A New Green and Efficient Br?nsted: Lewis Acidic DES for Pyrrole Synthesis

Article abstract of DOI:10.1007/s10562-018-2414-4

Abstract: Deep eutectic solvents (DESs) are fluids composed of different Lewis or Br?nsted acids and bases, generally acknowledged as new analogues to ionic liquids (ILs), because of their similar characteristics, but with more advantages related to preparation cost, environmental impact etc. Their preparation involve the simple mixing of two components generally with moderate heating that are inexpensive, non-toxic, biodegradable and the resulting mixture is capable to overcome the drawbacks of conventional organic solvents and ILs. Chemical reactions with these materials are significantly less hazardous and they can act as catalysts as well as reaction media. Here, three new DESs based on ZrOCl₂·8H₂O in combination with urea, ethylene glycol and glycerol are introduced. Physicochemical properties like phase behaviour, Freezing point, density, viscosity, thermal stability and miscibility properties in common solvents are determined. In addition, a new method for the determination of acidity of DESs having both Br?nsted and Lewis sites is also introduced in this work. A convenient synthesis of pyrrole through Paal–Knorr reaction is reported using a variety of amines which are used to establish the importance of this catalyst in organic reactions. The products are analysed by GC–MS, ¹H NMR and ¹³C NMR. By comparing the three DESs, DES 1 (formed from ZrOCl₂·8H₂O with urea) has the lowest density, viscosity, highest acidity and thermal stability. It was shown to be an excellent green catalyst for Paal–Knorr reaction. Reusability of the catalyst was also achieved up to 4 runs, without significant loss in its catalytic activity. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-018-2414-4

Catalysis Letters
https://doi.org/10.1007/s10562-018-2414-4
A New Green and Efficient Brønsted: Lewis Acidic DES for Pyrrole
Synthesis
M. Shaibuna1 · Letcy V. Theresa1 · K. Sreekumar1
Received: 4 March 2018 / Accepted: 13 May 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Deep eutectic solvents (DESs) are fluids composed of different Lewis or Brønsted acids and bases, generally acknowledged
as new analogues to ionic liquids (ILs), because of their similar characteristics, but with more advantages related to prepara-
tion cost, environmental impact etc. Their preparation involve the simple mixing of two components generally with moderate
heating that are inexpensive, non-toxic, biodegradable and the resulting mixture is capable to overcome the drawbacks of
conventional organic solvents and ILs. Chemical reactions with these materials are significantly less hazardous and they can
act as catalysts as well as reaction media. Here, three new DESs based on ZrOCl2·8H2O in combination with urea, ethylene
glycol and glycerol are introduced. Physicochemical properties like phase behaviour, Freezing point, density, viscosity, ther-
mal stability and miscibility properties in common solvents are determined. In addition, a new method for the determination
of acidity of DESs having both Brønsted and Lewis sites is also introduced in this work. A convenient synthesis of pyrrole
through Paal–Knorr reaction is reported using a variety of amines which are used to establish the importance of this catalyst
in organic reactions. The products are analysed by GC–MS, 1H NMR and 13C NMR. By comparing the three DESs, DES 1
(formed from ZrOCl2·8H2O with urea) has the lowest density, viscosity, highest acidity and thermal stability. It was shown
to be an excellent green catalyst for Paal–Knorr reaction. Reusability of the catalyst was also achieved up to 4 runs, without
significant loss in its catalytic activity.
Graphical Abstract
Keywords Deep eutectic solvents (DESs) · Green catalyst · Brønsted and Lewis acidity · Phase behaviour · Paal–Knorr
reaction
1 Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-018-2414-4) contains
Ionic liquids (ILs) have gained increasing interest from the
supplementary material, which is available to authorized users.
scientific community over the past few decades and the num-
* K. Sreekumar
bers of reported articles in the literature have grown expo-
nentially due to the introduction of air and moisture stable
imidazolium ILs. They are usually regarded as encouraging
alternatives for traditional volatile organic solvents due to
kskpolymer.cusat@gmail.com
1
Department of Applied Chemistry, Cochin University
of Science and Technology, Kochi, Kerala 682022, India
Vol.:(0123456789)
1 3

M. Shaibuna et al.
their unique properties. Nevertheless, in spite of these pos-
sible benefits, IL’s “green affiliation” is often challenged,
mainly due to their poor biodegradability, biocompatibil-
ity, sustainability and difficulty in synthesis [1, 2]. In 2003,
Abbott and co-workers had shown that it was possible to
lower the melting point of high melting salts, such as qua-
ternary ammonium salts and metal salt/metal salt hydrate, by
mixing them with hydrogen bond donors (HBD). This melt-
ing point depression was ascribed due to the charge delocali-
zation occurring through hydrogen bonding between them
[3–5]. Such mixtures are commonly called deep eutectic
solvents (DESs, also known in the literature as deep eutec-
tic ionic liquids, DEILs), and are fluids composed of differ-
ent Lewis or Brønsted acids and bases, which form liquids
at low temperature (lower than 100 °C, with melting point
much lower than the individual components) [6–8]. Their
formation is based on the depression in freezing point by
the addition of a solute to a solvent (colligative property).
They are the greener alternative to ILs because of their simi-
lar characteristics. They have more advantages related to
preparation cost, environmental impact, non-hazardous and
non-flammable nature etc [9–14]. DESs consist of the asso-
ciation of at least two molecules, one acting as hydrogen
bond acceptor (HBA) and the other as hydrogen bond donor
(HBD), respectively, via hydrogen bond interactions [15,
16]. Properties of the DESs may be tuned by changing salt/
HBD combination, but the extent of change is often fairly
limited [17]. There is no chemical reaction; only intermo-
lecular interactions are involved in the formation of DESs
with 100% atom economy, which is the most important fac-
tor, because all initial components are included in the final
mixture [18]. The purity of the DES depends only on the
purity of the individual components. No further purification
is required, which is an important advantage over ILs and
would favour large scale applications of DESs [19]. One of
the main applications of DESs and low melting mixtures
are in the field of organic synthesis. They have strong abil-
ity to donate/accept the electrons or protons, so they can be
used as catalysts. At the same time, they can act as environ-
mentally benign reaction medium by improving the contact
between the reactants and thus, promoting organic synthesis.
Some of the organic transformations promoted by DESs are
hydroxylation and demethoxylation of lignin [3], acylation
of secondary alcohols, phenols and naphthols [6], arylation
of benzoxazoles with aromatic aldehydes [9], addition of
organolithium reagent to imines and quinolines [20], Prepa-
ration of propargyl amines [21], synthesis of 3,4-dihydropy-
rimidin-2-ones [22], Fischer indole synthesis [23] etc.
The present study was focused on the preparation of
DESs, their characterisation and application in Paal–Knorr
pyrrole synthesis [24–27]. Common methods for the prepa-
ration of pyrroles include, Hantzsch reaction [28], annulation
reaction [29], Aza-Wittig reaction [30], Paal–Knorr [31] and
Barton–Zard synthesis [32]. Among these, Paal–Knorr reac-
tion is the most efficient and favourable method. 1,4-dicar-
bonyl compounds are converted to pyrroles in the presence
of ammonia or primary amines. Various kinds of homoge-
neous and heterogeneous acid catalysts were reported for
this reaction, such as acidic resin [33], Silica-supported
bismuth(III) chloride (BiCl3/SiO2) [34], layered zirconium
phosphate and zirconium sulfophenyl phosphonate [35],
PS (polystyrene-supported gallium trichloride)/GaCl3 [36],
montmorillonite KSF [37], xanthan sulfuric acid, Ti(OiPr)4
[38], graphene oxide [39], ionic liquid [40], under the con-
dition of conventional heat, microwave irradiation [41],
vitamin B1 [42]. silica sulfuric acid (SSA) [43], indium(III)
[44], DES (urea/glycerol-choline chloride) [45], Bi(OTf)3
[46], Sc(OTf)3 [47], CoCl2 [48], Al2O3 [49], Bi(NO3)3 [50]
etc were also used as catalysts. Fe3O4@γ-Fe2O3-SO3H and
γ-Fe2O3@SiO2–HA, were also employed in the synthesis
of N-substituted pyrroles [51]. However, these method-
ologies are associated with one or other drawbacks such
as prolonged reaction time, poor yield, non-recyclability
of catalyst, precious metals, elevated temperatures, use of
hazardous organic solvents, tedious workup leading to toxic
metal-containing waste and destruction of catalyst [52, 53].
By considering these issues, it is more important to continue
the search for a better catalyst for the synthesis of pyrroles in
terms of operational simplicity, reusability, economic viabil-
ity, and greater selectivity. In the present paper, a simple,
clean, recyclable and environmentally friendly process is
reported for the synthesis of N-substituted pyrrole deriva-
tives by reaction of various aliphatic and aromatic amines
with 2,5-hexanedione in DESs without any solvents at room
temperature. Three new DESs based on ZrOCl2·8H2O are
reported. The manuscript includes the study of their phys-
icochemical properties including phase behaviour, freezing
point, density, viscosity, thermal behaviour, solvation prop-
erties and for the first time, acidity of DESs was determined
by FTIR study and pH measurement. Their application in
Paal–Knorr reaction is also reported.
2 Results and Discussion
Type IV- DESs (which was formed from metal chloride
hydrate and hydrogen bond donor), containing both Bronsted
and Lewis acid sites were synthesised. Here, ZrOCl2·8H2O
is the metal chloride hydrate used and the hydrogen bond
donors (HBDs) are urea, ethylene glycol, and glycerol.
These HBDs interact with the anion of the metal chloride
hydrate and thereby increasing the effective size, this in
turn, decreases the interaction with the cation leading to a
freezing-point depression of the mixture [4]. The Type IV
DES- was selected because of the increased scope of DES
by using hydrated metal halides. In addition, their inherent
1 3

A New Green and Efficient Brønsted: Lewis Acidic DES for Pyrrole Synthesis
Table 1 DES prepared with different compositions
air/moisture insensitivity coupled with their relatively low
cost make their use more viable. Also, the availability of low
melting non hydrated metal halides to form type I DESs is
limited [5].
Entry
DES
Ratio
State at RT
1
2
3
4
5
6
7
8
9
10
Zr:U
Zr:U
Zr:U
Zr:U
Zr:U
Zr:U
Zr:EG
Zr:EG
Zr:Gly
Zr:Gly
1:1
1:2
1:3
1:4
1:5
1:6
1:1
1:2
1:1
1:2
Solid
Solid
Solid
Solid
Liquid
Liquid
Semi solid
Liquid
Semi solid
Liquid
At first, ZrOCl2·8H2O and Urea were used in different
molar ratios to make a new DES system. The different DES
compositions were prepared by varying the molar ratio
of urea with a fixed amount of metal salt hydrate. Some
of them (ZrOCl2·8H2O and urea in the ratio1:1, 1:2, 1:3,
and 1:4 (Table 1, entry 1–4)) became solid upon cooling to
room temperature. DESs with ratios 1:5 and 1:6 (Table 1,
entry 5 and 6) remained as a clear liquid at room tempera-
ture (Fig. 1). Similarly, ZrOCl2·8H2O with ethylene glycol
and glycerol at 1:1 ratio were unsuccessful (Table 1, entry
7 and 9), but successfully formed both at 1:2 ratio (Table 1,
entry 8 and 10). The successful combinations of the three
DESs were selected for further studies.
Zr ZrOCl2·8H2O, U urea, EG ethylene glycol, Gly glycerol
DES was selected for the construction of phase diagram by
cooling curve method. Their melting points were 400 and
133 °C respectively. The melting points of ethylene glycol
(− 12.9 °C) and glycerol (17.8 °C) are lower, so that their
phase diagrams are more difficult to draw. Freezing points
were measured by melting the mixture at different compo-
sitions until a clear, colourless melt was obtained followed
by uniform cooling and a phase diagram was drawn using
the freezing point obtained. The phase diagram obtained
was not simple but similar to previously reported choline
chloride–urea phase diagram [54]. The eutectic temperature
obtained from the phase diagram for ZrOCl2·8H2O/urea at
1:5 ratio was −30 °C (Table 2, entry 6 and Fig. 2). This was
considerably much lower than either of the constituents (mp
of ZrOCl2·8H2O=400 °C and urea=133 °C) and allow the
mixture to be used as an ambient temperature solvent. The
large value of depression in freezing point must arise from
an interaction between urea molecules and the chloride ion
in ZrOCl2·8H2O.
2.1 Cooling Curve and Phase Diagram
The prediction of the phase diagram of a DES is difficult,
since diverse effects interact and also the large freezing point
difference between the two compounds also makes some
complexity in the phase diagram. Here, ZrOCl2·8H2O–Urea
Table 2 Composition (%), corresponding ratio and freezing point of
DES1
Entry
Composition (%)
ZrOCl2·8H2O
Ratio
FP (°C)
Urea
1
2
3
4
5
6
7
8
9
10
100
0
1:0
1:1
1:1.25
1:1.5
1:4
400
54
42
32
11
− 30
10
22
40
133
84.3
81.2
78.16
72.86
51.77
40.15
34.93
28.7
0
15.70
18.80
21.84
27.14
48.23
59.85
65.07
71.30
100
1:5
1.25:10
1:10
0.75:1
0:1
Fig. 1 ZrOCl2·8H2O:urea with different compositions
1 3

M. Shaibuna et al.
Fig. 2 Phase diagram of DES1
The three successful deep eutectic solvents, DES 1
(ZrOCl2·8H2O with urea at 1:5 ratio), DES 2 (ZrOCl2·8H2O
with ethylene glycol at 1:2 ratio) and DES 3 (ZrOCl2·8H2O
with ethylene glycol at 1:2 ratio) were considered for further
investigations in this study, for measuring the physical prop-
erties like freezing point, density, viscosity, thermal stability,
solvation properties and acidity.
2.2 DSC Analysis
In the case of DES1 (ZrOCl2·8H2O/Urea at 1:5 ratio), freez-
ing point was observed at − 30 °C by the most common
strategy, differential scanning calorimetry (Fig. 3a). Hence
the eutectic point obtained from phase diagram was con-
firmed. But the other DESs (DES 2 and DES 3) didn’t show
a freezing point in the DSC thermogram, instead, a glass
transition temperature was observed. Similar phenomenon
was recently observed in two different DESs based on potas-
sium carbonate-glycerol [55] and choline chloride–lactic
acid [56], in which glass transition was observed rather
than freezing point for a wide range of ratios used in their
work. This group is called the low transition temperature
mixture (LTTM) [55]. Here, DES 2 and DES 3 behaved in
a similar way and had a glass transition temperature of 5.36
and 8.75 °C.
2.3 Density
Fig. 3 a DSC curve of DES 1, b DSC curve of DES 2 and c DSC
curve of DES 3
The densities of deep eutectic solvents are generally higher
than water, but comparable to those of ILs which vary
between 1.1 and 2.4 g/cm3. The lowest density was observed
for DES 1 (ZrOCl2·8H2O/urea at 1:5 ratio, density=1.49 g/
cm3, Table 3, entry 1), DES 2 (ZrOCl2·8H2O/ethylene gly-
col at 1:2 ratio) and DES 3 (ZrOCl2·8H2O/glycerol at 1:2
ratio) had the same density (1.57 g/cm3, Table 3, entry 2
and 3). From this, it could be concluded that the density of
DES could be highly affected by the type of the HBDs used.
As Abbott et al. mentioned, the differences of density in
DES were caused by the varying degrees of hydrogen bonds
in these systems [57]. The presence of hydroxyl groups in
1 3

A New Green and Efficient Brønsted: Lewis Acidic DES for Pyrrole Synthesis
Table 3 Properties of DESs
Entry
DES
Mole ratio
Abbreviation
DSC analysis (°C)
Density (g/cm3)
Viscosity
(η)/(mPa
s)
prepared
1
2
3
Zr: U
Zr: EG
Zr: Gly
1:5
1:2
1:2
DES 1
DES 2
DES 3
Tf = − 30
Tg = 5.36
Tg = 8.75
1.49
1.57
1.57
52.40
149.50
532.73
Zr ZrOCl2·8H2O, U urea, EG ethylene glycol, Gly glycerol
DES may increase hydrogen bonding and gave a closely and
neatly packed structure, which increases the density of DES.
But at the same time, an additional carbon atom slightly
decreases the hydrogen bond interactions due to steric hin-
drance. As a result, the free volume tends to increase and
density value decreased, this effect was previously reported
in ILs by Ribe et al. [58]. These two effects may result in the
same density value for DES 2 and DES 3.
developed. The present catalyst may contain both Lewis and
Brønsted acid sites. Here, for the first time, acidity of DESs
was determined by FTIR study (using pyridine as probe (Py-
IR)) and pH measurement (using pH meter).
Fourier transform infrared (FTIR) spectroscopy is widely
used in the characterization of catalysts due to its capacity to
provide information without destroying the matrix and this
method is mainly applied in the case of ILs and montmoril-
lonite clay catalysts [61, 62]. Interaction of pyridine with the
acid sites of the catalyst generates a series of signals, among
which two are prominent. The absorption peak at 1437 cm−1
was observed in the FT-IR spectrum of pyridine; by the
addition of DES, this band was shifted to 1450 cm−1, which
was indicative of pyridine coordinated to Lewis acid sites.
Here, pyridine can react with Lewis acid sites and the result-
ing Py–Lewis complex formed had a band at 1450 cm−1.
Similarly, a band near 1540 cm−1 is an indication of the
formation of pyridinium ions ([PyH]+) resulting from the
interaction of pyridine with Brønsted acid sites [63–69]. By
observing these two peaks, the acidic type of the sample can
be deduced. However, there were no other absorption bands
for the three DESs (DES 1, DES 2 and DES 3) samples
before adding pyridine (Fig. 4). FTIR spectra of the samples
after addition of pyridine are given in Fig. 5. Compared with
the spectra of DES 2 and DES 3, a new additional peak
appeared at 1450 cm-1 in the spectrum of DES 1, which
2.4 Viscosity
The viscosity is related to many important factors like
hydrogen-bond network, Van der Waals and electrostatic
interactions and free volume. The viscosities of DESs are
very important in organic reactions; they are strongly influ-
enced by the ability to transport the mass within the liquid.
Higher viscosity of the DES results in the limited mobility of
species and low conversion of products. Here, the lowest vis-
cosity was observed for DES 1 (52.40 mPa s, Table 3, entry
1) and highest for DES 3 (532.73 mPa s, Table 3, entry 3).
Density and viscosity are greatly dependent upon the HBDs
used. DES formed from glycerol is having a higher viscosity
value than ethylene glycol. The results are consistent with
other literature, higher than water and conventional solvents
but similar to the ILs and DESs. Most of the DESs show
lower viscosity level at the eutectic composition [59], DES
1 at its eutectic point has low viscosity of 52.40 mPa s and
the viscosity of others (DES 2 and DES 3) may be lowered
when reaching their eutectic point.
2.5 Acidity
It is difficult to study the acidity of DESs by the most com-
mon methods like temperature programmed desorption
(TPD) using a basic probe molecule, mostly ammonia and
Hammet titration. There has been only one study reporting
the determination of acidity (using pH meter) of low melt-
ing mixtures (LMMs) based on l-(+)-tartaric acid-dimethyl
urea (DMU), which is similar to DESs [60]. However, this
method is limited to the determination of Brønsted acidity
and not applicable to DESs having both Lewis and Brønsted
acid sites. This indicates that, a well-established procedure
for determination of the acidities of DESs has not yet been
Fig. 4 FTIR spectra of the three DESs prepared
1 3

M. Shaibuna et al.
due to the dehydration and complete decomposition took
place at 273.77 °C (Table 4, entry 1) compared with others
(DES 2=118.38 and DES 3=129.47, Table 4, entry 2 and
3). This indicated that DES 1 had thermal stability up to
273.77 °C, higher thermal stability among the three DESs.
Upon heating the DESs, dehydration occurred first followed
by the degradation.
2.7 Miscibility with Common Solvents
Solubility of DESs in water and some other organic solvents
were studied (Table 5), they exhibited unusual solvation
properties that were strongly influenced by hydrogen bond-
ing between the solvent and DESs. This indicated that DESs
had higher affinity with all compounds capable of donating
electrons or protons. As a result, protic solvents (e.g. metha-
nol, ethanol, or water, Table 5, entry 1–3) were miscible
with DESs, while aprotic ones (e.g. toluene, hexane, ethyl
acetate, acetonitrile, etc.) were immiscible [55]. Thus, ethyl
acetate may be used for the extraction of molecules of low
or medium polarity, allowing the DES to be reused.
2.8 Catalytic activity
Fig. 5 FTIR spectrum of neat pyridine, Py–complex with DES 1,
DES 2, DES 3
Paal–Knorr reaction was selected for the catalytic study. A
variety of conditions was studied using DES1 as the cata-
lyst, as well as reaction media involving Aniline (1 mmol)
and 2,5-hexanedione (1 mmol) as the model reaction at
room temperature (Table 6). Excess amine would add an
unnecessary purification step. At first, the reaction was
performed in the absence of catalyst and solvent; only
trace amount of product was obtained even after 1 h
(Table 6, entry1). The reaction was done in the presence
of 0.5 mmol of catalyst; 80% yield was obtained (Table 6,
entry 2). The outcome demonstrated the necessity of the
catalyst in this reaction. The process was also repeated to
find out better catalytic conditions for this reaction. An
excellent yield (93%) was obtained using 1 mmol of cata-
lyst and after that; there was no further increase in the
product yield (Table 6, entry 3 and 4). Effect of solvents
were also checked using MeOH, EtOH, CH3CN, DCM
and Hexane; reaction reached its highest performance
under solvent free condition (Table 6, entry 5–10). Fur-
ther optimization study demonstrated that efficient yield
indicated its Lewis acidity. Peak at ~1540 cm−1 is common
to all the three DESs, which indicated their Bronsted site.
The pH measurement was also performed (Table 4).
DES 1 is having a higher acidic pH value (Table 4, entry 1)
compared with DES 2 and DES 3. From both pH and FTIR
studies, it was concluded that DES 1 contained both Lewis
and Bronsted acid sites. The remaining DESs (DES 2 and
DES 3) are only slightly Bronsted acidic and have no Lewis
acid sites.
2.6 TG Analysis
Thermogravimetric analysis (TGA) of the DESs was per-
formed to investigate the thermal stability. The TGA curves
of the DESs are given below Fig. 6 (a) DES 1, (b) DES
2 and (c) DES 3. It was found that the DES formed from
ZrOCl2·8H2O and urea (DES 1) had higher thermal stability.
For this, decomposition started at 143.42 °C, which may be
Table 4 FTIR bands, pH values
Entry DES
Peak for Lewis Peak for Bron- pH
Complete decomposi-
tion takes place at T
(°C)
and decomposition temperature
of the DESs prepared
site (cm−1
)
sted site (cm−1
)
In non-aque- In aqueous
ous solution solution
1
2
3
DES 1 1450
~1540
~1540
~1540
2.14
6.93
6.97
2.20
6.99
6.99
273.77
118.38
129.47
DES 2
DES 3
–
–
1 3

A New Green and Efficient Brønsted: Lewis Acidic DES for Pyrrole Synthesis
was obtained within 5 min using 1 mmol of DES 1 at RT.
This was the optimum condition (Table 6, entry 11). The
effect of other DESs (DES 2 and DES 3) under the same
optimised condition was also examined (Table 6, entry
12 and 13). The result showed that DES 1 was a highly
efficient catalyst achieving very good yield of the pyrrole
within 5 min compared with others (Table 6, entry 11).
This catalyst was used for further studies.
One of the main objectives of this paper was to examine
whether the viscosity and acidity measured correlated with
the activity of the catalyst in Paal–Knorr reaction. A valid
result was obtained for this question, DES1 having lowest
viscosity and highest acidity was an excellent catalyst as
well as reaction medium for the reaction with high yield and
having a good correlation with previous reports. Solvents
may not be necessary in the case of liquid reactants, but in
the case of solid amines like naphthylamine, nitroanilines
etc, the DES provided an efficient medium in addition to
catalytic activity for their excellent performance.
This outcome caused to examine the scope and generality
of this novel protocol, under optimal conditions, for a variety
of amines (including aliphatic amines, aromatic amines), the
resulting pyrroles were obtained in good to excellent yield
(Table 7).
Both cyclic and acyclic aliphatic amines gave excellent
yield within a short period of time. The reactions of acyclic
alkyl amines are much faster than cyclic amines (Table 7,
entries 1–3). Benzyl amine gave more yield than aniline
(Table 7, entries 4 and 5), additional methylene group may
remove the electron withdrawing effect of the phenyl ring
from NH2 group.
To further extend the scope and utility of the catalyst,
reaction was repeated by using substituted anilines including
both meta and para substituted having both electron donating
and electron withdrawing groups. They were transformed in
to the pyrrole derivatives in good to excellent yield without
the formation of any side products (Table 8, entries 1–10).
Substituted anilines with electron-rich groups enhanced
the percentage conversion than anilines with electron with-
drawing substituent and the latter took more time to com-
plete the reaction. For example, in the case of 3-aminoben-
zoic acid, 30 min was required for 85% conversion (Table 8,
entry 4) and only traces of products were obtained using
3,5-diaminobenzoic acid. Even the Nitro derivatives of ani-
line (Table 8, entries 6, 7) gave expected product in appre-
ciable yield, which was not obtained by using many of the
previously reported catalysts. The activity of less nucleo-
philic amine like naphthylamine was examined using DES 1,
which provided a higher yield within a shorter period of time
(Table 8, entry 9). To further extend the scope and utility of
DES, reaction was performed between heteroaromatic amine
(2-aminopyridine) and 2,5-hexanedione (Table 8, entry 10);
it exhibited similar behaviour of other aromatic amines and
Fig. 6 a TG curve of DES 1, b TG curve of DES 2 and c TG curve
of DES 3
1 3

M. Shaibuna et al.
Table 5 Miscibility of DESs in
Entry
Solvent
ZrOCl2·8H2O
Urea
EG
Gly
DES 1
DES 2
DES 3
common solvents
1
2
3
4
5
6
7
8
Water
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Methanol
Ethanol
Acetone
CH3CN
DCM
CHCl3
DMSO
Hexane
EtOAc
THF
IS
IS
IS
IS
IS
IS
1S
IS
IS
IS
IS
IS
SS
SS
S
IS
IS
IS
IS
IS
IS
IS
S
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
IS
S
IS
IS
S
IS
IS
S
9
10
11
EG ethylene glycol, Gly glycerol, S soluble, IS insoluble, SS sparingly soluble
gave 88% yield within 15 min. This indicates the efficiency
and activity of DES1.
carbon followed by the subsequent loss of two molecules of
water leads to the formation of pyrrole and regeneration of
the catalyst DES.
The reaction was also extended to diamines. In the case
of o-Phenylenediamine, only monopyrrole product was
formed in both 1:1 and 1:2 ratios (Table 9, entry 1). But
in the case of 4,4′-methylene dianiline, with 2,5-hexanedi-
one at 1:1 molar ratio, selectively resulted in the formation
of monopyrrole as the major product and small amount of
bispyrrole was also formed. With 2 equivalents of dione,
complete conversion of diamine in to bispyrrole product was
achieved without the formation of mono pyrrole (Table 9,
entry 2). The reaction of ethylene diamine was also similar
to 4,4′-methylene dianiline (Table 9, entry 3). Here also, the
aliphatic diamine reacted much faster than aromatic one. All
the pyrrole derivatives were analysed by GCMS and melt-
ing point measurements. Some of them, which was more
difficult to get the product, especially electron withdrawing
anilines were also analysed by 1H NMR and 13C NMR.
The protonation step is important in this reaction mecha-
nism, DES1 has higher bronsted acidity among the three
deep eutectic solvent systems {pH=2.14 (non-aq) and 2.20
(aq), Table 4, entry 1) and exhibit a direct influence in the
reaction by providing an efficient pathway for high yield. In
addition, lowest viscosity of DES 1 (52.40 mPa s, Table 3,
entry 1) also makes a better condition by providing an effi-
cient reaction medium leads to higher yield for DES 1 com-
pared with DES 2 and DES 3.
A comparative study was also performed with the previ-
ous reports, there have been only two reports based on the
preparation of pyrroles through Paal Knorr reaction using
deep eutectic solvents. In 2013, Handy et al. first reported
the preparation of pyrroles using choline chloride-urea deep
eutectic solvents [45]. But this method involved higher
temperature (80 °C), bulk loading of catalyst (460 mol%),
prolonged reaction time (up to 12 h) and use of organic sol-
vent for product separation (DCM). Later in 2017, Tran and
co-workers reported the pyrrole synthesis using [Choline
chloride][ZnCl2]3 DES as effective catalyst under solvent
free sonication [27], but the DES preparation required higher
temperature (100 °C). Compared with this, the current work
presents the preparation of three new green deep eutectic
solvents by heating at 40–60 °C for 10–15 min. Moreover,
detailed studies on the physicochemical properties of the
newly developed DESs like phase behaviour (Eutectic tem-
perature and Eutecic point), DSC analysis, density, viscosity,
thermal stability and solubility properties have been carried
out. Also for the first time, acidity of DESs was determined
by FTIR study (using pyridine as probe (Py-IR)) and pH
measurement (using pH meter). All these explain the new
development of the current work.
2.9 Mechanism of the Formation of Pyrroles
Different types of mechanisms were reported in the litera-
ture for the formation of pyrrole from primary amine and
2,5-hexanedione. All the three DESs are common with
bronsted acidity and have given products with different
yields. Bronsted acidity may be the functioning factor. Veisi
reported a mechanism using silica sulphuric acid as the cata-
lyst [43]. Accordingly, a plausible mechanism is proposed
based on bronsted acidic condition for the DES catalysed
Paal–Knorr reaction using aniline with 2,5-hexanedione and
is given in Scheme 1. Initially, DES interacts with the oxy-
gen atom of carbonyl group of the 2,5-hexanedione to form
the hydrogen bonded activated complex, hydrogens may be
provided by the hydrogen bond donor in the DES mixture.
Attack of amino group of aniline with this activated car-
bonyl complex forms an adduct. Nucleophilic attack of the
NH group of this adduct on the second activated carbonyl
Comparative study was also extended with previously
reported catalysts other than DES by considering the
1 3

A New Green and Efficient Brønsted: Lewis Acidic DES for Pyrrole Synthesis
Table 6 Catalytic activity of DES at RT
NH2
O
O
DES
RT
N
Entry
catalyst
(mmol)
Solvent used
Time
(min)
Yield (%)
(g)
1
-
-
-
60
Trace
DES 1
2
0.311
0.622
0.933
0.622
0.622
0.622
0.622
0.622
0.622
0.622
0.5
1
-
30
30
30
30
30
30
30
30
10
5
80
93
93
90
92
88
85
92
93
93
3
-
-
4
1.5
1
5
MeOH
EtOH
CH3CN
DCM
Hexane
-
6
7
1
1
8
1
9
1
10
1
11
1
-
DES 2
12
0.446
1
-
5
5
70
65
DES 3
13
0.506
1
-
Reaction conditions: aniline (1 mmol), 2,5-hexanedione (1 mmol), DES 1 (1 mmol), RT
reaction of 2,5-hexanedione with aniline as a representative
example (Table 10). The present catalyst has a vital benefit
of yield, reusability, easy preparation method and reaction
condition over the previously reported ones (Table 10).
reagents for subsequent runs using the same procedure given in
the Sect. 4. It was found that the reusability of the catalyst was
achieved up to 4 runs, without significant loss in the catalytic
activity (Table 11).
2.10 Recyclability of the Catalyst
Recyclability study of the Catalyst was also investigated by
considering the reaction of 2,5-hexanedione with aniline as
1 3

M. Shaibuna et al.
Table 7 Reaction of 2,5-hexanedione with alkyl, cycloalkyl, and aromatic amines
Amine (1mmol)
Entry
Product
Time Yield
(min) (%)
5
98
98
95
93
95
1
N
NH2
5
N
2
3
NH2
NH2
10
5
N
NH2
NH2
4
5
N
5
N
Reaction conditions: amine (1 mmol), 2,5-hexanedione (1 mmol), DES 1 (1 mmol), RT
temperature range of −90 to 30 °C at a heating rate of 5 °C
per minute. The density was measured using pycnometer (or
specific gravity bottle) and Viscosity measurement was per-
formed using Ostwald viscometer at room temperature with
respect to water. To obtain the thermal stability of the DES,
TG/DTG analysis was performed on Perkin Elmer Pyris
Diamond 6 thermogravimetric/differential thermal analyzer
by heating the sample at a rate of 10 °C/min from 40 to
730 °C under N2. The nature of acidity of three DESs were
determined by FTIR spectroscopy using pyridine as probe
(py–IR), The freshly prepared sample was mixed with pyri-
dine in a volume ratio of 2:1, the complex formed was ana-
lysed using FTIR spectroscopy. FTIR spectrum was recorded
using JASCO FTIR 400 Spectrometer as KBr pellets in the
range 400–4000 cm−1. pH measurements were conducted
using ELICO pH meter in aqueous and non-aqueous media
which was precalibrated with buffer solutions of pH 4.0 and
7.0. TLC was done on silica coated alumina plates (Merck,
60F254). GC analysis was carried out on a 1200 L single
3 Conclusion
The present manuscript has outlined the systematic study
of the synthesis of three new Type IV-DESs, their phys-
icochemical properties like phase behaviour, density, vis-
cosity, thermal stability, acidity and solubility properties.
Viscosity and acidity measured by the simplified method
correlated with the activity of the catalyst. Among the three
DESs, DES 1 had lower density, viscosity and higher ther-
mal stability, acidity (Lewis and Brønsted), which was found
to be an excellent catalyst for Paal–Knorr reaction at room
temperature without organic solvents. Simple, environmen-
tally benign and organic solvent free condition makes this
an important method for the preparation of pyrroles. Reus-
ability of the catalyst was also achieved up to 4 runs, without
significant loss in the catalytic activity.
4 Experimental
Quadruple, Varian Gas Chromatograph model. 1H and 13
C
NMR Spectra were recorded on Bruker 400 MHz instrument
with TMS as internal standard in CDCl3 (SAIF, CUSAT).
4.1 Materials and Methods
ZrOCl2·8H2O, urea, ethylene glycol, glycerol, pyridine,
2,5-hexandione and various amines were purchased from
Aldrich and Merck and were used without further purifi-
cation. Freezing point and glass transition temperature
were measured using Mettler Toledo DSC 822e with a
4.2 Preparation of ZrOCl2·8H2O based DESs
DES was synthesized by mixing metal salt hydrate
(ZrOCl2·8H2O) with different HBDs at various molar
1 3

A New Green and Efficient Brønsted: Lewis Acidic DES for Pyrrole Synthesis
Table 8 Reaction of 2,5-hexanedione with substituted anilines and 2-aminopyridines
Entry
Amine (1mmole)
Product
Time (min)
Yield (%)
O
NH2
1
2
5
95
N
O
NH2
10
92*
N
3
4
5
10
30
95
N
NH2
NH2
N
85*
HOOC
HOOC
N
NH2
15
30
90
91
Cl
Cl
O2N
NH2
NH2
O2N
N
N
6
7
O2N
O2N
30
10
88
94
OH
OH
NH2
8
9
N
15
15
92
88
NH2
N
N
N
N
NH2
10
Reaction conditions: amine (1 mmol), 2,5-hexanedione (1 mmol), DES 1 (1 mmol), RT
aSeparated by column chromatography
ratios. Urea, ethylene glycol and glycerol were chosen as
HBDs. The two components were stirred at 40–60 °C for
10–15 min at different ratios until a clear, homogenous
liquid was formed. This was subsequently cooled to room
temperature and was kept for observation across a period
of 15 days in a desiccator as their sensitivity to moisture
might affect their physicochemical properties.
1 3

M. Shaibuna et al.
Table 9 Reaction of 2,5-hexanedione with diamines
Entry
Amine (1mmol)
Product
Time
(min)
Yield
(%)
NH2
NH2
N
15
95
NH2
1
(a & b)
N
NH2
10
93*
a)
2
H2N
NH2
N
N
b)
10
5
95
NH2
N
97*
a)
b)
3
H2N
NH2
N
N
5
98
Reaction conditions: diamine (1 mmol), 2,5-hexanedione (a = 1 mmol, b = 2 mmol), DES 1 (1 mmol), RT
aSeparated by column chromatography
was also investigated in the presence of various amines
and the corresponding yield was noted.
4.3 General procedure for Paal Knorr reaction
A mixture of 2,5-hexanedione (1 mmol), amine (1 mmol),
and DES (1 mmol), as catalyst/solvent was stirred in a
RB flask at room temperature for 5–30 min. Reaction was
monitored using TLC. After completion of the reaction,
appropriate amount of distilled water was added. The resi-
due was filtered. The reaction profile was very clean and
no by-products were formed. The product was analyzed by
TLC, GCMS, 1H NMR, 13C NMR and melting point meas-
urements (Supporting Information File 1). The reaction
4.4 Recycling of DES1
To recover the ZrOCl2·8H2O–Urea deep eutectic solvent
(DES 1), minimum amount of ethyl acetate was added to
the filtrate (containing water and excess reactants) after
completion of the reaction. The DES 1 present in the water
layer was separated from the organic layer which may con-
tain excess reactants. Water was evaporated under vaccum
1 3

A New Green and Efficient Brønsted: Lewis Acidic DES for Pyrrole Synthesis
Scheme 1 Plausible mechanism
H
H
H
H
of the formation of pyrroles
N
O
DES
2H
2O
O
H
H
H
H
DES
HO
OH2
O
O
N
H
DES
NH2
H
H
OH
O
H
..
H
NH2
O
H
O
..
DES
N
H
H
H
H
H
DES
H
Table 10 Comparison with
Entry Catalyst
Solvent Time/temp (°C) Yield (%)/[Ref] Reusability
previous reports
1
2
3
4
5
6
7
8
Ceric ammonium nitrate (CAN)
BiCl3/SiO2
Zirconium sulfophenyl-phosphonate
PS/GaCl3
Montmorillonite KSF
[Bmim]I ionic liquid
Vitamin B1
DES (urea (glycerol)-choline chloride)
Sc(OTf)3
CoCl2
Bismuth nitrate
(c-Fe2O3@SiO2-OSO3H)
DES1 (present work)
MeOH 15 min/RT
Hexane 1 h/RT
95 [31]
98 [34]
88 [35]
92 [36]
96 [37]
96 [40]
90 [42]
87 [45]
93 [47]
92 [48]
96 [50]
90 [51]
93
–
6 runs
–
5 runs
–
3 runs
–
4 runs
–
–
2 h/60 °C
CH3CN 20 min/reflux
DCM
–
10 h/RT
3 h/RT
Ethanol 1 h/RT
–
–
–
24 h/80 °C
9
20 min/30 °C
30 min/RT
10 h/RT
3 h/60 °C
5 min/RT
10
11
12
13
DCM
–
–
5 runs
4 runs
Table 11 Recyclability of the
at 60 °C followed by vacuum oven at 60–70 °C and reused
for four consecutive runs.
No. of cycles
Yield (%)
catalyst
1
2
3
4
93
93
91
89
Acknowledgements The authors thank SAIF STIC, CUSAT for vari-
ous analysis (TGA, DSC, 1H NMR & 13C NMR) and Cochin University
of Science and Technology for financial support.
1 3

M. Shaibuna et al.
36. Rahmatpour A (2012) J Organomet Chem 712:15–19
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1 3