Deep Eutectic Solvent/Lipase: Two Environmentally Benign and Recyclable Media for Efficient Synthesis of N-Aryl Amines

Article abstract of DOI:10.1007/s10562-017-2046-0

Abstract: Deep eutectic solvent (DES)/lipase catalyzed efficient synthesis of N-aryl amines from electron deficient aryl chlorides and amines at ambient temperature is reported. Its significant features include excellent yields of products, use of biodegradable, non-toxic and recyclable catalysts, thereby avoiding toxic metal catalyst/solvents making these protocols environmentally benign. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-017-2046-0

Catal Lett
DOI 10.1007/s10562-017-2046-0
Deep Eutectic Solvent/Lipase: Two Environmentally Benign
and Recyclable Media for Efficient Synthesis of N-Aryl Amines
Preeti Lalit Pant1 · Ganapati Subray Shankarling1
Received: 1 February 2017 / Accepted: 29 March 2017
© Springer Science+Business Media New York 2017
Abstract Deep eutectic solvent (DES)/lipase catalyzed
efficient synthesis of N-aryl amines from electron defi-
cient aryl chlorides and amines at ambient temperature is
reported. Its significant features include excellent yields
of products, use of biodegradable, non-toxic and recycla-
ble catalysts, thereby avoiding toxic metal catalyst/solvents
making these protocols environmentally benign.
Graphical Abstract
Key Features:
Metal free
Deep Eutectic Solvent (ChCl: Urea)
RT
R2
R1
Ligand free
R2
R1
H
X
Biodegradable & Recyclable
l
C
+
N
3
R3
1
X
N
R4
R3
R
O
Catalyst
R4
R
O
O
N
Lipase from Procine Pancreas (PPL)
Avoids use of organic aprotic
solvents
Cl
O
=
R1R2
N
O2
R3
R4
=
,
X
R
N
C
N
,
2
=
R
Substituted aromatic or cyclic amines
N
3
4
Less Reaction Time
High Yield
Keywords N-Arylation · Deep eutectic solvent (DES) ·
Lipase enzyme · Choline chloride (ChCl) · Aromatic
nucleophilic substitution (SNAr)
1 Introduction
N-Arylation is a significant transformation in organic chem-
istry and the resulting arylated products have been used
extensively in pharmaceutical and agrochemical indus-
tries [1]. The different approaches for N-arylation reaction
include aromatic nucleophilic substitution (SNAr) [2] of
amines with aryl halides or via metal catalyzed reactions
[3, 4]. The spectacular contributions of Buchwald and Ull-
mann [5, 6] to N-arylation reactions using metal as catalyst
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-017-2046-0) contains supplementary
material, which is available to authorized users.
* Ganapati Subray Shankarling
gsshankarling@gmail.com
1
Dyestuff Technology Department, Institute of Chemical
Technology, Matunga, Mumbai 400 019, India
Vol.:(0123456789)
1 3

P. L. Pant, G. S. Shankarling
has generated huge interest in this area of research. Despite
these significant achievements these coupling reactions suf-
fer from serious drawbacks: (1) use of expensive and toxic
metal catalysts and ligands, (2) tedious work up procedure,
(4) utilization of aprotic solvents and (5) non recyclability
of catalysts. One of the most promising solutions to this
problem is by using a simplified metal free approach. Lit-
erature reports reveal undue utilization of metal catalysts
in reactions involving activated halides which could be
avoided [7–13].
strategy for synthesis of N-aryl amines using lipase or DES
as catalyst (Scheme 1).
2 Experimental Methods
2.1 General Information
Lipase from Porcine pancreas (PPL), Candida antarctica
(CALB) and Mucor javanicus (MJL) was purchased from
Aldrich. FT-IR spectrums were recorded on Jasco FT-IR
ATR-PRO/4100 spectrophotometer. 1H NMR spectrums
were recorded on Jeol 400-MHz NMR spectrophotom-
eter and mass spectral data were obtained with Shimadzu-
LCMS with ESI probes. Common reagent grade chemicals
were procured from M/s S.D. Fine Chemical Ltd. India and
were used without further purification.
Lately, considerable improvements in metal free syn-
thesis have been reported by microwave heating [14–17],
ionic liquids [18, 19], aprotic solvents [20–23] at high tem-
perature [24] and pressure [25]. Although interesting, these
above methodologies remained linked to cyclic amines, and
were not applicable for aromatic amines. Milder conditions
(toluene, KOtBu, 135°C) were successfully applied by Bel-
ler et al. nevertheless they required longer reaction times
(36 h) to achieve high yields [26]. In continuation of our
endeavors, we have tried to overcome these limitations and
wish to report metal and ligand-free C–N cross coupling
reaction catalyzed by efficient and recyclable biocatalyst
lipase as well as DES.
2.2 Preparation of DES
The DES was prepared by combining ChCl with urea
according to the procedure reported in the literature [40].
Lipases are enzymes of considerable industrial impor-
tance and catalyze many important reactions [27–30].
Besides enzymatic catalysis greener methods such as
DES has fascinated significant attention due to their
unique properties. DES includes simple eutectics made
from combination of quaternary ammonium salts like
choline chloride with either hydrogen bond donors like
urea, glycerol or lewis acids with 100% atom econ-
omy. Relative to conventional ILs, DES has significant
advantages such as being non-toxic, insensitive towards
moisture, recyclable, cost-effective and bio-degradable
[31–38].
2.3 General Procedure for DES Catalyzed N-Arylation
of Amines with Aryl Halides
To a solution of amine (1.2 mmol) dissolved in 20% DES,
aryl halide (1 mmol) was added at room temperature and
stirred for appropriate time. The progress of the reaction
was monitored by TLC. After completion of the reaction
cold water was added to the reaction mixture. The precipi-
tated solid was filtered off, and recrystallized using ethanol.
2.4 General Procedure for Lipase Catalyzed
N-Arylation of Amines with Aryl Halides
In our previous work [39], we have reported N-alkyla-
tion of aromatic primary amines catalyzed by bio-catalyst
as well as DES. This work is an extension of previous
work, wherein we report an efficient, metal and ligand free
To a solution of amine (1.2 mmol) and ethanol (1 ml) con-
taining lipase catalyst (15% by weight of amine), aryl hal-
ide (1 mmol) was added. The reaction mixture was stirred
Scheme 1 Comparative representation of previous and present work
1 3

Deep Eutectic Solvent/Lipase: Two Environmentally Benign and Recyclable Media for Efficient…
for appropriate time at room temperature. The progress of
the reaction was monitored by TLC. After completion of
the reaction, the catalyst was filtered through filter paper
and washed with ethanol. The filtrate was evaporated on a
rotary evaporator and recrystallized using ethanol to afford
pure product.
4H), 1.74 (d, J=7.2 Hz, 6H); m/z (EI) 252 (M++1);
C11H13N3O4 calculated m/z: 251.24
2.5.6 4-Dinitro-N-phenylaniline (3 f)
Orange-red solid, mp 156 °C (lit mp 156–157 °C); IR
1
(neat, cm−1): 3319, 1518, 1495,1336; H NMR (CDCl3,
2.5 Selected Spectral Data
400 MHz): 9.98 (s, 1H, NH), 9.17 (d, J = 2.0 Hz, 1-H),
8.16 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.30–7.53 (m, 5H), 7.15
(d, J = 9.6 Hz, 1H); m/z (EI) 260 (M++1); C12H9N3O4 cal-
culated m/z: 259.22.
2.5.1 4- (4-Nitrophenyl) Morpholine (3a)
Yellow solid, mp 148°C (lit mp 148–150°C); IR (neat,
cm−1): 1602, 1511, 1490, 1331, 1243, 1119, 1109, 1052,
927, 825, 1H NMR (CDCl3, 400 MHz): 3.37 (t, J=4.8 Hz,
4H), 3.83 (t, J=4.8 Hz, 4H), 8.12–8.16 (m, 2H), 6.81–6.85
(m, 2H); m/z (EI) 209 (M++1); C10H12N2O3 calculated m/z:
208.21.
2.5.7 4-Fluoro-N-(2,4-dinitro phenyl) benzamine (3 g)
Yellow solid, mp 186 °C (lit mp 186–188 °C); IR (neat,
cm−1): 3315, 1515, 1490, 1330; 1H NMR (CDCl3,
400 MHz): 9.88 (s, 1H, NH), 9.18 (d, J= 3.2 Hz, 1H), 8.2
(dd, J = 7.2 Hz, 3.2 Hz, 1H), 7.18–7.32 (m, 4-H), 7.02 (d,
J = 7.4 Hz, 2H); m/z (EI) 278 (M++1); C12H8FN3O4 cal-
culated m/z: 277.21.
2.5.2 1-(4-Nitrophenyl)-piperidine (3b)
Yellow solid, mp 159°C (lit mp 158–160°C); IR (neat,
cm−1): 2942, 1508, 1450, 1311, 1248, 1200, 1109, 1H
NMR (CDCl3, 400 MHz): 8.06 (d, J=9.3 Hz, 2H), 6.77(d,
J=9.3 Hz, 2H),3. 43 (s, 4H), 1.68 (s, 6 H);m/z (EI) 207
(M++1); C11H14N2O2 calculated m/z: 206.11.
2.5.8 N-(3-Methoxy phenyl)-2,4-dinitrobenzenamine (3h)
Orange-red solid, mp 138 °C (lit mp 137–138 °C); IR
(neat, cm−1): 3312,1521,1499,1337,1303; 1H NMR
(CDCl3, 400 MHz): 9.87 (s, 1H, NH), 9.17 (d, J = 2.6 Hz,
1H), 8.15 (dd, J = 2.4 Hz, 9.6 Hz, 1H), 7.34 (t, J = 7.6 Hz,
7.6 Hz, 2H), 7.04–7.12 (m, 4H), 3.86 (s, 1H); m/z (EI)
290 (M++1); C13H11N3O5 calculated m/z: 289.24.
2.5.3 1-(4-Nitrophenyl)-4-phenylpiperazine (3c)
Yellow solid, mp 175°C (lit mp 174–176°C); IR (neat,
cm−1):1328 ,1590, 2831, 830, 1H NMR (CDCl3, 400 MHz):
8.16 (m, 2H), 7.31 (m, 2H), 6.94 (m, 5H), 3.59 (m,4H),
3.36 (m, 4H); m/z (EI) 284 (M++1); C16H17N3O2 calculated
m/z: 283.33.
2.5.4 4-(2, 4-Dinitrophenyl) Morpholine (3d)
3 Results and Discussions
Bright yellow needles, mp 117–118°C (lit mp 116–117°C);
Our initial studies focused on the reaction between
1-chloro-4-nitrobenzene (1a) and morpholine (2a) with
the aim of identifying reaction conditions. Initially, 10%
ChCl: urea DES proved to an efficient catalyst which
resulted in product with 80% yield respectively (Table 1,
entry 4). To confirm the role of ChCl: urea DES, the
reaction was conducted in the sole presence of ChCl or
urea for prolonged time which resulted in poor results
(entries 1–3).These results clearly showed the fundamen-
tal function of ChCl and urea in catalyzing the reaction.
The reason being ChCl and urea increase the reactivity of
the aryl halide by hydrogen bonding and act as a benign
media to drive the process.
1
IR (neat, cm−1): 3113, 1607, 1587, 1533, 1507, 1340; H
NMR (CDCl3, 400 MHz): 8.70 (d, J=2.8 Hz,1H),8.27
(dd, J=9.2 Hz, 2.8 Hz,1H), 7.10 (d, J=9.2 Hz, 1H), 3.87
(t, J=4.6 Hz), 3.27 (t, J=4.6 Hz); m/z(EI) 254 (M++1);
C10H11N3O5 calculated m/z: 253.07.
2.5.5 1-(2, 4-Dinitrophenyl) piperidine (3e)
Yellow solid, mp 92°C (lit mp 91–92°C); IR(neat, cm−1);
3100,1600,1585,1535,1360,1500; 1H NMR (CDCl3,
400 MHz):δ 8.68 (d, J=2.0 Hz, 1H), 8.20 (dd, J=9.4,
2.4 Hz, 1H), 7.09 (d, J=9.2 Hz, 1H), 3.26 (d, J=5.6 Hz,
1 3

P. L. Pant, G. S. Shankarling
Table 1 Optimization of reaction parameters
Entry no
Catalyst
Catalyst loading
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
ChCl
ChCl
Urea
Water
Ethanol
Ethanol
–
–
–
–
Ethanol
Methanol
DCM
60
60
60
20
20
20
20
60
60
60
60
60
60
80
80
55
50
20
80
82
88
88
65
55
50
60
58
62
NR
6
DES (ChCl: urea)
DES (ChCl: urea)
DES (ChCl: urea)
DES (ChCl: urea)
DES (ChCl: urea)
DES (ChCl: urea)
DES (ChCl: urea)
DES (ChCl: urea)
DES (ChCl: urea)
DES (ChCl: urea)
Blank (no enzyme)
10%
15%
20%
30%
20%
20%
20%
20%
20%
20%
–
9
10
11
12
13
14
15
THF
1,4-Dioxane
Acetonitrile
Ethanol
Ethanol
αAmylase from Asper-
15%
gillus oryzae
16
17
18
19
20a
Protease from Bacillus
15%
15%
15%
15%
15%
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
80
30
80
80
80
50
subtilus
Lipase from porcine
82
pancreas (PPL)
Lipase from Candida
antarctica (CALB)
60
Lipase from Mucor
50
javanicus (MJL)
Lipase from porcine
pancreas
Trace
21
22
23
24
25
26
27
28
29
30
Bovine serum albumin
Lipase
Lipase
Lipase
Lipase
Lipase
Lipase
Lipase
Lipase
15%
5%
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Methanol
DCM
THF
1,4-Dioxane
Acetonitrile
80
30
30
30
30
30
30
30
30
30
Trace
70
75
82
82
75
60
78
65
10%
15%
20%
15%
15%
15%
15%
15%
Lipase
62
The conditions highlighted in bold signify optimum reaction conditions for the reaction
Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), room temperature 32 2°C
aLipase from Porcine pancreas predenatured with urea at 100°C for 24 h
bIsolated yields
1 3

Deep Eutectic Solvent/Lipase: Two Environmentally Benign and Recyclable Media for Efficient…
Encouraged by the above results, the catalyst loading
studies (entries 4–7) reveal 20% ChCl: urea DES was most
effective resulting in the desired product with 88% yield
within 20 min (entry 6). Further increasing the amount of
catalyst showed no improvement in the yield (entry 7).Hav-
ing identified ChCl: urea as a suitable catalyst, a brief sol-
vent screen was conducted (entries 8–13). No substantial
improvement in the product yield was observed with the
other tested solvents. Therefore, solvent-free conditions
using 20% ChCl: urea DES proved to be an efficient cat-
alytic system. On the other hand, optimization study was
further extended by using different biocatalysts (entries
14–19). A control experiment was conducted without any
biocatalyst which displayed no catalytic activity (entry
14). Initially 15% (w/w) of lipase enzyme from porcine
pancreas (PPL) in ethanolic medium resulted in effective
results (entry 17). We carried the optimization study using
different lipase strains from Candida antarctica (CALB)
and Mucor javanicus (MJL) which exhibited the ability
to catalyze the reaction, but they were found to be ineffec-
tive (entries 18–19).When the reaction was incubated with
denatured PPL or bovine serum albumin respectively, the
reaction rate was almost comparable to that of the control
reaction (entries 20–21). These results suggest lipase from
porcine pancreas (PPL) as an efficient catalyst responsible
for this reaction. Catalytic loading studies reveal 15% (w/w)
of lipase enzyme as an effective catalyst (entries 22–25).
Solvent study suggests lipase in ethanolic medium as a best
solvent compared to other solvents (entries 26–30). Having
developed an effective protocol for C–N bond formation
with ChCl: urea or lipase as catalyst, we thought to evalu-
ate the scope and generality of this reaction by coupling
various amines and activated aryl halides.
In further experiments, we investigated the importance
of the electron-withdrawing functionalities in aryl halides.
Chlorobenzene lacking nitro functionality failed to react
with cyclic amines using our protocol, indicating that an
electron withdrawing nitro functionality was essential for
the reaction to proceed according to our protocol. The reac-
tion was extended to heterocyclic aryl chlorides such as 1c
and 1d which proceeded with excellent yields in short time.
To elaborate the scope of the catalyst, aromatic amines
with different electron donating and electro withdrawing
substituents were investigated. In case of electron donating
aromatic amine with electron donating substituents such as
4-methyl aniline (entry 11) the reaction was faster as com-
pared to electron withdrawing counterparts such as 4-fluoro
aniline (entry 12). N-Arylation of amines developed here
using the cheaper chloroarenes is more attractive than the
one using the expensive bromo- and iodoarenes in terms
of economic feasibility. The scope of our methodology
was further extended by reacting aryl halides with diverse
electron withdrawing functionalities like nitrile resulting in
moderate yields (50–55%) of desired N-arylated products
at room temperature. The yield of these substrates were
found to be enhanced (78%) as the reaction temperature
is increased to 80°C (entry 15). Intrigued by the above-
described results, we further investigated both these pro-
tocols for the synthesis of N-substituted 5-nitro anthranilic
acid derivatives (entry 16) which is a simple alternative to
palladium catalyzed Buchwald–Hartwig or copper cata-
lyzed Ullman–Goldberg reactions. Generally these reac-
tions suffer from drawbacks [41], the present methodology
eliminates these drawbacks, the carboxylic acid groups are
not required to be protected, and this procedure does not
require inert conditions. It can easily be scaled to mul-
tigram quantities for formation of some valuable inter-
mediates in synthesis of some pharmacologically active
compounds.
With a defined catalytic system, we applied our proto-
col towards amination of various activated aryl halides with
a range of aromatic and cyclic amines yielding the corre-
sponding N-aryl amines as summarized in Table 2. Cou-
pling of 1a with various cyclic amines (Table 2, entries
1–3) under optimized conditions resulted in good yields
(80–88%) at room temperature conditions in shorter time
(15–30 min) as compared to previously reported methods
which require use of metal catalyst [9–14] at high tempera-
ture (80–110°C) with (2–40 h) for completion. To expand
the scope of this protocol further, electron deficient aryl
chlorides were coupled with cyclic and aromatic amines to
give the corresponding N-arylated products in good yields.
It was observed that increase in presence of electron-with-
drawing nitro functionality in the aryl chloride moiety sig-
nificantly increased the yield as well as the rate of reaction,
on the other hand, no restrictions were observed for the
amine reaction partner.
3.1 Plausible Mechanistic Pathway
Based on the present experimental observations and litera-
ture reports [42–44], the proposed mechanism is depicted
in Schemes 2 and 3. The enhanced reactivity of aryl hal-
ides bearing an electron-withdrawing group and no reac-
tivity for electron-donating counterparts suggests that the
reactions occur via SNAr addition–elimination mechanism.
According to this mechanism in DES catalyzed reactions,
the hydrogen bonding interactions are responsible for facil-
itating the attack of aryl amine resulting in the product for-
mation. Lipase catalysts increase the nucleophilicity of aro-
matic amine by abstracting proton through Asp–His dyad,
thereby favoring product formation.
1 3

P. L. Pant, G. S. Shankarling
Table 2 N-Arylation of amines
with aryl halides at room
temperature
DESa Lipaseb
Yield (%)d Yield (%)d
t (min) t (min)
Entry Aryl halide
no.
Amine
Product
1
88 (20)
82 (30)
(2a)
(1a)
82 (30)
2
85 (15)
(2b)
(1a)
80 (15)
80 (25)
3
(3c)
(1a)
4
98 (8)
96 (10)
(1b)
(3d)
(3e)
(3f)
(3g)
(3h)
5
96 (5)
95 (5)
(1b)
6
95 (10)
85 (15)
92 (10)
80 (20)
(1b)
7
(1b)
8
82 (25)
90 (15)
80 (25)
88 (18)
(1b)
9
(3i)
(1b)
10
95 (30)
92 (15)
82 (30)
90 (10)
90 (40)
86 (20)
78 (45)
88 (10)
(1c)
(3j)
(3k)
(3l)
11
(1c)
12
(1c)
13
(1c)
(3m)
14
90 (25)
85(200)
85 (180)
82 (30)
(1d)
(3n)
(3o)
(3p)
15c
78(320)
76 (360)
(1e)
16c
(1f)
aReaction conditions: Aryl halide (1 mmol), amine (1.2 mmol), DES catalyst (20%
v/v), temp. 30 2°C. bAryl halide (1 mmol), amine (1.2 mmol), lipase catalyst (15%
by weight of amine), 2 ml ethanol, temp 30 2°C.cReaction performed at 80°C for
DES and 50°C for lipase catalyzed reaction dIsolated yields
1 3

Deep Eutectic Solvent/Lipase: Two Environmentally Benign and Recyclable Media for Efficient…
H
H
N
H
Ch
Cl
N
H
O
H
O
H
N +
OH
Cl
H
H
H
N
N
Cl
N
Cl
NH
NH
O
Cl
H
H
NO2
NO2
NO2
Hydrogen bonding
-H
interaction responsible
for formation of DES
NO2
N
NO2
O
N +
OH
Increase in reactivity of aryl halide
due to hydrogen bonding with DES
Where Ch-
Cl
NH
-Cl
HN
NO2
Cl
O
NH
O
Cl
O
NH
O
NO2
NO2
NO2
NO2
N
N
NO2
Scheme 2 Proposed mechanism for synthesis of N-aryl amines using DES as catalyst
Scheme 3 Proposed mechanism for synthesis of N-aryl amines using Lipase as biocatalyst
3.2 Recyclability Study
Table 3 Recyclability studies
No of cycles
To test the industrial applicability of our protocol, recycling
of DES and lipase catalysts studied up to four runs consid-
ering N-arylation of 1a (10 mmol) with 2a (10 mmol) in
DES under the above conditions. In view of the need for
Catalyst
Fresh
First
Second
Third
Fourth
DES (% yield)
Lipase(% yield)
88
82
87
82
86
80
86
77
84
75
1 3

P. L. Pant, G. S. Shankarling
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lyst is recovered by removing water under vacuum from
the filtrate. The work-up, thus, did not involve any volatile
organic solvent and is completely eco-friendly in nature. It
could be observed that DES could be recycled up to four
successive cycles, with slight decrease in the catalytic
activity after the fourth cycle (Table 3) without significant
loss in activity.
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The recycled lipase enzyme was used up to four runs with
decrease in yield from the third cycle (Table 3). This reduc-
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In summary, we have demonstrated a simple, metal and
ligand free strategy for facile synthesis of N-aryl amines
using deep eutectic solvent or lipase as a catalyst. The pro-
posed reaction proceeds under mild conditions resulting in
products with quantitative yields ranging from 76 to 98%.
Moreover, this method offers several advantages including
use of biodegradable and recyclable deep eutectic solvent
or lipase as biocatalyst, offers experimental simplicity, and
does not require an inert atmosphere and anhydrous sol-
vents, which is lacking in existing procedures. Exploitation
of this reaction media for other organic synthesis is cur-
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