammonia/DMSO
(1 : 10, v/v) can afford the optimal condition, affording the
product with a conversion of over 95.6% and a selectivity near
93.7% (Table 1, entry 11). The data showed that short reaction
Result and discussion
Our group has made continuous efforts into the industrial
application of the continuous-ow technique6c,6d,11 Among
others, the selective reduction of 1-(4-chlorophenyl)-3-((2-nitro-
benzyl)oxy)-1H-pyrazole (NA-1), a key intermediate of the anti-
fungal reagent pyraclostrobin, is a great challenge due to the
sensitive substituents of the benzyl and chloride groups
(Scheme 2).
Scheme 2 Catalytic hydrogenation for NA-1: the synthesis of a key intermediate for pyraclostrobin.
28586 | RSC Adv., 2020, 10, 28585–28594
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 1 Passivant screening for catalyst passivationa
No.
Passivantb
Time/h
HA-1 (%)
AM-1 (%)
Conv. (%)
Select. (%)
1
2
3
4
5
6
7
8
None
DMSO
DMSO
Ph2S
Ph2S
NH3
NH2CH2CH2NH2
NH3/DMSO ¼ 1 : 5
NH3/DMSO ¼ 1 : 5
NH3/DMSO ¼ 1 : 10
NH3/DMSO ¼ 1 : 10
NH3/DMSO ¼ 1 : 15
NH3/DMSO ¼ 1 : 15
6
6
16
6
16
6
6
6
27
6
32
6
35
0.0
2.8
5.8
1.9
4.4
100.0
0.3
1.6
0.1
0.6
95.2
70.6
3.0
10.8
0.2
$99.9
3.1
7.4
2.0
5.0
$99.9
$99.9
34.6
87.1
28.6
95.6
25.8
99.7
0.0
90.1
78.2
94.3
87.9
4.8
29.4
91.4
87.6
99.2
93.7
99.4
91.7
4.8
29.4
31.6
76.3
28.4
89.2
25.6
91.5
9
10
11
12
13
6.0
0.2
8.2
a
Reaction conditions unless noted otherwise: NA-1 (7.55 mmol, 2.50 g) and passivated catalyst (0.125 g) (400–500 mesh) were dispersed in THF (20
mL) within an autoclave, which was then reacted at ꢀ7 ꢁC under H2 atmosphere (0.6 MPa). The conversion and selectivity were determined by HPLC
analysis. b The ratio of binary passivant was based on volume.
Table 2 The influence of catalyst particle sizea
FT-IR was rst employed to nd the signals (Fig. 1). Compared
with the original RANEY®-Ni, three additional bands were
AM-1
(%)
Conv.
(%)
observed in catalysts treated with DMSO and aqueous
ammonia. The bands in the wavenumber range 3300–
3500 cmꢀ1 represent the N–H bond stretching vibration, sug-
gesting the presence of NH3. Meanwhile, the vibration in the
range 1300–1470 cmꢀ1 was assigned to the methyl group of
DMSO. Moreover, a slight shi in the bands of around
1000 cmꢀ1 was found, which indicated a coordination of both S
and O to the metal center. DA400r also showed a similar
pattern, indicating attachment of the passivant to the metal
center.
No.
Mesh
Name
HA-1 (%)
Select. (%)
1
2
3
4
80–120
DA80
17.5
33.0
65.6
41.4
4.0
0.3
0.3
1.0
21.5
33.3
65.9
42.6
81.2
99.0
99.5
97.6
200–300
400–500
400–500
DA200
DA400
DA400r
a
Reaction conditions unless noted otherwise: NA-1 (7.55 mmol, 2.50 g)
and passivated catalyst (0.125 g) were dispersed in THF (20 mL) within
an autoclave, which was then reacted at ꢀ7 ꢁC under H2 atmosphere (0.6
MPa). The conversion and selectivity were determined by HPLC analysis.
time results in low reaction conversion rate and better reaction
selectivity. As the reaction time increased, the reaction conver-
sion rate increased, but the reaction selectivity gradually
decreased.
The particle size of RANEY®-Ni was also examined due to the
potential inuence of the surface area. In contrast to our initial
hypothesis that a lower surface may afford better control, the
comparison between different sized catalysts showed that
a higher surface area afforded better results (Table 2, entries 1–
3) due to better passivation effects. DA400 of 400–500 mesh
rendered the best selectivity of 99.5% and a conversion of 65.9%
aer 20 h of reaction (Table 2, entry 3). It is noteworthy that the
reused catalyst (DA400r) still gave a good selectivity of 97.6%
(Table 2, entry 4), which indicated the possibility of catalyst
recycling. This interesting deviation from expectations aroused
our interest to elucidate the phenomenon, and the catalysts
were then rendered for characterization.
Catalyst characterization
Previously, ammonia and DMSO have been used in manipu-
lating catalyst activity by ligation.3a,3c,3d Thus, our work began
with identifying the presence of such compounds. Therefore, Fig. 1 FT-IR spectra for different catalysts.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 28585–28594 | 28587

View Article Online
RSC Advances
Paper
Fig. 2 SEM and TEM spectra for different catalysts: TEM for DA80 (a), DA200 (b), DA400 (c); SEM for DA80 (d), DA200 (e), DA400 (f).
Although the tests above prove the presence of DMSO and which was conrmed by subsequent Specic surface area (BET)
NH3 in the catalysts, the difference between the three catalysts analysis (see ESI† for details).
was not yet drawn. Thus, an elementary analysis was conducted
to determine the heteroatom density in the catalysts, and DA400
was found to possess the highest nitrogen and sulfur ratio
(0.46% N and 2.77% S, see ESI† for details). Furthermore,
energy-dispersive X-ray spectroscopy (EDS) suggested that these
elements were distributed evenly through DA400 (Fig. S3†),
while the corresponding signals acquired from the other two
samples were much weaker. The recovered DA400r was also
tested and showed an increased nitrogen density, which may be
due to product absorption.
Finally, the catalyst morphology and surface property was
compared (Fig. 2). Scanning electron microscopy (SEM) analysis
showed that DA200 and DA400 possessed a ne needle-like
surface, but DA80 only afforded a hollow surface. Trans-
mission electron microscopy (TEM) also indicated that the
surface of DA400 was much larger than the other catalysts,
Reaction process evaluation
Aer catalyst characterization and preliminary optimization in
the autoclave (see ESI† for more details), the reaction catalyzed
by DA400 was tracked by HPLC to understand its progress.
As shown in Fig. 3, the transformation underwent a clear
two-stage process. The desired N-arylhydroxylamine was
generated smoothly during the rst 24 h, which was followed by
a rapid accumulation of amine in the second stage aer the
complete consumption of the nitroarene. The intermediate
nitrone was found to remain at a low level (<1%) during the
reaction period, whereas its down-stream byproducts, azoxy and
azo, were absent from the reaction. Mechanistically, these
phenomena indicated that the three-step reduction was well
controlled by the passivated catalyst, in which the rst and the
second steps were facilitated by ammonia.3c In addition, the
undesired third reduction was inhibited by DMSO, which has
28588 | RSC Adv., 2020, 10, 28585–28594
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
However, the poor performance of 1,4-dioxane in the batch
reactor was reverted in the mPBR, with an enhanced selectivity
observed when using the continuous-ow technique (see Table
S2, entry 5 in ESI†). Noticeably, the ethylacetate afforded aniline
product, conclusively, under various conditions. This
phenomenon contrasts with the previous prediction of selec-
tivity co-relationship with the dielectric constant of the sol-
vent,3a where the performance of ethylacetate should range
between that of THF and 1,4-dioxane. Ethanol was also exam-
ined (not listed), where its poor solubility made us turn to a mix-
solvent (Table 3, entries 10–11). However, this combination did
not afford acceptable results in these cases.
Then, our attention was moved to the parameters for the
continuous-ow reactor. The hydrogen gas pressure was
screened rst, which showed a strong inuence on the
outcomes. By increasing the pressure in the tube, the reaction
performance was gradually enhanced (Table 4, entries 1–3),
where a pressure of 30 psi was found to be the optimal choice.
Further pressurization led the conversion toward being
Fig. 3 Kinetic profile of the batch reaction.
been previously observed in batch reactors.3a,3c The selectivity
loss at the end of the rst-stage may be accounted for by the
competitive ligation due to elevated hydroxylamine concentra-
tion. Thus, this interesting kinetic feature may be of further
benet in the continuous-ow reactor.
Table 4 Influence of pressure and resident timea
Conv.
No.
P/psi
s/s
HA-1 (%)
AM-1 (%)
Select. (%)
(%)
Continuous-ow reaction optimization
Since the process analysis revealed a promising prole for
a continuous-ow reactor, the reaction was then repeated in
a mPBR. Unfortunately, the rst attempt at 0 C only afforded
1
2
3
4
5
6
7
8
9
10
0
600
600
600
600
600
600
200
120
86
73.1
91.1
97.2
91.6
78.6
97.2
97.8
99.2
77.6
63.5
6.4
5.1
2.4
8.1
21.4
2.4
2.1
0.2
3.5
1.7
91.9
94.7
97.6
91.9
78.6
97.6
97.9
99.8
95.7
97.4
79.5
15
30
45
60
30
30
30
30
30
96.2
99.6
99.7
ꢁ
a moderate selectivity of 75.0% (Table 3, entry 1), which made
us doubt the strategy. Despite the concern for selectivity
erosion, the situation was improved by elevating the tempera-
ture. Both selectivity and conversion were improved dramati-
cally (Table 3, entries 2–4), and an acceptable result was found
at 25 ꢁC (Table 3, entry 4). The inection-point occurred at
approximately 30 ꢁC, where the selectivity erosion was observed
aerward (Table 3, entries 5–6).
100
99.6
99.9
99.4
81.1
65.2
60
a
Reaction conditions: NA-1 (c ¼ 80 g Lꢀ1) in dioxane was added through
the mPBR at 25 ꢁC with a constant feeding rate. The H2 gas was
pressurized with a back pressure. The conversion and selectivity were
determined by HPLC analysis.
The solvent-effect for the transformation was also examined.
THF remained the optimal choice for the transformation.
Table 3 Influence of solvent and temperaturea
Conv.
(%)
No.
Solvent
Temp.(ꢁC)
HA-1 (%)
AM-1 (%)
Select. (%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
DCM
1,4-Dioxane
EtOAc
0
15
20
25
30
35
25
25
25
25
25
37.1
58.8
84.2
92.5
94.6
85.1
45.3
97.7
0
12.0
3.4
4.7
2.1
3.7
14.1
54.7
2.1
100
22.1
19.7
75.6
94.5
94.7
97.8
96.2
85.8
45.3
97.9
0.0
49.1
62.2
88.9
94.6
98.3
99.2
100
99.8
100
100
97.3
9
10
11
EtOH : THF (1 : 9)
EtOH : 1,4-dioxane (1 : 4)
77.9
77.6
77.9
79.8
a
Reaction conditions: NA-1 (c ¼ 80 g Lꢀ1) in solvent was added through the mPBR at a specic temperature and constant rate of 0.1 mL minꢀ1. The
H2 gas was pressurized with a back pressure of 30 psi. The conversion and selectivity were determined by HPLC analysis.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 28585–28594 | 28589

View Article Online
RSC Advances
Paper
Fig. 4 Result for reaction performance and catalyst regeneration.
complete (Table 4, entries 4–5). However, the selectivity drop- was 120 s for this case, where one achieved a conversion and
ped dramatically, which could hardly satisfy the requirement. selectivity of over 99%. A further increase in the feeding speed
The nal part of optimization was conducted for the resident did not offer any better result. In contrast, a signicant decrease
time. Interestingly, it was found that the amine could be further in conversion was found (Table 4, entry 10), which may be
suppressed by fastening the feeding speed (Table 4, entries 6–9), attributed to an insufficient time for substrate adsorption on
which supported our initial strategy. The optimal resident time the catalyst due to the ow rate being too fast.
Scheme 3 Conformed mechanism of catalytic hydrogenation of pyraclostrobin intermediate.
28590 | RSC Adv., 2020, 10, 28585–28594
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 5 Preliminary substrate scope examinationa
Entry
R of NAs
Product no.
Select.b (%)
%Conv.b (%)
1
2
3
4
5
6
7
2-Cl
3-Cl
4-Cl
4-Br
2-OBn
4-CO2Me
4-Ac
HA-2
HA-3
HA-4
HA-5
HA-6
HA-7
HA-8
99.1
88.1
99.2
93.9
90.1
39.4
99.3
83.8
90.1
88.0
94.2
91.3
89.1
90.4
a
Reaction conditions: NA (c ¼ 80 g Lꢀ1) in THF was added through the mPBR at 25 ꢁC with a resident time of 120 s. The H2 gas was pressurized with
a back pressure of 30 psi. b The conversion and selectivity were determined by HPLC analysis aer the reaction reached a steady state.
used to ush the column overnight, avoiding potential activity
blocking. The evaluation showed that the catalyst activity was
recovered (Fig. 4, middle). Although the selectivity remained
above 99.0%, a continuous drop in the conversion was observed
aer the initial 32 h. This phenomenon was further veried by
a third run, in which the conversion dropped to 94.0% aer 107
hours of operation (Fig. 4, right).
Reaction performance evaluation and catalyst regeneration
Aer the optimal condition was established, the durability of
the catalytic system was also examined. Aer 144 h of operation,
the selectivity was found to rain above 99.0%, where a slight
drop in conversion was detected during the last 24 h (Fig. 4,
le). The overall product was obtained with 99.0% conversion
with an excellent selectivity of 99.5%. However, this result could
hardly satisfy our expectation about the mPBR due to the
tedious packing work involved. Thus, an additional exploration
for catalyst treatment was conducted.
Validation of mechanism
According to the Horiuti–Polanyi mechanism, the aromatic
nitro compound is adsorbed on the surface of the metal cata-
lyst, and the nitrogen–oxygen double bond of the nitro group is
complexed with the metal, so that the nitrogen–oxygen double
bond is pulled up, and the bond energy is weakened. At the
same time, hydrogen molecules were also adsorbed on the
surface of the catalyst, and bond cracks occurred on the surface
The reason for the loss of conversion rate may be caused by
the product covering the catalyst surface. Thus, replenishing
the passivant and removing the cover may improve the perfor-
mance. To avoid packing, the regeneration was expected to be
conducted in a column. Instead of pumping the DMSO solely,
a combined passivant, ammonia/DMSO ratio of 1 : 10 (v/v) was
Fig. 5 The setup scheme for the micropacked bed continuous reactor.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 28585–28594 | 28591

View Article Online
RSC Advances
Paper
of the catalyst, and active hydrogen atoms were obtained. The
reactive hydrogen is inserted directly between the nitrogen–
oxygen bonds, binding with the nitrogen to form the amino
group, while losing a molecule of water to form a hydroxyl-
amine-like compound with oxygen atoms complexing with the
metal. The hydroxylamine compounds can be divided into two
pathways to synthesize the corresponding aromatic hydroxyl-
amine and aromatic amine compounds, and then the aromatic
amine or aromatic hydroxylamine desorbs from the catalyst
surface and leaves the catalyst surface to form the correspond-
ing products (Scheme 3). If the aromatic hydroxylamine
compound failed to desorb from the catalyst surface, it would
be further reduced to the corresponding aromatic amines. If the
aromatic amine compound could not be desorbed from the
catalyst, the active site of the catalyst would be gradually
covered and lost activity.
Experimental section
General information
Materials. The substrate 1-(4-chlorophenyl)-3-[(2-nitro-
phenyl)methoxy]-1H-pyrazole (NA-1) was purchased from
Shanghai Energy Chemical Co., Ltd. RANEY®-Ni was purchased
from Deqing Donglai Chemical Co., Ltd. Other chemicals were
purchased from Sinopharm Chemical Reagent Co., Ltd. All
purchased chemicals were used without further purication
unless indicated otherwise. All the chemicals were obtained
commercially and used without any prior purication. The
reaction process was tracked by HPLC analysis, which was
performed using a FULI 2200 high-performance liquid chro-
matography. 1H and 13C NMR spectra were recorded by a Bruker
Advance 500 spectrometer (or Mercury PLUS-400 (Oxford)) at
ambient temperature with CDCl3 (or DMSO) as solvent and
tetramethylsilane (TMS) as the internal standard. Melting
points were determined by using an X-5 data microscopic
melting point apparatus. Compounds for HRMS were analyzed
by positive mode electrospray ionization (ESI) using an Ultimate
3000 (Thermo) mass spectrometer.
Examination of substrate scope
Finally, a preliminary substrate scope examination was con-
ducted to determine the functional group tolerance (Table 5).
To our delight, substrates bearing halogen or benzyl groups
afforded satisfactory results affording desired N-arylhydroxyl-
amines with moderate to high yields.12 However, the methyl-
ester rendered an extremely poor selectivity toward
hydroxylamine, where amine was found to be the main product.
This result was similar to that found for EtOAc (Table 3, entry 9),
indicating that the ester group may inuence the catalytic
activity. Further examination using 4-acetyl substrate suggested
that the carbonyl part did not account for this phenomenon.
Due to the instability of N-arylhydroxylamines, the nitrogen was
amide derivatized.
Catalyst preparation, nomenclature, characterization and
activity evaluation
The passivated catalysts are prepared according to the following
procedure: RANEY®-Ni (20.00 g) was thoroughly washed by
deionized water until neutral. Then, the obtained solid was
suspended and stirred in the passivant (DMSO : NH3$H2O ¼
10 : 1, 45 mL) at 48 ꢁC for 24 h. Aer ltration, the catalysts were
obtained and named aer the following rules: D for DMSO, A for
amine, 400 for mesh size, r for recovery.
Infrared (IR) spectroscopy was measured using Fourier-
transform infrared spectroscopy, Bruker Vertex 70 V, using
KBr powder for sample preparation. Powder X-ray diffraction
(PXRD) was recorded by a Bruker D8 Advance diffractometer
Conclusion
A protocol for the selective catalytic hydrogenation of nitro- with a CuKa (l ¼ 0.154 nm) X-ray source operated at 40 kV.
arenes to N-arylhydroxylamines was demonstrated to reveal the Energy dispersive X-ray spectroscopy (EDS) was conducted with
potential application of the continuous-ow technique in the an Element instrument made by EDAX. The elemental compo-
preparation of labile compounds. In addition, the potency of sition was analyzed using an Elementar Vario EL cube element
the protocol was revealed by the preparation of pyraclostrobin's analyzer. Scanning electron microscopy (SEM) was carried out
key intermediate HA-1, affording the product with excellent using a Hitachi S-4800 eld emission SEM, with a working
conversion and selectivity on average. The employment of voltage of 10 kV. Transmission electron microscopy (TEM)
a micropacked bed reactor enabled the high-efficiency hetero- images were captured with a Hitachi HT-7700 working at 100
geneous catalysis using passivated RANEY®-nickel, which was kV. Nitrogen adsorption–desorption isotherms for the samples
treated by a combined liquid of aqueous ammonia and DMSO. were obtained using a TriStar II analyzer, with all samples
Mechanistically, both components contribute to excellent degassed at 200 ꢁC for 6 h to remove moisture and volatile
kinetic control of the selective hydrogenation, where ammonia impurities.
speeds up the initial nitro- and nitrone-reduction and the
The evaluation of catalyst performance was carried out in
DMSO inhibits the undesired hydroxylamine-reduction. More- a Teon-lined stainless-steel autoclave (50 mL). Typically, the
over, a strategy is proposed for the regeneration of catalyst in substrate 1-(4-chlorophenyl)-3-((2-nitrobenzyl)oxy)-1H-pyrazole
the mPBR. By pumping the passivant liquid through the mPBR, (7.55 mmol, 2.50 g) and passivated catalyst (0.125 g) were mixed
the catalyst could be reused for another 200 h, affording the with THF (20 mL) in the autoclave. Then, the reactor was sealed
desired product with acceptable selectivity (>95%). A prelimi- and purged with N2 for three times. The autoclave was held at
ꢁ
nary scope for substrates was examined, which showed good a temperature of 38 C with magnetic stirring at 700–800 rpm.
results. Further studies including mechanistic elucidation are Aer 30 min of stirring, the reactor was cooled down to ꢀ7 ꢁC,
still under investigation in our laboratory.
purged with H2 for three times and pressurized to 0.6 MPa.
28592 | RSC Adv., 2020, 10, 28585–28594
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Then, the reaction was tracked with HPLC analysis until
complete.
Acknowledgements
The authors would like to acknowledge the nancial support
from Zhejiang Provincial Key R&D Project (No. 2018C03074 &
2020C03006) and the Natural Science Foundation of Zhejiang
Province (No. LQ20B060006).
Micropacked bed continuous-ow reactor setup
The setup for the micropacked bed continuous-ow reactor
refers to the apparatus setup reported by Jensen.9 The packed
bed was laid horizontally in a water bath for temperature
control. The hydrogen gas was controlled by a hydrogen-specic
mass ow controller (DO7-19BM, max pressure 10 MPa), which
was protected by a check valve. The liquid ow was supplied
with a dual-piston HPLC pump (LC-500P constant pressure
infusion 0–15 MPa). The gas and liquid were mixed in a T-shape
mixture before the entrance of the mPBR (SS-98 max pressure
3.5 MPa). All tubes were made of stainless-steel with an outer
diameter of 1/16 inch. A manual back-pressure regulator was
placed at the outlet of the reactor to control the system pres-
sures (Fig. 5).
The catalysts were loaded into a clean HPLC column with
a diameter of 4.6 mm and a length of 150 mm, and compacted
with a high-pressure vacuum tube. The column was further
blown with nitrogen gas until the pressure of nitrogen gas
reached 0.2–0.5 MPa. The procedure was repeated several times
until the column was completely lled (approximately 4.1 g of
catalyst), and both ends were sealed with a sealing nut for use.
References
1 (a) A. D. McGill, W. Zhang, J. Wittbrodt, J. Wang,
H. B. Schlegel and P. G. Wang, Bioorg. Med. Chem., 2000, 8,
405–412; (b) J. S. Yadav, B. V. S. Reddy and P. Sreedhar,
Adv. Synth. Catal., 2003, 345, 564–567; (c) A. El-Faham and
F. Albericio, Eur. J. Org. Chem., 2009, 2009, 1499–1501; (d)
S. Sabir, G. Kumar and J. L. Jat, Org. Biomol. Chem., 2018,
16, 3314–3327.
2 (a) M. Orlandi, D. Brenna, R. Harms, S. Jost and M. Benaglia,
Org. Process Res. Dev., 2016, 22, 430–445; (b) H. Goksu,
H. Sert, B. Kilbas and F. Sen, Curr. Org. Chem., 2017, 21,
794–820.
3 (a) S. L. Karwa and R. A. Rajadhyaksha, Ind. Eng. Chem. Res.,
1987, 26, 1746–1750; (b) M. Studer, S. Neto and H. U. Blaser,
Top. Catal., 2000, 13, 205–212; (c) Y. Takenaka, T. Kiyosu,
J.-C. Choi, T. Sakakura and H. Yasuda, Green Chem., 2009,
11, 1385–1390; (d) Y. Takenaka, T. Kiyosu, J.-C. Choi,
T. Sakakura and H. Yasuda, ChemSusChem, 2010, 3, 1166–
1168; (e) D. V. Jawale, E. Gravel, C. Boudet, N. Shah,
V. Geertsen, H. Li, I. N. N. Namboothiri and E. Doris,
Chem. Commun., 2015, 51, 1739–1742.
4 (a) T. Gubica, J. Stroka and A. Temeriusz, J. Phys. Org. Chem.,
2007, 20, 375–383; (b) Y. Chen, L. Xiong, W. Wang, X. Zhang
and H. Yu, Front. Environ. Sci. Eng., 2015, 9, 897–904.
5 (a) D. Cantillo, M. M. Moghaddam and C. O. Kappe, J. Org.
Chem., 2013, 78, 4530–4542; (b) M. B. Plutschack,
B. Pieber, K. Gilmore and P. H. Seeberger, Chem. Rev.,
2017, 117, 11796–11893; (c) J. Britton, S. Majumdar and
G. A. Weiss, Chem. Soc. Rev., 2018, 47, 5891–5918; (d)
F. M. Akwi and P. Watts, Chem. Commun., 2018, 54,
13894–13928.
Experiment process for continuous-ow reaction
The substrate 1-(4-chlorophenyl)-3-((2-nitrobenzyl)oxy)-1H-pyr-
azole was prepared as a 0.24 mol Lꢀ1 stock solution in dioxane.
The packed-bed reactor was placed into a water bath of 25 ꢁC, in
which the passivated catalyst stored in EtOAc was drained by
owing H2 gas. Aer the back pressure reached 30 psi (less than
1 min), the solution was introduced to the reactor. Aer purging
for 7–10 reactor volumes (approximately 20 min), the system
reached a steady state. The sample was collected for 2–3 times,
where the sampling interval was 20–30 minutes. Reactor vari-
ables were then adjusted and sampled aer reaching the steady
state (approximately 20 min). When the experiments were
complete, the water bath was removed rst, and the back
pressure released to the atmosphere. Following the depressur-
ization, the mPBR was drained by H2 before stopping the H2
gas. Then, the EtOAc was introduced into the mPBR, where 5–7
reactor volumes were owed over before the reactor was sealed
with this solvent for storage.
6 (a) L. Ducry and D. M. Roberge, Angew. Chem., Int. Ed. Engl.,
2005, 44, 7972–7975; (b) Z. Wen, F. Jiao, M. Yang, S. Zhao,
F. Zhou and G. Chen, Org. Process Res. Dev., 2017, 21,
1843–1850; (c) Z. Yu, X. Ye, Q. Xu, X. Xie, H. Dong and
W. Su, Org. Process Res. Dev., 2017, 21, 1644–1652; (d)
Z. Yu, J. Chen, J. Liu, Z. Wu and W. Su, Org. Process Res.
Dev., 2018, 22, 1828–1834.
Method for product analysis
HPLC conditions. C18 chromatographic column; HPLC
acetonitrile and 0.1% phosphoric as mobile phase, mobile
phase acetonitrile stayed at 62% for 3 min, from 62% to 85% for
17 min, stayed at 85% for 5 min, from 85% to 62% for 3 min,
and stayed at 62% for 2 min; ow rate of mobile phase of 1.0
mL minꢀ1; detection wavelength at 254 nm.
7 P. J. Cossar, L. Hizartzidis, M. I. Simone, A. McCluskey and
C. P. Gordon, Org. Biomol. Chem., 2015, 13, 7119–7130.
8 (a) M. Irfan, T. N. Glasnov and C. O. Kappe, ChemSusChem,
2011, 4, 300–316; (b) R. Munirathinam, J. Huskens and
W. Verboom, Adv. Synth. Catal., 2015, 357, 1093–1123; (c)
K. Masuda, T. Ichitsuka, N. Koumura, K. Sato and
S. Kobayashi, Tetrahedron, 2018, 74, 1705–1730; (d)
M. B. Said, T. Baramov, T. Herrmann, M. Gottfried,
J. Hassfeld and S. Roggan, Org. Process Res. Dev., 2017, 21,
705–714.
Conflicts of interest
There are no conicts to declare.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 28585–28594 | 28593

View Article Online
RSC Advances
Paper
9 C. Yang, A. R. Teixeira, Y. Shi, S. C. Born, H. Lin, Y. Li Song,
B. Martin, B. Schenkel, M. Peer Lachegurabi and
K. F. Jensen, Green Chem., 2018, 20, 886–893.
10 L. Li, T. V. Marolla, L. J. Nadeau and J. C. Spain, Ind. Eng.
Chem. Res., 2007, 46, 6840–6846.
11 (a) Z. Yu, G. Tong, X. Xie, P. Zhou, Y. Lv and W. Su, Org.
Process Res. Dev., 2015, 19, 892–896; (b) Z. Yu, G. Lu,
J. Chen, S. Xie and W. Su, J. Flow Chem., 2018, 8, 51–57; (c)
X. Xie, S. Xie, H. Yao, X. Ye, Z. Yu and W. Su, React. Chem.
Eng., 2019, 4, 927–931.
12 The reported conversion and selectivity was based on the
HPLC analysis aer the reaction reached the steady-state.
However, due to the lability of the N-arylhydroxylamines,
the further structure characterization was conducted aer
the protection of methoxy carbonyl group.
28594 | RSC Adv., 2020, 10, 28585–28594
This journal is © The Royal Society of Chemistry 2020