“Zero VOC” Synthetic Strategy – Aromatic Amination Reactions in Deep Eutectic Solvents

Article abstract of DOI:10.1002/ejoc.201800785

Rising concern for environment hazards resulting from the use of volatile organic compounds (VOCs) is prompting many chemists to use “green” solvents like water, polyethylene glycol, ionic liquids and deep eutectic solvents (DES). With a few notable exceptions, many of these processes still need to use volatile organic solvents for the workup and isolation of products. In the present report, we demonstrate a “zero VOC” protocol which eliminates the need to use organic solvents for any stage of the reaction. As a proof of concept, nucleophilic aromatic substitution reactions of 1-halo-2,4-dinitrobenzene with secondary amines were carried out in deep eutectic solvents. The reaction workup involved the addition of water for separating the product from the DES. Evaporation of water led to recovery of the DES, which exhibited good recyclability. The reaction in deep eutectic solvents was much faster than that in many other solvents, as confirmed by the kinetic studies. An attempt was made to elucidate the origin of this rate enhancement based on analysis activation parameters and correlation with the polarity parameters. The results show that use of deep eutectic solvents can take chemists a step closer towards the “zero VOC” synthetic strategy.

Full text of DOI:10.1002/ejoc.201800785

A Journal of
Accepted Article
Title: "Zero VOC" Synthetic Strategy - Aromatic Amination Reactions in
Deep Eutectic Solvents
Authors: Arun Valvi and S. Tiwari
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800785
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800785
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201800785
FULL PAPER
“
Zero VOC” Synthetic Strategy – Aromatic Amination Reactions
in Deep Eutectic Solvents
[a]
[a]
Arun Valvi and Shraeddha Tiwari*
[
3]
Abstract:Rising concern for environment hazards resulting from the
use of volatile organic compounds (VOCs) is prompting many
chemists to use “green” solvents like water, polyethylene glycol,
ionic liquids and deep eutectic solvents (DES). With a few notable
exceptions, many of these processes still need to use volatile
organic solvents for the workup and isolation of products. In the
present report, we demonstrate a “zero VOC” protocol which
eliminates the need to use organic solvents for any stage of the
reaction. As a proof of concept, nucleophilic aromatic substitution
reactions of 1-halo-2,4-dinitrobenzene with secondary amines were
carried out in deep eutectic solvents. The reaction workup involved
the addition of water for separating the product from the DES.
Evaporation of water led to recovery of the DES, which exhibited
good recyclability.The reaction in deep eutectic solvents was much
faster than that in many other solvents, as confirmed by the kinetic
studies. An attempt was made to elucidate the origin of this rate
enhancement based on analysis activation parameters and
correlation with the polarity parameters. The results show that use of
deep eutectic solvents can take chemists a step closer towards the
phase separation. This approach is not appropriate for
reactions which are water-sensitive or sluggish in aqueous
media. A typical example of such reactions is the nucleophilic
aromatic substitution reactions.
Nucleophilic substitutions on aromatic substrates are a
synthetically important class of organic transformations which
are equally challenging. Intermolecularnucleophilic substitutions
of aromatic substrates have been used to synthesize a variety of
[
4]
[5]
compounds such as tertiary aryl-alkyl ethers, carbohydrate-aryl
[
6]
[7]
[8]
ethers, aryl-aryl
functionalized
ethers, ortho-alkoxybenzaldehydes
fluoronitro-substituted aromatic
and
amino
[
9]
acids while the intramolecular analog has been employed as
the key step in numerous macrocyclisation reactions.[10],[11] The
generally accepted mechanism for this class of reaction involves
the SNAr pathway i.e. an addition–elimination pathway with the
formation of a zwitterionic intermediate. The formation of H
adducts can be a competing pathway and the reaction outcome
is the result of numerous factors including solvation, which
makes this class of reactions extremely sensitive to the choice of
reaction medium.[12] It is well known that the reaction is
particularly sensitive to the choice of solvents and the choice of
an appropriate solvent has been widely used synthetic strategy
“zero VOC” synthetic strategy.
to improve the yield and selectivity of nucleophilic substitution
reactions.[2],[13]
Introduction
An interesting aspect is that while the compounds like
nitroaniline show increased reactivity as substrates for
nucleophilic substitutions in aqueous media,[14] the reactivity of
Increasing awareness for environmental safety has led to efforts
in substituting the commonly used organic solvents and utilizing
“
green” solvents like water, ionic liquids and deep eutectic
1
-halo-2,4-dinitrobenzenes with secondary amines is known to
solvents as reaction media. Water could be a promising
candidate due to its reasonable cost, ready availability and its
environmentally benign nature.[1] However, the limited solubility
of many organic substrates in water,imposes a constraint on the
scaling up of the aqueous process to industrially relevant scales
of operation. Ionic liquids have been promising reaction media,
showing excellent reactivity and stereoselectivity.[2] But, in most
cases the work up of organic reactions carried out in ionic liquid
involves the use of a biphasic medium (water + organic solvent)
and is not entirely environmentally-benign. The synthesis of
most commonly used imidazolium or pyridinium ionic liquids
consists of an alkylation step followed by anion metathesis –
each step requiring the use of organic solvents. Till date, very
few reports can claim to have completely excluded the use of
organic solvents in their workup stage. A special mention should
be made for organic reactions carried out in “on water”
conditions – where product isolation can be achieved by simple
be lower in aqueous media as compared to the reactivity
observed in organic solvents like acetonitrile. Ionic liquids and
their mixtures with molecular solvents have been used as
solvents for the aromatic amination reactions of these substrates
with improved yields and reduced reaction times.[16]For example,
[15]
the second-order rate constant for the ethanolysis of 1-fluoro-
2,4-dinitrobenzene was at least an order of magnitude higher in
ionic liquids than that in molecular solvents under the same
conditions.[17]Ionic liquids also offer the added advantage of
improved solubility of the organic substrates and products as
compared to those observed in water – a factor which may be
critical in scaling up of the reactions. As mentioned earlier, a
major limitation in all the reports employing ionic liquids as
reaction media, is that the workup procedures involved use of
organic solvents, thereby undermining the environmental
advantage of using ionic liquids.
[
a]
Mumbai INDIA – 400 019
Email: ss.tiwari@ictmumbai.edu.in
Department of Chemistry, Institute of Chemical Technology,
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201800785
FULL PAPER
Deep eutectic solvents have emerged in the last decade as
a class of solvents which are both similar and complementary to
ionic liquids in many respects.[ They are known to be
nonvolatile, thermally stable and chemically benign, like ionic
liquids.Unlike commonly used ionic liquids based on imidazolium,
pyridinium, ammonium or phosphonium moieties, deep eutectic
solvents are synthesized from substrates that are cheaper and
readily available.Most of the substrates such as urea, glycerol,
etc. are bio-based components and more environmentally
compatible as compared to the components of conventional
ionic liquids.These promising propertiesof deep eutectic solvents
have led to their utilizationas media for a host of organic
reactions suchasDiel-Alder cycloaddition,[19] Fischer indole
annulations,[20]bromination,[21]Paal-Knorr reaction,[22]etc.
18]
In the present work, a series of nucleophilic aromatic
substitution reactions of substituted haloarenes with secondary
amines were carried out in deep eutectic solvents (DES) under
ambient conditions, leading to high yields in short reaction times.
The kinetics of the nucleophilic aromatic substitution of 1-halo-
Scheme 1
2
,4-dinitrobenzenes with morpholine were studied in three deep
The results of comparative runs are summarized in Table 1
and indicate that the nucleophilic substitution reactions are as
facile when carried out in DES as acetonitrile. The % conversion
observed for the fluoro-substituted reactant (1a) was marginally
higher than that for the chloro-substituted reactant (1b), in
agreement with the previously reported reactivities of the two
substrates. Most of the substitution reactions led to > 80% yields
eutectic solvents i.e. reline, ethaline and glyceline.
Thermodynamic parameters are calculated for the reaction
which was carried out over the temperature range 298–318 K to
understand the solvent–solute interactions in DES. The reaction
workup involved addition of water for separating the crude
product from the aqueous phase containing the DES. The DES
regenerated from the aqueous phase could be recycled up to
three times. The results indicate that DES can provide an
entirely benign reaction medium for carrying out the aromatic
nucleophilic substitution reactions, which remain one of the
challenging class of substitution reactions. More importantly, the
work provides proof-of-concept for the synthetic strategy of
using deep eutectic solvents as reaction medium and water for
product isolation, which could completely eliminate the need for
using any volatile organic solvents.
–
the reactions of (1b + 2c) in reline and (1b + 2d) in reline or
ethaline being the only exceptions, where approximately 70%
conversion was obtained. This is not surprising given the fact
that the reactivity of the secondary amines for such substitution
reactions is known to follow the order 2a>2b>2c2d. It should
be noted that glyceline (1:2 mixture of choline chloride +
glycerol) provided the best results in terms of % conversion,
which was even better than the conversions observed in
acetonitrile. For example, the reaction of (1b + 2c) gave 83%
yield when glyceline was used as the reaction medium, which is
comparable to the 88% conversion obtained in acetonitrile and
much better than the 70 – 75 % yields observed in other DESs.
More notably, the reactions between 1a and 2c / 2d gave better
conversion when glyceline, rather than acetonitrile, was used as
the medium. This observation was particularly encouraging
because it underlines the ability of DES to accelerate reactions
between substrates which are traditionally regarded as
challenging targets due to the lower conversions. The %
conversion observed for the bromo-substituted reactant (1c) was
similar to that for the iodo-substituted reactant (1d). It was
observed that glyceline (1:2 mixture of choline chloride +
glycerol) provided the best results in terms of % conversion,
which was even better than the conversions observed in
acetonitrile. For example, the reaction of (1c + 2a) gave 85%
yield when glyceline was used as the reaction medium, which is
comparable to the 78% conversion obtained in acetonitrile.
Similarly, the reaction of (1d + 2a) gave 84% yield when
glyceline was used as the reaction medium, which is
comparable to the 78% conversion obtained in acetonitrile. This
confirmed the efficiency of DES in facilitating the nuceophilic
Results and Discussion
The substitution reaction of 1-halo-2,4-dinitrobenzenes with a
series of secondary amines was chosen as the model reaction
to test the viability of using deep eutectic solvents as reaction
media (Scheme 1). Acetonitrile was chosen as a model organic
solvent, since it is known to be an efficient medium for this class
of reactions. For comparison, the three most commonly used
DES – namely reline (1:2 mixture of choline chloride and urea),
ethaline and glyceline were used as model DES media. The
reaction was carried out by mixing 1-halo-2,4-dinitrobenzene
(
halo = chloro or bromo) with appropriate secondary amine at
room temperature. Despite the hygroscopic nature of DES, we
observed that the reaction did not need N -atmosphere and
2
proceeded smoothly even in the absence of moisture-free
conditions. The progress of the reaction was monitored using
TLC and the reported yields correspond to reaction time after
which no further conversion was observed. In most of the cases,
the reaction completed within 120 – 180 minutes to give the
substituted aromatic products in almost stoichiometric yields.
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European Journal of Organic Chemistry
10.1002/ejoc.201800785
FULL PAPER
substitution reactions, thus encouraging further exploration of
their role as reaction media.
Table 1. Comparison of acetonitrile and DES as reaction media for the
reaction of 1-halo-2,4-dinitrobenzenes with secondary amines[
a]
The observed reactivity of SNAr substrates (F > Cl ≈ Br > I)
is consistent with that previously reported and is commonly
referred to as the “element effect”. The observed order of
reactivity is considered as evidence for a mechanism in which
the first step i.e. addition of the nucleophile is rate determining
step.[23] The factors that can account for the element effect and
for SNAr reactivity in general are manifold, and have been
thoroughly discussed in the literature. Weiming Wu and group
examined experimentally the SNAr reactions of 2,4-dinitrophenyl
halides and ring-substituted N-methylpyridinium substrates with
piperidine, respectively and provide computational results aimed
at elucidating the reasons for the element effect.[24]
Yield (%)[b]
Substrate
Amines
Acetonitrile
Reline
91
Ethaline
91
Glyceline
1a
1a
1a
1a
2a
2b
2c
2d
92
96
83
84
94
94
89
90
93
94
87
89
The results were interesting because the viscosity of
88
86
glyceline (259 cP at 25C) is much higher than that of ethaline
25]
(
37 cP at 25C).[ The observations indicate that the choice of
1b
1b
2a
2b
2c
2d
2a
2a
88
89
85
88
78
78
85
87
74
75
70
72
88
89
85
70
64
72
87
85
87
83
85
84
the hydrogen bond donor (urea / ethylene glycol / glycerol) in the
DES could be a significant factor in determining the reaction
outcome. While it is difficult to delineate the exact cause for such
drastic change in reactivity, the most plausible explanation could
be related to the variation in solute – solvent hydrogen bonding
interactions. We examined the reported solvatochromic
properties of the three DESs employed in the present
work(Table 2). The trend in reactivity for the different DES
1
b
b
1
1c
(
glyceline > reline > ethaline) for the amination of the less
reactive substrate 1b is mirrored in the E
T
1d
N
values of the
respective solvents. This may indicate that the more polar
solvent is a better reaction medium, if all other parameters are
less relevant. It may also be noted that an increasing value of
the solvatochromic parameter (hydrogen bond acceptor
basicity) of the DES corresponds to a decreasing yield of the
reaction. The observation indicates the critical role of the
hydrogen bonding between the solvent components and the
transition state, but any further discussion is hampered by the
limited physicochemical and solvatochromic data available for
DES.
In order to verify the general applicability of the reaction
protocol to different DES samples, the reaction of 1a with 2a
was carried out in three additional choline chloride-based DES
having different hydrogen bond donors (malonic acid,levulinic
acid and glutaric acid). Another eutectic mixture composed of
choline chloride and zinc chloride, which represents an entirely
different class of DES, was examined as a potential reaction
medium. Table 3 reports the yields of the product 3 obtained
after 2 h of stirring under ambient conditions. The results in
Table 3 indicate that the choice of the components making up
the DES can have a substantial impact on the efficiency of the
DES as a reaction medium, particularly for the less reactive
substrates like 1b. For example, the yield of product 3 resulting
from 1b + 2a dropped to 71% in the choline chloride – glutaric
acid DES as compared to the almost stoichiometric conversion
[
a] 94 mmol of substrate and 282 mmol of secondary amine were added to 1
mL of solvent and stirred at room temperature for 2 h. Workup involved
addition of cold water to the reaction mixture, followed by filtration.
[b] Yield of solid product reported after workup.
Table 2. Reported solvatochromic parameters of the DES [a]
DES mixture
ET
N
*


[
[
[
Ch]Cl:urea
0.835
0.822
0.845
1.192
1.112
1.161
0.860
0.891
0.903
0.559
0.640
0.544
Ch]Cl:ethylene glycol
Ch]Cl:glycerol
[
a] Reference 26
Table 3. Comparison of solvent efficiency for the reaction of 1-halo-2,4-
dinitrobenzene with secondary amines in different DES
DES
1a + 2a
1b + 2a
ChCl:malonic acid (1:2)
90
98
(
98%), when glutaric acid was replaced bymalonic acid. Of all
ChCl:levulinic acid (1:2)
ChCl:glutaric acid (1:2)
87
84
91
76
71
88
the DESs studied, it appears that the DES composed of 1:2
mixture of choline chloride and malonic acid offers the highest
increase in reactivity.
2
ChCl:ZnCl (1:2)
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European Journal of Organic Chemistry
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Another important observation was concerned with the
workup strategy adopted to isolate the products. All the four
substituted products (3–6) are solids at room temperature. The
products3 and 4 have a lower solubility in the DES medium and
some solid precipitation was observed in the reaction vessel at
the end of the reaction. In all the cases, the DES had changed
its appearance from colourless to yellow (or brown, in some
cases), indicating that some of the reactants / products were still
dissolved in it. Distilled water was then added to induce further
precipitation of the products. The addition of water clearly led to
the appearance of a solid – liquid biphasic mixture. Substantially
greater amount of solid precipitated in the case of 3 and 4
(ascompared to the amount precipitated before addition of
water).For the reaction of 2c or 2d, the resulting products (5 or 6,
respectively) had greater solubility in DES and did not precipitate
out spontaneously. However, addition of water induced the
precipitation of products 5 and 6 as solids. The components of
the DES (choline chloride, urea, ethaline, glyceline, etc.) being
water-soluble were extracted in the aqueous phase.
The DES was recovered by evaporation of water, which was
coloured in appearance. The regenerated DES was also tested
for recyclability. The recyclability studies showed that the DES
could be recycled for up to 3 cycles (Figure 1) with considerably
good but decreasing yields. Another characteristic observation
was the persistently coloured nature of the regenerated DES,
which was an indication of the marginal solubility of the
reactants / products in the DES + aqueous phase. Stirring the
aqueous phase with activated charcoal after the product had
been filtered out, resulted in complete decolourization of the
DES. Surprisingly, the yield of the substituted product was
affected only marginally by the absence or the presence of
coloured impurities in the successive runs, indicating that the
impurity does not interfere with the yield and there could be
additional factors leading to the decline in efficiency after three
runs. It was reasoned that using cold water for extraction could
Table 4. Performance of maline (ChCl : malonic acid eutectic mixture) as
reaction medium for reaction of 1-fluoro-2,4-dinitrobenzene(1a) with various
amines
Amine
% yield
Piperidine (2b)
Diethylamine
94
88
86
78
61
67
70
51
56
40
Diethanolamine
Aniline
p-toluidine
p-anisidine
p-chloroaniline
Propylamine
Butylamine
Imidazole
In order to confirm the scope of the reaction, the reactivity of
a variety of amines was examined in maline (eutectic mixture of
ChCl + malonic acid) since it appeared to be the most efficient
reaction medium. The isolated yields of the products obtained
from the reaction of 1a with different amines is listed in Table 4.
It can be observed that high to moderate yields were obtained
for all the amines used within a few hours under benign reaction
conditions. The order of reactivity observed for the amines is
consistent with that observed in molecular solvents, in spite of
the much higher viscosity of the DES (1124 cP at 25C)
employed.
lead to
a decrease in solubility of the organic reaction
components. However, the strategy was not very effective in
reducing the colour of the recycled DES.
The chemical nature and concentration of the coloured
impurities in the recycled DES was investigated by a series of
characterization techniques and by comparing the results with
those obtained for the “unrecycled” DES. It was observed that
the NMR spectrum of pure reline and recycled reline with the
coloured impurity were similar (Fig. S1 in Supporting
Information) except for the presence of a peak for moisture (at 
3.43 ppm) in the case of recycled DES sample. The infrared
spectra of the two samples also showed similar patterns in the
fingerprint region (Fig. S2 in Supporting Information). This
indicates that the compound/s imparting the colour to the
recycled DES is present in low quantities. It may be possible that
the impurity has a high absorption in the visible range, so that a
small quantity would be sufficient to impart
a coloured
appearance. In order to confirm this, we also compared the UV-
visible spectra of the recycled DES showed the presence of an
intense peaks due to product in all the cases. (Fig. S3 in
Supporting Information). The observations indicate that the
colour in the recycled DES originates from the partial solubility of
Figure 1. Recycling experiments in the reaction between 1-fluoro-2,4-
dinitrobenzene with morpholine in reline at room temperature. (A = pure
reline, B = reline regenerated using charcoal and C = recycled reline with
coloured impurities).
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European Journal of Organic Chemistry
10.1002/ejoc.201800785
FULL PAPER
the coloured product in each case, which is present in very small
amount (such that it is not detected in the NMR spectrum).
Additional methodologies for optimizing the work up conditions
are being explored in our research group.
Majority of the reports which state that the product is isolated
using an aqueous work-up, invariably employ abiphasic
aqueous-organic solvent system, which seriously undermines
the “green” quotient of the synthetic methodology. An
anion) suffer from the limitation of being extremely viscous (or
even solids) at room temperature.Another important aspect to be
noted is that the synthesis of ionic liquids involves the use of
organic solvents for extraction of unreacted starting material.
In contrast, synthesis of DES does not require any use of
organic solvents. The water-compatible nature of the
components may render the DES reaction media amenable to
the use of water as the sole extractant. This can be said to be a
unique characteristic of DESs, which should be utilized
universally. It is indeed surprising that this aspect of reaction
engineering in DESs has not been exploited to its complete
potential till date. To the best of our knowledge, there are only
two reports which utilize this property of DES. Zhao et. al.
isolated the solid products of the Morita–Baylis–Hillman by
simple filtration.[ In another report, Ramon et. al. have also
isolated the products of the aldol reaction were extracted from
the reaction mixture using only water, although the authors did
not explicitly highlight the advantage of such an approach in
terms of being an environment-friendly workup strategy.[
environmentally-benign
synthetic
methodology
should
completely exclude organic solvents from all the stages, but we
are aware of very few reports which can claim to have achieved
that ideal. Most of these reports use water as the reaction
medium and the product isolation involves phase separation or
filtration, facilitated by the limited solubility of many organic
compounds in water.[27] However, this strategy cannot be
extended to reactions in which water is not an efficient medium,
such as the current nucleophilic aromatic substitution, or which
use water-incompatible substrates / reagents. The other class of
reactions which are particularly amenable to VOC-free workup
30]
31]
are
solvent-free
synthetic
approaches
wherein
[
28]
mechanochemical strategies are adopted.
The use of green solvents as reaction media is only a partial
solution to the challenge of environmentally benign synthesis.
The waste generated in the work-up, during product isolation,
purification and regeneration of solvents/catalysts also need to
be considered for a more comprehensive solution to the problem.
In fact, for synthetic approaches using green solvents as
reaction media, the organic solvents used for the work-up
remains the major contributor to the waste generated.[32]It
appears as if chemists have resigned to the notion that use of
organic solvents in the workup is a necessary evil which is here
to stay.
The proposed workup strategy using DES as reaction
medium and water as the extractant is attractive in many ways.
It can be instrumental in reducing the consumption of organic
solvents, which are the primary pollutants in many synthetic
methodologies employing green solvents. The results are
encouraging as they show that a workup strategy completely
devoid of organic solvents is possible and that DES are
extremely promising class of solvents for such an approach. The
low cost components required for the synthesis of DES, the
benign reaction conditions and the excellent yields obtained
indicate a promising potential for scale-up to commercially
relevant amounts of products. It will bring us a step closer to the
complete elimination of VOCs from any stage of organic
synthesis.
In order to facilitate further analysis of the efficiency of DES
as reaction media, a thorough kinetic study was undertaken.
Pseudo first order rate constants for the four 1-halo-2,4-
dinitrobenzenes with morpholine as the secondary amine at 298
K in various reaction media were determined and are shown in
Table 5. It was observed that the rate constants for the reaction
in DES was 7 times less as compared to the acetonitrile and
water, respectively when the 1a is used in the reaction, while the
reaction using 1b shows reverse results – the rates in reline and
ethaline are higher than that observed in acetonitrile and
water.The rate of substitution of 1bin glyceline and acetonitrile is
Figure 2. Representation of the proposed synthetic strategy with DES.
However, reactions carried out in ionic liquids (“green
solvents”) have often suffered from this shortcoming. For
example, an completely aqueous extraction cannot be carried
out in a water – insoluble ionic liquids (such as ionic liquids with
–
–
the [NTf
2
] or [PF
6
] anions) unless the product is water soluble
(
limited probability for organic compounds).The methodology
reported in the present report of extracting the reaction medium
in the aqueous phase leading to product isolation can be
extended to water-soluble ionic liquids (for example, ionic liquids
primarily based on the halide or [BF
ionic liquids containing the [BF
]– anion, it has been reported that
4
]– anion). For water-soluble
4
the anion undergoes hydrolysis in presence of water[29] – a
property which hampers the repeated use of aqueous extraction
and recyclability when ionic liquids are used as reaction
media.Other water soluble ionic liquids (based on the halide
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European Journal of Organic Chemistry
10.1002/ejoc.201800785
FULL PAPER
similar. The reactions (1c + 2a) and (1d + 2a) have similar rate
constants for acetonitrile, reline, ethaline and glyceline. Rate
constant for these reactions in water was less than the other
solvents. It was clearly observed that the rate constants for the
reaction in DES was in a good agreement with the acetonitrile
and water.[15],[33]
as well as DES. It must be noted that in spite of the enthalpy
compensation, the differences in the free energy of activation
between reactions carried out in acetonitrile and those carried
out in reline, ethaline and glyceline, was less than 3.2 kJmol-1
while for the reactions carried out in acetonitrile and maline was
less than 8 kJmol-1.
-
1
Table 5. Pseudo first order rate constants (kobs / s ) for the reactions of 1-
halo-2,4-dinitrobenzene substrates with morpholine in acetonitrile, water,
reline, ethaline and glyceline at 298 ± 0.1K.
Conclusions
Substrate
Solvents
1
a
1b
1c
1d
We have successfully demonstrated that the nucleophilic
amination reactions of 1-halo-2,4-dinitrobenzenes, which are
generally sluggish in water, can be accelerated in deep eutectic
solvents to give excellent yields. Preliminary comparison with of
the yields with the reported polarity parameters of the reaction
media, suggests that the nature of solute – solvent interaction
can influence the reaction outcome. In future, a thorough
understanding of the molecular interactions could help in better
selection of the reaction media. We have also demonstrated the
proof-of-concept for reaction workup using only water. In fact,
we wish to emphasize that the synthesis of DES and their
application as reaction media can be carried out through this
Acetonitrile
Water
3.02 X 10-2
3.6 X 10-4
6 X 10-4
1.4 X 10-4
1.43 X 10-2
4 X 10-5
3 X 10-5
9 X 10-6
Reline
9 X 10-3
1.5 X 10-3
7.7 X 10-4
1.6 X 10-4
4 X 10-3
1.6 X 10-3
7.4 X 10-4
2.1 X 10-4
Ethaline
Glyceline
2 X 10-3
4.1 X 10-4
2.9 X 10-4
7.3 X 10-5
“
zero VOC” approach. Chemists could exploit the difference in
physical parameters to aid product separation and purification. A
highly efficient and selective chemical process, combined with
proper reaction engineering, should be another step in
eliminating the environmental hazards associated with the use of
organic solvents.
Table 6. Activation parameters for the reactions of 1-chloro-2,4-dinitrobenzene
1b) with morpholine (2a) in acetonitrile, reline, ethaline and glyceline.
(
H≠
∆S
≠
∆G (kJmol
≠
-
E
a
(kJmol )
∆
Reaction medium
-
1
-1
-1
1
[a]
-1 [a]
(
kJmol )
(JK mol )
)
Acetonitrile
Reline
32.14
33.08
28.66
37.83
105.26
-164.71
-148.64
-163.75
-144.49
43.54
83.52
80.35
80.74
83.05
91.42
34.79
35.72
31.31
40.47
107.91
Experimental Section
Ethaline
Glyceline
Maline
1
-halo-2,4-dinitrobenzenes (1a-d) and the secondary amines
morpholine (2a), piperidine (2b), diethylamine (2c) and diethanolamine
2d) – used for the reactions were of the highest quality available.
–
(
Choline chloride, urea, ethylene glycol, glycerol, malonic acid, levulinic
acid, glutaric acid and zinc chloride used for DES synthesis were of
highest purity available. The products of the nucleophilic substitution
reactions, N-(2,4-dinitrophenyl) amines were characterized by 1H NMR
spectroscopy. (Please refer Supporting Information for details).
[
a] At 318 K
The activation parameters for the reactions were determined
by applying the Eyring equation to the temperature-dependent
kinetic data (Supporting Information). A large negative entropy of
activation was a consistent feature observed for the reaction of
Preparation of DES
1
b with 2a in all the reaction media except maline. It was
Deep eutectic solvents were prepared by mixing choline chloride with
various hydrogen bond donor reagents, in a mole ratio of 1:2 followed by
stirring under heating (∼80°C) until a homogeneous, colourless liquid
has been formed.
observed that the free energy of activation for acetonitrile was
less than the glyceline and maline while for reline and ethaline it
was much lower, verifying the higher rate constants observed in
reline and ethaline. While the entropic cost of activation is
comparable for acetonitrile and all the DES studied except
maline, it is compensated by the enthalpy variation in reline and
ethaline. The enthalpy variation in maline was much more than
acetonitrile and all the DES studied. The results indicate that the
transition state is similarly “ordered” in the conventional solvents
Synthesis of N-(2,4-dinitrophenyl)-amine products
A
mixture of 1-halo-2,4-dinitrobenzene (94 mmol) with appropriate
secondary amine (282 mmol) in solvent (1 ml) was stirred for 2h. The
product was precipitated by addition of cold water (150 uL) and washed
with cold water (500 L). Evaporation of the water using high vacuum
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European Journal of Organic Chemistry
10.1002/ejoc.201800785
FULL PAPER
pump for at least 2-3 h led to the recovery of the DES. The regenerated
solvent was then recycled up to three times.For decolourising the
regenerated DES, 200 mg activated charcoal was added in aqueous
phase after extraction and heated for 5-10 min. The hot solution was then
filtered and colourless DES was regenerated by evaporation of water.
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Acknowledgements
A. V. thanks UGC for UGC-BSR fellowship (Grant no.: F4-
/2006(BSR)/7-227-2009(BSR)). S.T. acknowledges
1
Department of Science and Technology for DST-INSPIRE
faculty award (IFA13-CH95) and SERB for Fast Track grant (and
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Keywords:green
chemistry•solvent
effects•waste
prevention•nucleophilic substitution•kinetics
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Table of Contents
FULL PAPER
Nucleophilic aromatic substitution
Arun Valvi, Shraeddha Tiwari*
reactions
dinitrohalobenzene
of
2,4-
with
Page No. – Page No.
secondary amines were carried
out in Deep Eutectic Solvents to
“
–
Zero VOC” Synthetic Strategy
Aromatic Amination
give
excellent
yields.
The
Reactions in Deep Eutectic
Solvents
(
(Insert TC Graphic here: max. width:
reaction workup involved the
addition of water for seperating
the product which indicates that
DES is entirely benign reaction
medium for the SNAr reactions.
More importantly, the Deep
5
.5 cm; max. height: 5.0 cm))
Eutectic
Solvents
exhibited
excellent recyclability.
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