Glucose:urea:NH4Cl low melting mixture for the synthesis of symmetric azines

Article abstract of DOI:10.1080/00397911.2019.1657151

Alternate reaction media have become very important due to the problems created by the highly volatile nature of the solvents. The deep eutectic mixture is a kind of an alternate reaction medium which has emerged in recent years. Low melting mixtures were introduced by making the deep eutectic mixture more cost-effective and renewable by introducing carbohydrates into it. The properties of low melting mixtures include easiness to prepare, usage of low-cost components, biodegradability, solubility in water, easy separation from organic compounds, etc. The low melting mixtures such as glucose:urea:NH₄Cl, glucose:ChCl, glucose:urea:ChCl, glycerol:urea:NH₄Cl, and ethylene glycol:urea:NH₄Cl were used in different ratios for the reactions. The properties such as viscosity, density, acidity, glass transition temperature, and thermal stability were studied. An unusual method for the synthesis of symmetrical azines is introduced wherein benzaldehyde and hydroxylamine are reacted in the presence of glucose:urea:NH₄Cl. The method of synthesis needs only less reaction time, temperature and the product was easily separated. The products were confirmed using GC-MS and NMR techniques. The recyclability of glucose:urea:NH₄Cl was studied.

Full text of DOI:10.1080/00397911.2019.1657151

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Glucose:urea:NH4Cl low melting mixture for the
synthesis of symmetric azines
Letcy V. Theresa, M. Shaibuna & K. Sreekumar
To cite this article: Letcy V. Theresa, M. Shaibuna & K. Sreekumar (2019): Glucose:urea:NH4Cl
low melting mixture for the synthesis of symmetric azines, Synthetic Communications, DOI:
10.1080/00397911.2019.1657151
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https://doi.org/10.1080/00397911.2019.1657151
Glucose:urea:NH4Cl low melting mixture for the synthesis
of symmetric azines
Letcy V. Theresa, M. Shaibuna, and K. Sreekumar
Department of Applied Chemistry, Cochin University of Science and Technology, Cochin, India
ABSTRACT
ARTICLE HISTORY
Received 2 July 2019
Alternate reaction media have become very important due to the
problems created by the highly volatile nature of the solvents. The
deep eutectic mixture is a kind of an alternate reaction medium
which has emerged in recent years. Low melting mixtures were
introduced by making the deep eutectic mixture more cost-effective
and renewable by introducing carbohydrates into it. The properties
of low melting mixtures include easiness to prepare, usage
of low-cost components, biodegradability, solubility in water,
easy separation from organic compounds, etc. The low melting mix-
tures such as glucose:urea:NH4Cl, glucose:ChCl, glucose:urea:ChCl,
glycerol:urea:NH4Cl, and ethylene glycol:urea:NH4Cl were used in dif-
ferent ratios for the reactions. The properties such as viscosity, dens-
ity, acidity, glass transition temperature, and thermal stability were
studied. An unusual method for the synthesis of symmetrical azines
is introduced wherein benzaldehyde and hydroxylamine are reacted
in the presence of glucose:urea:NH4Cl. The method of synthesis
needs only less reaction time, temperature and the product was eas-
ily separated. The products were confirmed using GC-MS and NMR
techniques. The recyclability of glucose:urea:NH4Cl was studied.
KEYWORDS
Catalysis; deep eutectic
mixtures; green chemistry;
low melting mixtures;
symmetric azines
GRAPHICAL ABSTRACT
O
H
NH2OH.HCl
R
R
N
N
60 oC, 5 min
R
Low melting mixture
Introduction
Most of the solvents used in organic reactions are highly volatile in nature. A solvent
loss to the environment leads to human and eco-toxicity issues, process safety hazards,
CONTACT K. Sreekumar
kskpolymer.cusat@gmail.com
Department of Applied Chemistry, Cochin University of
Science and Technology, Cochin University Road, Cochin 682022, Kerala, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
L. V. THERESA ET AL.
and waste management issues. This paved the way for studies on alternate reaction
media. Many alternate media for reactions were proposed such as solvent-free
method,[1] supercritical CO2,[2] water,[3] polyethylene glycol,[4] perfluorinated solvents,[5]
ionic liquids,[6] deep eutectic solvents (DES)[7] and low melting mixtures.[8] In recent
years, deep eutectic solvents have become attractive due to their interesting physico-
chemical properties,[9] low cost of components, easiness to prepare, low inflammability,
low toxicity,[10] biorenewability and biodegradability.[11] Environment-friendly deep
eutectic solvents made of ChCl-malonic acid were used effectively for the synthesis of
functionalized pyrroles.[12] ChCl-Urea based deep eutectic solvent was used as a green
solvent for the synthesis of spiro-oxindole dihydropyrimidines using supported molyb-
denum graphene oxide/Fe3O4.[13] Recently ChCl-lactic acid deep eutectic solvent was
introduced for the synthesis of spiro[indoline-3,40-pyrazolo[3,4-b]pyridines] through
three-component reactions of pyrazol-5-amine, isatin, and enolizable C–H activated
compound.[14] Deep eutectic solvent based on L-proline and oxalic acid was demon-
strated as an efficient catalyst for the synthesis of 4,7-dihydropyrazolo[3,4-b]pyridine-5-
carbonitrile derivatives.[15] It was used as a catalyst and solvent for one-pot synthesis of
13-aryl-13H-benzo[g]benzothiazolo[2,3-b]quinazoline-5,14-diones.[16] Choline chloride
(ChCl)/glycerol as a green solvent under microwave irradiation was used effectively for
the synthesis of 3,6-di(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile deriva-
tives.[17] Since carbohydrates are the most important and widespread renewable
compound on earth, it was used to prepare deep eutectic mixtures.[18] This gave a cost-
effective and renewable low melting mixture.
Azines have multiple applications which include its use as antimicrobial drugs,[19]
antitumor,[20] anticonvulsant agents,[21] antioxidant,[22] pigments and dyes,[23] liquid
crystals.[24] Azines are used for the purification, characterization, and isolation[25] of
carbonyl compounds.[26] Azines showed their application as conducting polymers (poly-
azine)[27] and nonlinear optical materials.[28] The established method for the production
of azines is the reaction starting from the ketone, ammonia, and hydrogen peroxide.[29]
The scheme of the reaction is given in Scheme 1.
Synthesis of azines was done using different methods. Some of them are preparation
of azines from a mixture of aldehyde or ketone,[30] hydrazine sulfate and triethyl-
amine,[31] aldehydes with potassium hexacyanoferrate (II)[32] and aldehydes with Br2/
hydrazine hydrate.[33] Condensation of aldehydes or ketones with hydrazine in ethanol
solution under reflux conditions resulted in the formation of symmetrical azines.[34]
Azines were also synthesized using hydrazine and semicarbazone at high tempera-
tures.[35] One of the recent methods developed was the synthesis of azines using iodo-
benzene acetate and aldehyde.[36] These reactions have many drawbacks, like, the use of
volatile organic solvents, longer reaction time, use of toxic reagents and catalysts. One-
pot synthesis of symmetric azines using aromatic aldehydes and hydroxylamine hydro-
chloride in the presence of low melting mixtures is presented here. Benzaldehyde and
H2N
H
N
N
O
NH
NH3
NH3
H2O2
N
N
O
Scheme 1. Usual method of preparation of azines.

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3
O
O
ChCl/Urea
ChCl/ZnCl2
NH2OH.HCl
Ph CN
Ph
NH2
100 O
C
Ph
H
M.W irradiation
Scheme 2. Reaction of benzaldehyde and hydroxylamine hydrochloride with two different deep
eutectic solvents.
Table 1. Densities of low melting mixtures.
Melt
Ratio
Density(g/cm3)
Glucose:Urea:NH4Cl
Glucose:Urea:ChCl
Glycerol:Urea:NH4Cl
Ethylene glycol:Urea:ChCl
Glucose:ChCl
3:7:1
1:2:1
5:4:1
5:4:1
4:6
1.37
1.34
1.32
1.24
1.36
hydroxylamine hydrochloride together gave different results in two different deep eutec-
tic mixtures as shown in Scheme 2
The reaction of aldehydes and hydroxylamine hydrochloride using ChCl/urea as cata-
lyst gave nitriles.[37] When the reaction was performed in ChCl/ZnCl2 at 100 ꢀC, the
corresponding primary amides were obtained in good yields.[38] This result has made us
examine the product obtained in the presence of a sugar-based low melting mixture,
which was symmetric azines.
Results and discussion
Low melting mixtures were prepared at different ratios, among which the
glucose:urea:ChCl (1:2:1), glucose:urea:NH4Cl (3:7:1), glycerol:urea:NH4Cl (5:4:1), ethylene
glycol:Urea:NH4Cl (5:4:1), glucose:ChCl (4:6) gave clear melts at temperatures below 80 ꢀC.
Physical properties of Glucose:Urea:NH4Cl melt
Density
The density of the mixtures was found using relative density bottle. The mass of the mix-
ture was found out using weighing balance and calculated using the following formula:
Density ¼ mass=unit volume
(1)
The densities of the low melting mixtures are given in Table 1.
Viscosity
The viscosity of the mixture was found using Ostwald viscometer. The viscosity was cal-
culated based on Poiseuille’s law. According to this law, the rate of flow of a liquid
through a capillary tube having viscosity coefficient g can be expressed as follows:
pr4tp
g ¼
(2)
8Vl

4
L. V. THERESA ET AL.
Table 2. Viscosities of various melts.
Melt
Ratio
Viscosity (cP)
116
Glucose:Urea:NH4Cl
Glucose:Urea:ChCl
Glycerol:Urea:NH4Cl
Ethylene glycol:Urea:ChCl
Glucose:ChCl
3:7:1
1:2:1
5:4:1
5:4:1
4:6
32
40
Figure 1. DSC plot of Glucose:Urea:NH4Cl mixture.
Usually, the dynamic viscosities g for DES are reported in centipoise (cP) which corre-
sponds to milli Pascal-second (mPa s) in SI units. The viscosity of the mixtures was found
to be high compared to other solvents. The viscosity of the mixtures decreased with the
increase in temperature. The extensive hydrogen bond network between the components
may be responsible for the high viscosities at low temperatures and for the strong tem-
perature dependence. The viscosity of the mixtures seemed to be high compared to other
solvents. Due to the highly viscous nature of the glucose:urea:ChCl and glucose:ChCl the
viscosity measurement using Ostwald viscometer was very difficult. Comparing to other
mixtures, ethylene glycol:urea:ChCl, and glycerol:urea:NH4Cl are less viscous. The viscos-
ities of the prepared melts is given in Table 2.
Glass transition temperature
The glass transition temperature was determined using differential scanning calorimetry.
The model used for the measurement was Mettler Toledo DSC 822e (STIC, CUSAT).
The measurements were performed with a heating rate of 10 ꢀC minꢁ1 from ꢁ50 to
250 ꢀC. Figure 1 shows the DSC plot of glucose:urea:NH4Cl mixture. The glass transi-
tion was from 108.72 to 166.17 ꢀC.
Thermal stability
The thermal stability and decomposition temperatures were determined with a thermogravi-
metric analyzer in the temperature range 40–730 ꢀC at a heating rate of 20ꢀC/min. The

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5
Figure 2. TG and DTG plot for Glucose:Urea:NH4Cl mixture.
Table 3. pH of various melts prepared.
Melt
Ratio
Acidity (pH)
Glucose:Urea:NH4Cl
Glucose:Urea:ChCl
Glycerol:Urea:NH4Cl
Ethylene glycol:Urea:ChCl
Glucose:ChCl
3:7:1
1:2:1
5:4:1
5:4:1
4:6
6.20
6.34
7.46
5.66
4.81
model of the instrument used was Perkin Elmer Diamond 6. Figure 2 shows the TGA plot
of glucose:urea:NH4Cl mixture. From the TGA and DTG plots, it was found that the mix-
ture got decomposed after 150 ꢀC.
Acidity
The pH of the low melting mixtures was found out using pH meter. The low melting
mixtures were found to be acidic except for glycerol:urea:NH4Cl which was found to be
slightly basic. The pH of various melts is given in Table 3.
Synthesis of symmetric azines using low melting mixtures
The low melting mixtures were used to study the reaction of Benzaldehyde with
Hydroxylamine hydrochloride. The product reported with DES was benzonitrile, but the
product obtained in the present case was symmetric azines. The reaction is given in
Scheme 3.

6
L. V. THERESA ET AL.
Scheme 3. Synthesis of azines.
Table 4. Optimization of solvent/catalyst.
Sl.No.
Solvent/Catalyst
Time (min)
Yield (%)
1
2
3
4
5
6
7
Glucose:Urea:ChCl (1:2:1)
Glucose:Urea:NH4Cl (3:7:1)
Glycerol:Urea:NH4Cl (5:4:1)
Ethylene glycol:Urea:NH4Cl (5:4:1)
Glucose:ChCl (4:6)
Water
Solvent/Catalyst free
15
5
12
60
10
120
120
72
92
80
traces
80
No reaction
No reaction
Reaction condition: Benzaldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol), at 60ꢀC.
Table 5. Optimization of temperature.
Entry
Temperature (ꢀC)
Yield (%)
1
2
3
4
5
30
50
60
70
80
20
75
92
92
92
Reaction conditions: Benzaldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol) and
Glucose:Urea:NH4Cl (0.5 mmol) for 5 min.
1
The product was confirmed using GC/MS and H NMR spectroscopy. The reaction
was optimized using various low melting mixtures prepared in the laboratory. The opti-
mization of the solvent/catalyst is given in Table 4.
It was found that glucose:urea:NH4Cl (3:7:1) gave more yield in short reaction time.
Water was not a suitable medium for the reaction to occur. The yield obtained for other
mixtures were low. Glucose:urea:ChCl (1:2:1) gave azines very fast with low tempera-
ture, but the yield was low. By optimization of the solvent/catalyst, it was found that
glucose:urea:NH4Cl (3:7:1) low melting mixture could be used as a reaction medium
and catalyst for the synthesis of symmetric azines.
The temperature and amount of sugar melt were optimized. The reaction was con-
ducted with benzaldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol) and
glucose:urea:NH4Cl (0.5 mmol). The optimization of temperature is given in Table 5.
The reaction was performed from room temperature to 80 ꢀC. A good yield was
obtained at 60 ꢀC and many variations were not seen even after increasing the tempera-
ture. Simple mixing of reactants was also performed using mortar and pestle. But the
yield was noted to be very less. So the reaction temperature was optimized with 60 ꢀC.
The reaction was optimized with the change in the amount of solvent using benzalde-
hyde (1 mmol) and hydroxylamine hydrochloride (1 mmol) at 60 ꢀC. The results are
given in Table 6.
It was found that with a small amount of the solvent (0.25 mmol) the reaction gave a
very good yield. We have explored the applicability of the solvent using various

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7
Table 6. Optimization of amount of solvent.
Entry
Amount of solvent (mmol)
Yield (%)
1
2
3
4
5
0
0.10
0.25
0.50
1.00
79
92
92
92
Reaction conditions: Benzaldehyde (1 mmol) and hydroxylamine hydrochloride (1 mmol) at
60ꢀC for 5 min.
derivatives of aromatic aldehydes which gave symmetric aromatic azines. The summary
of the results is given in Table 7.
It was noted that the reaction with various aldehydes and hydroxylamine hydrochlor-
ide resulted in sufficiently good yield. Aldehydes having electron-donating or electron-
withdrawing groups gave good to excellent yield of products. The low melting mixture
can perform the role of the reaction medium as well as that of the catalyst. The reaction
medium and catalyst activity is due to the hydrogen bonding interactions of the low
melting mixture. The plausible mechanism for the reaction is given in Scheme 4.
Reusability of low melting mixtures
The reusability of the solvent/catalyst was examined with the synthesis of azines.
Reaction conditions used was benzaldehyde (1 mmol), hydroxylamine hydrochloride
(1 mmol), and 0.25 mmol of glucose:urea:NH4Cl mixture, at 60 ꢀC for 5 min. After com-
pletion of the reaction, ethyl acetate was added to the reaction mixture and it was
stirred for five minutes. The ethyl acetate layer was separated and the recovered
glucose:urea:NH4Cl was reused. It was found that the low melting mixture could be
reused for up to four successive cycles with a gradual decrease in the product yield
(Fig. 3).
Conclusions
The low melting mixtures prepared could be used in organic synthesis. The advantages
of low melting mixtures include less reaction time, easy workup and less hazardous
wastage. The low melting mixture prepared was used both as catalyst and solvent. A
new method for the synthesis of symmetrical azines was developed which was done in
the presence of low melting mixture. Properties of low melting mixtures satisfy green
chemistry principles.
Experimental Section
Preparation of low melting mixtures
Glucose:Urea:NH4Cl mixture
The low melting mixture was prepared using glucose, urea, and NH4Cl in various pro-
portions. A mixture of 3:7:1 ratio of glucose:urea:NH4Cl was taken. The solid mixture

8
L. V. THERESA ET AL.
Table 7. Reactions with various aldehydes.
Entry
Aldehydes
Product
Yield (%)
92
O
H
N
N
A
OCH3
O
N
N
H
B
91
93
H3CO
H3CO
NO2
O
N
N
H
C
D
E
O2N
O2N
O
OH
N
N
H
OH
90
89
OH
O
O
N
N
H
O
O
H3CO
O
H3CO
OCH3
OCH3
H
N
N
N
N
F
90
87
H3CO
OCH3
O
Cl
H
G
Cl
Cl
O
O
N
N
H
I
66
87
H
N
N
Br
H
Br
Br
Reaction conditions: Benzaldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol) and
Glucose:Urea:NH4Cl (0.25 mmol) for 5 min at 60ꢀC.

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9
Scheme 4. Plausible mechanism for the synthesis symmetric azines.
93
92
Reusability
91
90
89
88
87
86
85
84
83
Cycle 1 Cycle 2 Cycle 3 Cylce 4
Figure 3. Reusability of Glucose:Urea:NH4Cl.
was taken in a round bottom flask and heated to 80 ꢀC. It was heated until a miscible
liquid was obtained. A light brown colored liquid was obtained.
Glucose:Urea:ChCl
The low melting mixture was prepared in a round bottom flask using glucose, urea, and
choline chloride in the ratio 1:2:1. This mixture was heated in an oil bath for 1 h at a
temperature of 70 ꢀC. A light brown clear liquid was obtained.
Glycerol:Urea:NH4Cl
The low melting mixture was prepared using glycerol, urea, NH4Cl in various propor-
tions. A mixture of 5:4:1 ratio of glycerol:urea:NH4Cl was taken. The mixture was taken
in a round bottom flask and heated at 60 ꢀC. The mixture was heated until a clear
liquid was obtained.

10
L. V. THERESA ET AL.
Figure 4. Low melting mixtures prepared.
Ethylene glycol:Urea:NH4Cl
The low melting mixture was prepared using Ethylene glycol, urea, NH4Cl in various
proportions. A mixture of 5:4:1 ratio of ethylene glycol:urea:NH4Cl was taken in a
round bottom flask and heated at 60 ꢀC. The mixture was heated until a clear liquid
was obtained.
Glucose:ChCl
The low melting mixture was prepared using glucose and choline chloride in the ratio
4:6, respectively. This mixture was heated at a temperature of 60 ꢀC. A clear liquid was
obtained. The low melting mixtures prepared are shown in Figure 4
Synthesis of N,N-Dibenzylidenehydrazine (7a)
In a 50 mL round bottom flask, the reaction medium (Glucose:urea:NH4Cl, 0.25 g,
0.25 mmol) was taken. To this, a mixture of benzaldehyde (0.102 mL, 1.0 mmol) and
hydroxylamine hydrochloride (0.696 g, 1 mmol) was added. The reaction mixture was
stirred at 60 ꢀC for 5 min. The formation of the product was monitored by thin-layer
chromatography. Water was added to the mixture and the product was separated, puri-
fied and dried.
Spectroscopic data of N,N-Dibenzylidenehydrazine (7a)
1
Yellow solid (92%); Melting point (92–97)ꢀC; GC-MS: tR ¼ 22.683 min, (Mþ): 207.1; H
NMR (400 MHz, CDCl3): d (ppm) 8.69 (s, 2 H), 7.85–7.87 (m, 4H), 7.45–7.47 (m, 6H);
13C NMR (100 MHz, CDCl3): d 128.41 (CH), 128.72 (CH), 130.76 (CH), 132.31 (C)
164.80 (CH).[25]

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11
Synthesis of azine derivatives (7b–7i)
The reaction procedure was the same for N,N-Dibenzylidenehydrazine. The derivatives
were prepared using various aldehydes (1 mmol) and reacting it with hydroxylamine
hydrochloride (1 mmol) in glucose:urea:NH4Cl (0.25 mmol).
1
Full experimental details, spectral data of the products, GC-MS, H NMR, 13C NMR
of selected compounds can be found through Supplementary Content section of this
article’s Web page
Funding
The authors thank Cochin University of Science and Technology for the financial support
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