Mechanosynthesis of N-methyl imines using recyclable imidazole-based acid-scavenger: In situ formed ionic liquid as catalyst and dehydrating agent

Article abstract of DOI:10.1071/CH18408

1,1′-(1,4-Butanediyl)bis(imidazole) was prepared by a modified method and its application as an efficient promoter was demonstrated for the mechanosynthesis of N-methyl imines using ball milling as a non-conventional process under solvent-free conditions. In this new protocol design, the bis-imidazole acted as a recyclable acid-scavenging agent. This efficient approach to the N-methyl imines displays a combination of the synthetic virtues of a non-conventional condensation reaction with ecological benefits and convenience of a facile mechanosynthetic process. The current method has advantages such as reduced waste by avoiding solvent, exclusion of hazardous materials during the reaction, elimination of handling an anhydrous gas in an evacuated container or a solution of methylamine in ethanol, good yields for relatively unreactive benzaldehydes containing electron-donating substituents, short reaction times, and metal- and acid-free conditions. Furthermore, the promoter was easily regenerated and reused several times with no significant loss of activity.

Full text of DOI:10.1071/CH18408

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
https://doi.org/10.1071/CH18408
Mechanosynthesis of N-Methyl Imines Using Recyclable
Imidazole-Based Acid-Scavenger: In Situ Formed Ionic
Liquid as Catalyst and Dehydrating Agent
A
,
C
A
B
Nader Ghaffari Khaligh,
Ong Chiu Ling, Taraneh Mihankhah,
A
A
Mohd Rafie Johan, and Juan Joon Ching
A
Nanotechnology and Catalysis Research Center, 3rd Floor, Block A, Institute of
Postgraduate Studies, University of Malaya, 50603 Kuala Lumpur, Malaysia.
B
Environmental Research Laboratory, Department of Water and Environmental
Engineering, School of Civil Engineering, Iran University of Science and Technology,
6765-163, Tehran, Iran.
1
C
Corresponding author. Email: ngkhaligh@gmail.com
0
1
,1 -(1,4-Butanediyl)bis(imidazole) was prepared by a modified method and its application as an efficient promoter was
demonstrated for the mechanosynthesis of N-methyl imines using ball milling as a non-conventional process under
solvent-free conditions. In this new protocol design, the bis-imidazole acted as a recyclable acid-scavenging agent. This
efficient approach to the N-methyl imines displays a combination of the synthetic virtues of a non-conventional
condensation reaction with ecological benefits and convenience of a facile mechanosynthetic process. The current
method has advantages such as reduced waste by avoiding solvent, exclusion of hazardous materials during the reaction,
elimination of handling an anhydrous gas in an evacuated container or a solution of methylamine in ethanol, good yields
for relatively unreactive benzaldehydes containing electron-donating substituents, short reaction times, and metal- and
acid-free conditions. Furthermore, the promoter was easily regenerated and reused several times with no significant loss of
activity.
Manuscript received: 16 August 2018.
Manuscript accepted: 31 October 2018.
Published online: 23 November 2018.
Introduction
[14]
antiproliferative,
analgesic, anti-inflammatory and antipy-
[16]
[15]
Mechanochemistry has been developed as an applicable tech-
nique that enables a cleaner and green approach to chemical
retic, and anticancer and antifungal.
often exhibit noteworthy properties such as aggregation,
corrosion inhibition,
[
cence, and can act as dyes and pigments. They have been
studied for the treatment of diseases, such as leishmaniasis,
trypanosomiasis, and malaria.
tant role as intermediates in a variety of organic syntheses such
as the asymmetric synthesis of a-amino nitriles,
of secondary amines,
Schiff-bases have been widely applied as the ligand in metal
Certain Schiff bases
17]
[
[
1]
[18]
[19]
transformations. The ball milling process was initially used
to grind materials into extremely fine powders, since then it has
progressed to playing a role in solvent-free organic synthesis to
minimize the use of toxic and volatile organic solvents and
reduce environmental pollution. In spite of numerous papers
that have been published using the ball milling process in a
variety of organic syntheses, in comparison with other methods
of energy entry such as microwave and ultrasound, little effort
has been made in view of organic syntheses using a ball milling
technique which utilises mechanical energy (friction, impact,
fluorescence,
photolumines-
20]
[21]
[
22–25]
Schiff-bases play an impor-
[
26]
preparation
[28,29]
[
27]
and cycloaddition reactions.
[
30,31]
complexes,
logical activity including anti-urease activity.
and some of these complexes displayed bio-
[
32]
These inter-
esting features encouraged much effort towards the synthesis of
[
2]
collision). Planetary ball mills have been broadly utilised in
[4]
[3]
laboratories for the synthesis of catalysts, heterocycles,
N-methyl imines and imine derivatives as valuable lead com-
[33–44]
[
metal complexes, catenanes and rotaxanes, the formation
5]
[6]
pounds.
However, some of these methods have drawbacks
[
7]
of metal–organic frameworks (MOFs), C–C bond formation
reactions, protection of functional groups, fullerenes, and
redox processes.
Imines and their derivatives (Schiff bases) as nitrogen-
containing compounds represent key building blocks in organic
chemistry. They constitute the core of valuable compounds
exhibiting a broad and interesting spectrum of biological activi-
such as toxic noxious gas handling, long reaction times, moder-
ate yields, use of toxic and volatile organic solvents, use of
mineral or Lewis acids, and expensive reagents. Therefore, the
development of a simple and clean method for the synthesis
of imine derivatives is highly attractive. The basic idea in
this paper is to use an imidazole-based promoter as an acid-
scavenger reagent to form an in situ imidazolium ionic liquid in
the course of the reaction; the formed ionic liquid can act as a
dual solvent–catalyst and dehydrating agent.
[
2]
[
8]
[9]
[10]
ties including antioxidant, herbicidal, antibacterial, anti-
[
fungal and antifertility,
11]
[12]
[13]
antitumour,
antitubercular,
Journal compilation � CSIRO 2018
www.publish.csiro.au/journals/ajc

B
N. G. Khaligh et al.
Results and Discussion
afforded 2d in 98 % yield within 10 min (Table 1, entry 6);
however, a shorter milling time of ,5 min led to a reduction in
the yield (Table 1, entry 7). Decreasing the amount of promoter
caused a gradual decline in the yield (Table 1, entry 8) while no
difference in the yield of 2d was observed with increasing
promoter loading within 5 and 10 min (Table 1, entries 9 and 10).
The influence of technical parameters such as revolutions per
minute (rpm), and size and number of balls in the mill on
performing the model reaction were investigated. As shown in
Table 2, the results displayed that rpm have an important
influence on the yield of the desired product, at which point
the best yield of 2d was observed at 600 rpm of the planetary ball
mill within 10 min (Table 2, entries 1–3). As reported in the
Methylamine is commercially available in three forms: a com-
pressed gas, a methylamine hydrochloride salt, and a 40 %
aqueous solution. The 40 % methylamine solution is not explo-
sive, but it is flammable and should be handled with the usual
care taken for toxic flammable liquids, especially regarding
exposure to open flame or to an ignition source. Initially, to
optimize the reaction conditions, the ball milling of a solid
mixture of 4-nitrobenzaldehyde (1d) and methylamine hydro-
chloride was chosen as a model reaction (Scheme 1). The equi-
molar mixture of the model reactants were ground together at
room temperature under solvent- and catalyst-free conditions
using a planetary ball mill inwhich the reaction completely failed
after 2 h (gas chromatography–mass spectrometry (GC-MS)
analysis) (Table 1, entry 1). No notable difference was observed
in the yield of N-(4-nitro-benzylidene)methylamine (2d) when
the model reaction was conducted with higher molar ratio of
CH NH ꢀHCl to 1d under the same conditions (Table 1, entry 2).
[45]
literature,
the parameters such as size and the number of
milling balls directly influence the active surface area and total
mass of the milling balls. While the other parameters were kept
constant, the size and the number of milling balls were changed.
When experiments were carried out with a larger size and higher
number of mill balls, 2d was afforded in higher yield (Table 2,
entries 4 and 5).
3
2
Interestingly, 2d was obtained in 99 % yield in the presence
0
of 1,1 -(l,4-butanediyl)bis(imidazolium) (1,4-(Im) Bu) as a pro-
2
To investigate the scope as well as the effectiveness of the
non-conventional protocol for the synthesis of the N-methyl
imines, a variety of aryl and heteroaryl aldehydes were screened
under the optimized reaction conditions (Scheme 2).
The results indicated that the electronic properties and the
steric demand of the substituent on the aryl aldehyde play a
decisive role on the yield of the desired product (Table 3). The
aryl aldehydes bearing electron-withdrawing substituents gave
higher yields than those with electron-donating substituents as it
was expected (Table 3, entries 2, 4, 8, 10, 13, and 15). It is
moter after 30 min (Table 1, entry 4). The reaction of an
equimolar mixture of CH NH ꢀHCl and 4-nitrobenzaldehyde
3
2
Different
conditions
CHO
ϩ CH NH ·HCl
CH3
N
3
2
Ball milling,
neat, r.t.
O N
O N
2
2
1d
2d
Scheme 1. Optimization of the reaction conditions.
Table 1. Effects of 1,4-(Im)
2
Bu loading, reactants molar ratio, and the milling time on the reaction of 4-nitrobenzaldehyde (1d)
and methylamine hydrochloride
Reaction conditions: number of ball mill: 4, rotation speed: 600 rpm, ball mill diameter: 7 mm, room temperature, solvent free. Entry in
bold shows optimized reaction conditions
A
Yield [%]
Entry
Amount of promoter [g]
Aldehyde:CH
3
NH
2
ꢀHCl [mmol/mmol]
5/5
Time [min]
1
2
3
4
5
6
7
8
9
—
—
120
120
120
30
30
10
5
0
0
5/10
5/10
5/10
5/5
0.5
0.5
0.5
0.5
0.5
0.4
0.6
0.6
99
99
98
98
76
78
76
98
5/5
5/5
5/5
10
5
5/5
10
5/5
10
A
Determined by GC-MS.
Table 2. Effects of revolution per minute (rpm) and size and number of mill balls on the reaction of 4-nitrobenzaldehyde (1d)
and methylamine hydrochloride
Reaction conditions: amount of promoter/CH
3
NH
2
ꢀHCl/4-nitrobenzaldehyde (2.6 mmol : 5.0 mmol : 5.0 mmol), milling time (10 min),
room temperature, solvent-free
A
Entry
Number of mill balls
Rotational speed [rpm]
Mill ball diameter [mm]
Yield [%]
1
2
3
4
5
4
4
4
4
2
600
500
300
600
600
7
7
7
5
7
98
88
52
68
66
A
Determined by GC-MS.

Non-Conventional Preparation of Schiff Bases
C
[42]
temperature after 2 h or overnight,
noteworthy that 2-methoxybenzaldehyde (Table 3, entry 11)
gave the desired N-methyl imines in higher yield compared with
whereas, it was reported
that 2g was obtained in quantitative yield by the solid-state
3
- and 4-methoxybenzaldehyde (Table 3, entries 5, 16) which
reaction of the crystalline 4-(dimethylamino)benzaldehyde with
In
[33]
gaseous methylamine at room temperature overnight.
can be assigned to the decrease of conjugation between the 2-
methoxy group and the phenyl ring caused by steric interference
in the 2-methoxybenzaldehyde. Furthermore, the heteroaro-
matic aldehydes (Table 3, entries 19–21) were efficiently con-
verted into the desired N-methyl imines in good to excellent
yields. Terephthalaldehyde was also transformed into an imine
using two equivalents of CH NH ꢀHCl under optimized reaction
addition, the grinding of salicylaldehyde with CH NH ꢀHCl
3
2
and NaHCO in a molar ratio of 1 : 5 : 5 afforded 2-[(E)-(methy-
3
limino)methyl]phenol (2h) in 55% yield after 1 h in the presence
[42]
of a non-recyclable alkali metal catalyst. In comparison to the
the present method gave 2g and
[33,42]
aforementioned methods,
2h in 80 and 88% yield under optimized conditions(Table 3,
entries 7 and 8). The present protocol exhibited other advantages
including avoiding solvent and metal or transition metal catalyst,
the regeneration and recyclability of the promoter, a broad-
substrate scope, short reaction time, and good to excellent yields.
Recycling of reagents plays a crucial role in large scale and
3
2
conditions (Table 3, entry 22).
Although the reported methods provide the desired N-methyl
imines, they suffer from some challenges including the hazardous
and specific handling of an anhydrous gas in an evacuated
container, unwanted toxicity from residual metal contamination,
and non-recyclability of reagent. For example, it was reported
thatN-(4-methoxybenzylidene)methylamine (2e) was affordedin
industrial processes; therefore, 1,4-(Im) Bu was regenerated by
2
neutralization via the incremental addition of NaHCO as the
3
6
and NaHCO in a molar ratio of 1 : 5 : 5 for 3 h. In the current
5 % yield by grinding 4-methoxybenzaldehyde, CH NH ꢀHCl,
cheapest chemical commercially available (Scheme 3). The
regenerated 1,4-(Im) Bu was then used in four consecutive runs
3
2
[42]
3
2
method, 2e was obtained in 80 % yield after 10 min under
optimized reaction conditions (Table 3, entry 5). The synthesis
of N-(p-dimethylaminobenzylidene)methylamine (2g) failed in
the presence of an alkali metal-containing catalyst at room
that afforded 2d in 98–96 % yield (Table 3, entry 4).
Furthermore, the model reaction was conducted on a 10 g
scale to afford 2d in 82 % yield after 20 min milling time under
optimized reaction conditions.
1
,4-(Im) Bu (0.5 g)
2
CH3
Ϫ
R
CHO ϩ CH NH ·HCl
3
2
R
N
N
N
N
Cl
N
Ball milling, neat, r.t., 10 min
ϩ NaHCO3
ϩN
N
1
2
N
H
N
5
mmol
5 mmol
(74–98 % yield)
NaCl ϩ H O ϩ CO
2
2
Scheme 2. The synthesis of N-methyl imines under optimized reaction
conditions.
2
Scheme 3. Regeneration of 1,4-(Im) Bu.
2
Table 3. The reaction of aryl aldehydes with methylamine hydrochloride in the presence of 1,4-(Im) Bu
Reaction conditions: aryl aldehyde (5.0 mmol), CH
3
NH
2
2
ꢀHCl (5.0 mmol), 1,4-(Im) Bu (0.5 g), milling time (10 min), room temperature, solvent free
A
Entry Aldehyde
N-methyl imine
Yield [%]
Mp [8C]
Found
Reported
[
43]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
C
6
H
5
ꢁ
-CHO
2a
2b
2c
2d
2e
2f
94
oil
oil
oil
oil
oil
[43]
43]
[43]
4-Cl C
4-CH -C
4-O N-C
4-CH O-C
4-HO-C
6
H
4
-CHO
-CHO
-CHO
96
[
3
6
H
4
94
oil
B
2
6
H
4
98 (98, 96, 96)
104–106
oil
104–106
[43]
oil
3
6
H
4
-CHO
80
91
80
88
83
97
87
86
90
85
94
81
84
91
92
82
74
[33]
175
6
2
H
4
-CHO
177–179
54–56
oil
[43]
54–56
4-(CH
ꢁ
3
)
N-C
-CHO
-CHO
-CHO
-CHO
-C -CHO
-CHO
6
H
4
-CHO
2g
2h
2i
[43]
2-Cl C
6
H
4
oil
oil
oil
oil
oil
oil
oil
oil
oil
oil
oil
oil
oil
[
[
[
[
43]
42]
43]
43]
2-CH
2-O N-C
2-CH O-C
3
-C
6
H
4
oil
0
1
2
3
4
5
6
7
8
9
0
1
2
2
6
H
4
2j
oil
3
6
H
4
2k
2l
oil
3,4-(CH
ꢁ
3
O)
2
6
H
3
oil
[42]
3-Cl C
6
H
4
2m
2n
2o
2p
2q
2r
2s
oil
[42]
[42]
[42]
[46]
[43]
[43]
[43]
3-CH
3-O N-C
3-CH O-C
3
6
-C H
4
-CHO
-CHO
-CHO
oil
2
6
H
4
oil
3
6
H
4
oil
Salicylaldehyde
Vanillin
oil
oil
Pyridine-4-carbaldehyde
Furan-2-carboxaldehyde
Pyrrole-2-carboxaldehyde
Terephthalaldehyde
oil
2t
oil
2u
2v
oil
–
–
C
90
88–90
A
B
Isolated yields.
Product yield after three consecutive recycling in the presence of the recovered solid base catalyst.
C
3 2 2
Reaction conditions: terephthalaldehyde (5.0 mmol), CH NH .HCl (10.0 mmol), 1,4-(Im) Bu (1.0 g), milling time (10 min), room temperature, solvent-free.

D
N. G. Khaligh et al.
Ϫ
Cl
N
N
CH NH ·HCl ϩ N
N
N
N
N
CH NH
ϩ
3 2
3
2
ϩN H
N
Ϫ
Cl
N
H
N
ϩ
H
Ϫ
N
N
Cl
ϩN
H
N
O
N
H
H
Ϫ
Cl
H
N
N
Ar
N
CH3
O
Ar
N
ϩ
ϩN
H
CH3
N
H
H
N
H
Ar
H2O
H C
3
(I)
2
Scheme 4. A plausible mechanism to promote the synthesis of N-methyl imines in the presence of 1,4-(Im) Bu.
A
Table 4. Atom economy (AE ), reaction mass efficiency (RME ), mass
B
Based on the in situ formation of an imidazolium-based ionic
C
D
liquid and the potential dual solvent–catalyst and dehydrating
properties of ionic liquids, a possible mechanism is given for
the mechanosynthesis of N-methyl imines (Scheme 4). Based
on the BASIL process in which the BASF company used N-
methylimidazole as a base to neutralize a formed hydrogen
productivity (MP ), and environmental impact factor (E-factor ) cal-
culations for the current base-catalyzed mechanosynthesis of 2d
ꢁ1
Compound
MW [g mol
]
Moles [mmol] Weight [g]
4
-NO
CH NH
,4-(Im)
4-NO -C H -CH=NCH
2
-C
ꢀHCl
Bu
6
H
4
-CHO
151.12
67.52
190.24
164.16
227.71
58.44
44.01
18
5
0.76
0.34
0.5
[
47]
chloride,
scavenger and facilitate the gradual liberation of methylamine,
in the first step, 1,4-(Im) Bu can act as acid-
2
3
2
5
1
2
2.6
4.9
2.6
2.6
2.6
2.6
0
meanwhile, 1,1 -(l,4-butanediyl)bis(imidazolium) chloride
0.8
2
6
4
3
(
as a Br o¨ nsted acid catalyst for the synthesis of N-methyl
1,4-(Im) BuꢀHCl) generated in situ can be capable of acting
1,4-(Im) BuꢀHCl
0.59
0.15
0.11
0.05
2
2
NaCl
CO
2
imines. It is postulated that 1,4-(Im) BuꢀHCl can activate the
2
Water
carbonyl group by an acidic hydrogen along with the C2–H
hydrogen bond of the imidazole ring, and made it more
susceptible to attack by the liberated methylamine. The
methylamine could also be activated through a hydrogen bond
between the nitrogen atom of the imidazole ring and –NH2.
Dehydration of the intermediate (I) could be promoted in the
A
1
64:16
Atom economy ð%Þ ¼
ꢂ 100 ¼ 75:1%
ð151:12þ67:52Þ
B
0:8
Reaction Mass efficiency ð%Þ ¼
ꢂ 100 ¼ 72:7%
ð0:76þ0:34Þ
C
0:8
Mass productivity ð%Þ ¼
ꢂ 100 ¼ 50:0%
ð0:76þ0:34þ0:50Þ
E-factor ðexcluding CO2 and H2OÞ ¼ 0 ¼ 0:19;
D
0:15
:80
presence of 1,4-(Im) BuꢀHCl as an efficient dehydrating
0:31
2
E-factor ðinluding CO and waterÞ ¼
¼ 0:39
2
0:80
[
48–50]
agent
and finally N-methyl imine is produced. Further
investigations aimed at fully elucidating the precise mecha-
nism of this reaction along with the separation and characteri-
zation of the intermediates in the course of reaction, are
currently underway in our laboratory.
[
53,54]
greener processes.
The present methodology exhibited
high atom economy (AE) and RME as well as a good MP.
The energy efficiency is also an important category in green
chemistry. The present methodology operates at room tempera-
ture and atmospheric pressure under the ball milling process and
requires and consumes much less energy compared to high
pressure and conventional thermal processing.
The chemical toxicity resources such as PubChem and the
EPA’s ACToR exhibited no data for the potential toxicity of
,4-(Im) Bu. Furthermore, methylamine hydrochloride as a
The research on green chemistry development is growing and
continually being improved. In order to assess the ‘greenness’ of
a process, scientists must consider and choose the right green
chemistry metrics and measure them at key synthesis steps. The
right metrics can serve as indicators of reduced manufacturing
costs, reflecting lower process materials inputs and outputs,
reduced costs from hazardous and toxic waste disposal,
improved manufacturing capacity utilisation, and reduced
[
55]
[56]
1
2
[
51,52]
stable solid is safer than as gas or an aqueous solution (40 %)
of the methylamine, which are an explosive and extremely
flammable gas and a highly flammable liquid, respectively.
energy demand.
The common metrics were grouped into
three categories: materials efficiency, energy efficiency, and
[
53]
toxicity.
In order to assess the greenness of the present
methodology, the common materials efficiency metrics were
measured and calculated for the synthesis of 2d (Table 4).
The E-factor was calculated including and excluding CO2
Conclusion
In summary, a simple and efficient method for the preparation of
0
and water as waste in the regeneration of the 1,4-(Im) Bu
2
N-methyl imines in the presence of 1,1 -(l,4-butanediyl)bis
(
Table 4). An E-factor closer to zero means the process will
(imidazole) (1,4-(Im)
developed. 1,4-(Im) Bu acts as a multi-task promoter, i.e. as an
acid scavenger, in situ Br o¨ nsted acid, and dehydrating agent in
the synthesis of N-methyl imines. The present protocol has
advantages such as use of commercially available and safe to
Bu) as a recyclable promoter has been
2
generate less waste and thus it is more sustainable and greener.
However, the E-factor as a metric of the environmental impact
of the synthesis process did not consider the hazards and the
environmental risk of the produced waste. In general, the
reaction mass efficiency (RME) and mass productivity (MP)
were the most valuable metrics for driving the adoption of
2
handle CH NH
prevention of handling an anhydrous and toxic gas in an
ꢀHCl, minimal waste and solvent usage, the
3
2

Non-Conventional Preparation of Schiff Bases
E
evacuated container, good yields for relatively unreactive ben-
zaldehydes containing electron-donating substituents, shorter
reaction time, and metal- and acid-free reaction conditions. In
addition, the promoter can be easily regenerated and reused
several times with no significant loss of its activity.
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[
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The modified method of the synthesis of 1,1 -( 1,4-butanediyl)
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