Preparation, characterization and utilization of a novel dicationic molten salt as catalyst for the synthesis of bis(6-amino-1,3-dimethyluracil-5-yl)methanes

Article abstract of DOI:10.1007/s11164-019-04036-3

Abstract: In this research, firstly, preparation and characterization of a novel dicationic molten salt, namely N,N,N′,N′-tetramethylethylenediaminium bisulfate ([TMEDA][HSO₄]₂), by ¹H NMR, ¹³C NMR, FT-IR, mass,

Full text of DOI:10.1007/s11164-019-04036-3

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-04036-3
Preparation, characterization and utilization of a novel
dicationic molten salt as catalyst for the synthesis
of bis(6‑amino‑1,3‑dimethyluracil‑5‑yl)methanes
Abdolkarim Zare1 · Aysoda Ghobadpoor1 · Tayebeh Safdari1
Received: 19 August 2019 / Accepted: 28 October 2019
© Springer Nature B.V. 2019
Abstract
In this research, frstly, preparation and characterization of a novel dicationic molten
salt, namely N,N,N′,N′-tetramethylethylenediaminium bisulfate ([TMEDA][HSO4]2),
1
by H NMR, 13C NMR, FT-IR, mass, thermogravimetry, derivative thermogravim-
etry and diferential thermal analysis data have been reported. Thereafter, utilization
of [TMEDA][HSO4]2 as a recyclable catalyst for the solvent-free synthesis of bis(6-
amino-1,3-dimethyluracil-5-yl)methanes via the reaction of 6-amino-1,3-dimethylu-
racil (2 eq.) and arylaldehydes (1 eq.) has been described.
Graphic abstract
O
H2N
NH2 Ar
Ar
H
CH3
O
H3C
O
O
O
N
N
+
H3C
O
CH3
O
[TMEDA][HSO4]2
(25 mol%)
N
N
N
N
O
O
Solvent-free
120 °C
CH3
Time: 15-30 min
Yield: 81-97%
H3C
N
N
NH2 H2N
H3C
CH3
H3C
H
N
CH3
N
[HSO4]2
[TMEDA][HSO4]2 =
H
H3C
CH3
Keywords Dicationic molten salt · N,N,N′,N′-Tetramethylethylenediaminium
bisulfate ([TMEDA][HSO4]2) · Bis(6-amino-1,3-dimethyluracil-5-yl)methane ·
6-Amino-1,3-dimethyluracil · Solvent free
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-019-04036-3) contains supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
Vol.:(0123456789)
1 3

A. Zare et al.
Introduction
Ionic liquids are defned as salts containing organic cations and organic/inorganic
anions, which melt below 100 °C; and molten salts (MSs) form from organic/
inorganic cations and anions and melt above 100 °C [1]. MSs are of great impor-
tance in chemistry and industry; for example, some applications of them include:
(1) usage as catalyst [1–6] and reaction media [7–12] in chemical reactions, (2)
application in electrolysis [13], (3) utilization as heat transfer and thermal energy
storage [14, 15], (4) usage in separation [16] and (5) application as electrolyte in
rechargeable zinc–air battery [17].
The advantages of performing reactions in solvent-free conditions in com-
parison with carrying out them in solvents have been mentioned in the literature
[18–21].
Uracil is one of the main structural units of nucleobases and RNA [22] and
has essential roles in human life [23]. Moreover, numerous medical and biologi-
cal activities have been reported for uracil derivatives, including antiviral [24],
anticancer [25], adenosine receptor antagonist [26], antifungal [27], antibacte-
rial [27], insecticidal [28], acaricidal [28], thymidylate synthase inhibitor [29]
and antiproliferative [30] properties. 6-Amino-1,3-dimethyluracil and its fused
derivatives are useful scafolds for the production of several biologically active
compounds, such as theophylline, theobromine, penciclovir and cafeine [31–34].
Bis(6-amino-1,3-dimethyluracil-5-yl)methanes could be prepared via the reaction
of 6-amino-1,3-dimethyluracil (2 eq.) and aldehydes (1 eq.); some catalysts have
been reported for this transformation [35–41]. It is noteworthy that there are a
few reports on this reaction in the literature; hence, introducing new catalysts to
perform this transformation is of importance.
Herein, we have synthesized a novel dicationic molten salt, namely N,N,N′,N′-
tetramethylethylenediaminium bisulfate ([TMEDA][HSO4]2), and characterized it
by 1H NMR, 13C NMR, FT-IR, mass, thermogravimetry (TG), derivative thermo-
gravimetry (DTG) and diferential thermal analysis (DTA) data. Afterward, we
have utilized [TMEDA][HSO4]2 as a recyclable catalyst to carry out the reaction
of 6-amino-1,3-dimethyluracil (2 eq.) and aldehydes (1 eq.) under solvent-free
conditions to aford bis(6-amino-1,3-dimethyluracil-5-yl)methanes.
Experimental
Materials and instruments
The used chemicals and solvents were bought from Merck or Fluka Chemical
Companies. The known products were identifed by comparing their melting
points/spectroscopic data with those mentioned in the literature. Thin-layer chro-
matography (TLC) using silica gel SIL G/UV 254 plates was applied to observe
the reactions’ progress. The melting points were measured on a Büchi B-545
1 3

Preparation, characterization and utilization of a novel…
device. A Shimadzu IR-60 apparatus was used for recording FT-IR. The 1H NMR
(500 MHz) and 13C NMR (125 MHz) were run on a Bruker Avance DPX, FT-
NMR spectrometers. Mass spectra were recorded by Shimadzu GC-MS-QP 1100
EX device. Thermal gravimetric analysis (TGA) was achieved using a Bahr STA
504 apparatus (Germany), at 50–500 °C, with a temperature increase rate of
10 °C/min in an argon atmosphere.
Preparation of [TMEDA][HSO4]2
Sulfuric acid (0.98 g, 10 mmol) was added dropwise to N,N,N′,N′-
tetramethylethylenediamine (0.58 g, 5 mmol) at room temperature, and the resulting
mixture was stirred for 1 h at room temperature to give [TMEDA][HSO4]2 as pale
yellow solid; m.p. 119–121 °C.
General procedure for the synthesis of bis(6‑amino‑1,3‑dimethyluracil‑5‑yl)
methanes
A mixture of 6-amino-1,3-dimethyluracil (2 mmol, 0.310 g), aldehyde (1 mmol)
and [TMEDA][HSO4]2 (0.25 mmol, 0.078 g) was stirred by a small rod at 120 °C.
Observation of the reaction progress was achieved by TLC; after that, the reactants
were consumed, the reaction mixture was cooled to room temperature, and the
resulting solid was purifed by recrystallization from ethanol (95%).
Note Spectral data and original spectrums of [TMEDA][HSO4]2 and the synthe-
sized bis(6-amino-1,3-dimethyluracil-5-yl)methanes have been given in the supple-
mentary material.
Results and discussion
The catalyst characterization
N,N,N′,N′-Tetramethylethylenediaminium bisulfate ([TMEDA][HSO4]2) was syn-
thesized via the reaction of N,N,N′,N′-tetramethylethylenediamine and sulfuric acid
(Scheme 1). The molten salt was characterized by analyzing its 1H NMR, 13C NMR,
FT-IR, mass, TG, DTG and DTA data.
In the 1H NMR spectrum of [TMEDA][HSO4]2 (Figure S1), the two sin-
glet peaks observed at 2.78 and 3.41 ppm are related to the CH3 and CH2 groups,
CH3
N
H3C
CH3
H
Neat, r.t.
N
H3C
[HSO4]2
+
2H2SO4
N
N
CH3
H
H3C
CH3
CH3
Scheme 1 Preparation of [TMEDA][HSO4]2
1 3

A. Zare et al.
Table 1 FT-IR data of
Peak (cm−1
)
Corresponded bond or functional group
[TMEDA][HSO4]2
1056
Bending of S–OH
1194
1479
Symmetric bending of S–O
Bending of C–H
2938
Stretching of C–H
3200–3700
OH groups of two bisulfates and two
NH+ of the cation
Table 2 Efect of the catalyst
amount and temperature on the
model reaction (Scheme 2)
Entry Mol% of
[TMEDA]
Temp. (°C) Time (min) Yielda (%)
[HSO4]2
1
2
3
4
5
20
25
27
25
25
120
120
120
110
125
20
20
20
30
20
87
95
95
81
95
aIsolated yield
correspondingly. The two broad peaks at 6.42 and 9.45 ppm are corresponded to NH
and bisulfate, respectively.
In the 13C NMR spectrum (Figure S2), the peaks related to CH3 and CH2 carbons
of the molten salt appeared at 43.3 and 50.9 ppm, respectively. The peaks observed
at 38.2–39.2 ppm are corresponded to the carbons of DMSO-d6 (the solvent).
The peaks corresponded to all expected bonds and functional groups of the cata-
lyst were observed in the FT-IR spectrum (Figure S3); the obtained data are sum-
marized in Table 1.
The peaks related to molecular mass (312) and [M++1] (313) of [TMEDA]
[HSO4]2 were seen in the mass spectrum (Figure S4).
The TG, DTG and DTA diagrams showed good thermal stability of the catalyst
(Figure S5); one main weight loss was observed at about 250–320 °C.
Examining catalytic activity of [TMEDA][HSO4]2 for the synthesis
of bis(6‑amino‑1,3‑dimethyluracil‑5‑yl)methanes
In the beginning, a model reaction was designed {the condensation of 6-amino-
1,3-dimethyluracil (2 mmol) and 4-chlorobenzaldehyde (1 mmol)}, and infu-
ence of the catalyst amount and temperature on the reaction were investigated;
the results are exhibited in Table 2. According to the results, the optimal cata-
lyst amount and temperature were 25 mol% and 120 °C, respectively (Table 2,
entry 2). The lower catalyst amount and temperature aforded the product in
lower yields (Table 2, entries 1 and 4). Furthermore, increasing the amount of
1 3

Preparation, characterization and utilization of a novel…
Cl
O
CHO
Cl
H2N
NH2
H3C
O
CH3
O
H3C
O
N
[TMEDA][HSO4]2
Solvent-free
N
N
2
+
N
NH2
N
N
O
O
CH3
CH3
H3C
Scheme 2 Condensation of 6-amino-1,3-dimethyluracil and 4-chlorobenzaldehyde
[TMEDA][HSO4]2 up to 27 mol% or increment of the temperature up to 125 °C
did not improve the results (Table 2, entries 3 and 5).
To evaluate the scope of [TMEDA][HSO4]2 for the production of bis(6-amino-
1,3-dimethyluracil-5-yl)methanes, 6-amino-1,3-dimethyluracil was reacted with
benzaldehyde, and also arylaldehydes bearing nitro, chloro, fuoro, methoxy and
methyl substituents under the optimal conditions; the results are displayed in
Table 3. High yields and relatively short reaction times were observed for the
synthesis of all products. Additionally, arylaldehydes bearing two substituents
Table 3 Solventless preparation of bis(6-amino-1,3-dimethyluracil-5-yl)methanes catalyzed by
[TMEDA][HSO4]2
H2N
O
NH2 Ar
CH3
O
H3C
O
O
H3C
O
N
N
[TMEDA][HSO4]2 (25 mol%)
Solvent-free, 120 °C
N
2
+
Ar
H
N
N
N
NH2
O
O
CH3
H3C
CH3
Compd. no.
Ar
Time (min)
Yielda (%)
M.p. (°C) [lit.]
1
C6H5
20
20
20
30
15
20
20
20
30
20
30
92
91
97
92
94
95
81
96
89
93
92
294–296 (296–299) [37]
259–261 (261–263) [36]
226–228 (224–225) [37]
281–283 (282–283) [36]
262–264 (259–260) [36]
267–269 (268–270) [37]
283–284 (>300) [35]
261–263 (263–265) [36]
274–276 (273–275) [37]
270–271 (new)
2
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
4-FC6H4
4-CH3OC6H4
2,5-(CH3O)2C6H3
4-CH3C6H4
3
4
5
6
7
8
9
10
11
272–274 (274–276) [36]
aIsolated yield
1 3

A. Zare et al.
Table 4 Recyclability of
Run
Time (min)
Yielda (%)
[TMEDA][HSO4]2
Fresh catalyst
20
20
20
30
95
94
91
86
First recycling
Second recycling
Third recycling
aIsolated yield
aforded good results (Table 3, compounds 7 and 10). Considering the excellent
results, the molten salt was a general catalyst for the synthesis.
Recyclability of the catalyst was checked on the reaction of 6-amino-1,3-di-
methyluracil (2 mmol) and 4-chlorobenzaldehyde (1 mmol). After completion of
the reaction, and cooling to room temperature, ethanol (95%) (2 mL) was added,
refuxed (accompanied with stirring) for 2 min, cooled to room temperature, and
fltered. (The precipitate is the pure product.) The fltrate solvent was evaporated
under vacuum, and the residue (including the catalyst) was used to promote the
next run. The reaction residue was reused two times without signifcant loss of
catalytic activity; nevertheless, in third recycling, the catalytic activity was
slightly decreased. The recycling results are illustrated in Table 4.
[TMEDA][HSO4]2 has acidic and basic (weak) groups. (The hydrogen of
bisulfate is acidic, and the negative oxygen of it is basic.) So, it can act as a dual-
functional (acidic–basic) catalyst.
A mechanism, based on the literature [36, 37], and also dual functionality of
the molten salt, was proposed for the reaction (Scheme 3). The catalyst roles con-
sist of: (1) activation of electrophiles (by the acidic group) to accept nucleophilic
addition (steps 1 and 3), (2) helping the nucleophiles (by the basic site) for addi-
tion to the electrophiles (steps 1 and 3), and (3) assistance for removing H2O by
the acidic and basic sites (step 2). The dual functionality of the catalysts bearing
bisulfate and similar anions has been mentioned in the literature [42, 43].
Conclusions
In summary, we have introduced [TMEDA][HSO4]2 as a novel molten salt cat-
alyst for the synthesis of bis(6-amino-1,3-dimethyluracil-5-yl)methanes. The
advantages of our work consist of wide scope, relatively short reaction times,
high yields, no need for column chromatography for purifying the products,
recyclability of the catalyst, simplicity, easy preparation of the catalyst and good
compliance with green chemistry protocols.
Acknowledgements We thank the Research Council of Payame Noor University for the support of this
work.
1 3

Preparation, characterization and utilization of a novel…
Me
Me
H
O
OH
O
N
S
N
CH3
N
H
Me
HSO4
O
N
H
Me
O
H
OH
O
N
N
CH3
O
CH3
O
Ar
[TMEDA][HSO4]2
Me
Ar
H2N
N
[TMEDA][HSO4]2
O
H
Step1
Ar
H
O
H
CH3
Me
H
O
O
N
HSO4
Me
N
S
H
Me
O
O
Me
Me
O
O
O
O
H
N
S
N
H
H
Me
Me
H
HSO4
O
N
O
O
CH3
O
H3C
Ar
N
[TMEDA][HSO4]2
N
Ar
_
H2O
H
N
O
N
NH
Step 2
H
CH3
CH3
HSO4
Me
O
Me
H
N
O
S
O
N
H
Me
OH
Me
H
Me
Me
HSO4
N
N
Me
OH
O
O
Me
H
S
CH3
N
O
H
H
N
O
O
H2N
NH2 Ar
N
CH3
CH3
H3C
H3C
O
N
N
N
Ar
O
Step3
O
O
N
N
NH
H
N
O
O
HSO4
Me
CH3
CH3
H3C
The product
Me
H
O
O
N
N
S
H
Me
O
O
Me
Scheme 3 Reaction mechanism
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Preparation, characterization and utilization of a novel…
Afliations
Abdolkarim Zare1 · Aysoda Ghobadpoor1 · Tayebeh Safdari1
* Abdolkarim Zare
abdolkarimzare@pnu.ac.ir; abdolkarimzare@yahoo.com
1
Department of Chemistry, Payame Noor University, PO Box 19395-3697, Tehran, Iran
1 3