Efficient synthesis, spectroscopic characterization and DFT based studies of novel 1-amide 4-sulfonamide-1,2,3-triazole derivatives

Article abstract of DOI:10.1016/j.molstruc.2019.07.032

In the present study, for the first time 1-amide 4-sulfonamide-1,2,3-triazole scaffolds were synthesized by using an azide-alkyne Huisgen cycloaddition reaction. The target products were obtained in moderate to good yields (45–75%) by using catalytic CuI and green system H₂O/EtOH. The easy availability of the inexpensive starting materials, avoiding isolation and handling of hazardous organic azides and mild reaction conditions make this method a valuable tool for generating functionalized 1,2,3-triazole derivatives. The unambiguous characterization of synthesized compounds was accomplished by using various spectroscopic techniques such as ¹H NMR, ¹³C NMR, and FT-IR. The information regarding optimized geometry, were obtained by applying DFT/B3LYP-6-31G(d) method. The electrophilicity index, ¹H and ¹³C chemical shift values, lithium and sodium ion affinities of the desired product 3b have been also calculated by the mentioned method. As a whole, the calculated results were found in close agreement to that of experimental data. The studies revealed that the compound 3b possesses good Li⁺ and Na⁺ affinity and cation π interaction plays a vital role in the complexation of 3b. For the first time, nucleus–independent chemical shift index was used to confirm the cation π interaction of 3b.

Full text of DOI:10.1016/j.molstruc.2019.07.032

Accepted Manuscript
Efficient synthesis, spectroscopic characterization and DFT based studies of novel
1-amide 4-sulfonamide-1,2,3-triazole derivatives
Sarvenaz Rouhi Bonyad, Zohreh Mirjafary, Hamid Saeidian, Morteza Rouhani
PII:
S0022-2860(19)30866-X
10.1016/j.molstruc.2019.07.032
MOLSTR 26785
DOI:
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Accepted Date:
20 April 2019
05 July 2019
Please cite this article as: Sarvenaz Rouhi Bonyad, Zohreh Mirjafary, Hamid Saeidian, Morteza
Rouhani, Efficient synthesis, spectroscopic characterization and DFT based studies of novel 1-
amide 4-sulfonamide-1,2,3-triazole derivatives, Journal of Molecular Structure (2019), doi: 10.1016
/j.molstruc.2019.07.032
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form.
Please note that during the production process errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Efficient synthesis, spectroscopic characterization and DFT based studies of
novel 1-amide 4-sulfonamide-1,2,3-triazole derivatives
Sarvenaz Rouhi Bonyad, Zohreh Mirjafary, Hamid Saeidian, Morteza Rouhani
R2
N
1.981
N
N
R2
R1HN
p-Ts
N
CuAAC
+ Li+
N
Br
+
+
NaN3
p-Ts
3
O
O
R1HN
[3b+Li]+

ACCEPTED MANUSCRIPT
Efficient synthesis, spectroscopic characterization and DFT based studies of novel 1-
amide 4-sulfonamide-1,2,3-triazole derivatives
Sarvenaz Rouhi Bonyad a, Zohreh Mirjafary *a, Hamid Saeidian b, Morteza Rouhania
a Department of Chemistry, Tehran Science and Research Branch, Islamic Azad University, Tehran, Iran
b Department of Science, Payame Noor University (PNU), PO Box: 19395-4697, Tehran, Iran
Abstract
In the present study, for the first time 1-amide 4-sulfonamide-1,2,3-triazole scaffolds were synthesized by
using an azide-alkyne Huisgen cycloaddition reaction. The target products were obtained in moderate to
good yields (45–75%) by using catalytic CuI and green system H2O/EtOH. The easy availability of the
inexpensive starting materials, avoiding isolation and handling of hazardous organic azides and mild
reaction conditions make this method a valuable tool for generating functionalized 1,2,3-triazole
derivatives. The unambiguous characterization of synthesized compounds was accomplished by using
1
various spectroscopic techniques such as H NMR, 13C NMR, and FT-IR. The information regarding
optimized geometry, were obtained by applying DFT/B3LYP-6-31G(d) method. The electrophilicity index,
1H and 13C chemical shift values, lithium and sodium ion affinities of the desired product 3b have been also
calculated by the mentioned method. As a whole, the calculated results were found in close agreement to
that of experimental data. The studies revealed that the compound 3b possesses good Li+ and Na+ affinity
and cation π interaction plays a vital role in the complexation of 3b. For the first time, nucleus–independent
chemical shift index was used to confirm the cation π interaction of 3b.
Keywords: 1,2,3-Triazole; Sulfonamide; Huisgen reaction, DFT method; Electrophilicity index; Cation
affinity.
1

ACCEPTED MANUSCRIPT
1. Introduction
Click chemistry is a phrase that nominated first time by K.B. Sharpless, to connect the small parts quickly
and efficiently for preparation of different substances in various fields such as organic synthesis, material
sciences, catalysis chemistry, drug design and bioconjugation [1-5]. In organic synthesis, 1,3-dipolar
cycloaddition has been known as the most famous reaction type in click chemistry, which was initially
introduced by Dimorth in 1902 [6], and its mechanism was reported several decades later by Huisgen in
1965, profoundly [7]. 1,2,3-triazoles were studied by Huisgen for the first time in 1960 [8]. Mainly, they
have been synthesized through a one-pot copper-catalyzed click reaction between terminal alkynes and
azides [9]. The concerted [3+2] cycloaddition offers a mild and convenient reaction conditions for synthesis
of triazole derivatives in high yields and excellent regioselectivity. Triazoles are very stable against
oxidation, reduction, hydrolysis, metabolic degradation and undesirable reactions [10-12]. From
pharmaceutical viewpoint, they can act as a possible isostere of ester, carboxylic acid and amide group.
Triazoles can be found in the chemical structure of many drugs [13]. The researchers have reported diverse
pharmaceutical activities for 1,2,3-triazoles such as anti-bacterial, anti-fungal, anti-tubercular, anti-tumor,
anti-inflammatory, anti-leishmanial, anti-trypanosomal, antiviral, antimalarial, anti-HIV, anti-diabetic,
antioxidant, and anti-allergic activities [14-24].
In continuation of our previous research on the synthesis of diversely functionalized heterocycles such as
triazole derivatives [25-35], herein, a convenient method was reported for synthesis of novel 1-amide 4-
sulfonamide-1,2,3-triazole derivatives 3 via a three-component reaction of N-propargylsulfonamides 1,
sodium azide, and α-chloroamide 2 in the presence of CuI as a catalyst (Scheme 2). Moreover, a
computational investigation has been done at B3LYP/6-31G(d) method to obtain the thermochemical
values, 1H NMR, 13C NMR data, electrophilicity index and cation affinity (Li+ and Na+) of 3b in the ground
state.
2

ACCEPTED MANUSCRIPT
R1
R1
N
O
S
Br
K2CO3
O
S
Cl
O
S
NH
pyridine
+ R1NH2
O
O
O
r.t, 2 h
Me
CH3CN, 80 °C
8 hr
Me
Me
Me
1
2R3RN
O
2R3RN
H2O/EtOH
CuI (10%) H2O/EtOH
60 °C, 10 hr
S
Cl
+
NaN3
N3
O
N
3
R1
N
O
N
N
60 °C, 1 hr
O
2
O
2R3RN
R1 = Bn, 4-OMe-Ph, -CH2Furyl, n-Bu; R2 = Ph, Bn, 3-Cl-Ph; R3 = H, Me
Scheme 1. The general method for synthesis of novel 1-amide 4- sulfonamide-1,2,3-triazoles 3.
2. Experimental
2.1. General information
All the chemicals required for the synthesis of 1-amide 4- sulfonamide-1,2,3-triazole derivatives 3 were
purchased from Sigma-Aldrich (St. Louis, MO, USA), Fluka (Neu-Ulm, Germany) and Merck (Darmstadt,
Germany) companies. The all desired products gave satisfactory spectroscopic data (supporting
information). A Bruker (DRX-400 Avance) NMR was used to record the 1H and 13C NMR spectra in DMSO
at room temperature. FT-IR spectra were taken by a Nicolet spectrometer (Magna 550), using KBr pellets.
2. 2. Computational details
The geometries of the considered structures in this study are optimized at the DFT-B3LYP level with 6-
31G(d) basis set using the Gaussian 09 software [36]. Nucleus-Independent Chemical Shift (NICS) values
are calculated at the same level of theory, using the gauge-including atomic orbital (GIAO) method [37].
The probe atom (Bq) is placed at the ring center of the considered structures (0.0 Å).
2. 3. General synthesis process for α-chloroamides 2
3

ACCEPTED MANUSCRIPT
o
To a cold solution of arylamine (0.1 mol) at 0 C, chloroacetyl chloride (0.15 mol) was added dropwise
during 10 minutes, with vigorous stirring and then 10% NaOH solution (15 mL) was added. α-Chloroamide
2 separated as a solid from the reaction mixture, filtered and washed with water and dried.
2.4. General synthesis process for N-propargylsulfonamides 1
To a stirred solution of amine (5 mmol) in 3 mL pyridine, aryl sulfonyl chloride (7 mmol) was added and
stirred for 3 hours at room temperature. After completion of the reaction, the mixture was poured into ice
cold water and stirred for 15 min, which resulted in precipitation of the desired sulfonamide in high yield.
To a stirred solution of the synthesized sulfonamide (1 mmol) and K2CO3 (1 mmol) in acetonitrile (5 mL),
was added dropwise propargyl bromide (1.1 mmol). The reaction mixture was heated at 80 °C for 8 h. After
completion of the reaction, as monitoring by TLC, the mixture was evaporated under vaccum. Water was
added, and the reaction mixture was extracted by DCM (3 × 5 mL). The combined organic extracts were
dried with Na2SO4, filtered, and then evaporated to obtain pure N-propargylsulfonamides 1 in high yields.
2. 5. General synthesis process for 1,2,3-triazole derivatives 3
α-Chloroamide 2 (1 mmol) was dissolved into EtOH/H2O (1:1, 5 mL). NaN3 (1.2 mmol) was added, and
the resulted solution was stirred at room temperature for 1 h, then CuI (10% mmol) and N-
propargylsulfonamide 1 (1 mmol) were added. The resulted mixture was stirred at 60 ºC until the reaction
was over by TLC monitoring. After completion of the reaction, 10 mL of water was added and the mixture
was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtrated,
and evaporated under vacuum. The desired products 3 were purified by column chromatography using ethyl
acetate/hexane (1:1).
2.6. Spectral data of the 1-amide 4-sulfonamide-1,2,3-triazoles 3
4

ACCEPTED MANUSCRIPT
(3a). 1HNMR (400 MHz, DMSO): δ = 2.36 (s, 3H), 4.35 (s, 2H), 4.37 (s, 2H), 5.24 (s, 2H), 7.26-7.43 (m,
13
10H), 7.61 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.87 (s, 1H), 10.47 (s, 1H). CNMR (100 MHz,
DMSO): δ = 21.54, 41.91, 50.66, 52.40, 124.26, 127.53, 127.55, 127.93, 127.59, 128.70, 128.85, 129.38,
130.17, 136.61, 136.97, 138.88, 143.59, 144.35, 166.44 ppm. FT-IR (KBr): 3420, 1681, 1597, 1526, 1447,
1331, 1153 Cm-1. (3b). 1HNMR (400 MHz, DMSO): δ = 2.38 (s, 3H), 4.39 (s, 4H), 5.30 (s, 2H), 6.29 (m,
1H), 6.36 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.34-7.41 (m, 4H), 7.53 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.67
(d, J = 8.0 Hz, 2H), 7.93 (s, 1H), 10.48 (s, 1H).13CNMR (100 MHz, DMSO): δ = 21.47, 42.06, 43.55, 52.61,
110.30, 110.95, 119.67, 124.27, 126.07, 127.53, 129.41, 130.08, 136.87, 138.90, 142.38, 143.52, 143.58,
149.55, 164.56 ppm. FT-IR (KBr): 3429, 2922, 2858, 1684, 1445, 1332, 1153 Cm-1. (3c). 1HNMR (400
MHz, DMSO): δ = 2.38 (s, 3H), 3.24 (s, 3H), 4.34 (s, 2H), 4.36 (s, 2H), 4.93 (s, 2H), 7.25-7.36 (m, 7H),
7.46-7.55 (m, 5H), 7.70 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H). 13CNMR (100 MHz, DMSO): δ = 21.43, 36.25,
41.88, 50.62, 51.23, 126.25, 127.57, 127.92, 127.98, 128.70 (2C), 128.87, 130.17, 130.49, 136.62, 137.05,
141.88, 142.38, 143.57, 165.19 ppm. FT-IR (KBr): 3435, 2923, 2856, 1673, 1457, 1334, 1153, 548 Cm-1.
(3d). 1HNMR (400 MHz, DMSO): δ = 2.42 (s, 3H), 3.71 (s, 3H), 4.53 (d, J = 15.6 Hz, 2H), 4.98 (ABd, J =
16.8 Hz, 1H), 5.18 (ABd, J = 16.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 9.2 Hz, 2H), 7.10 (t, J =
7.6 Hz, 1H), 7.28-7.42 (m, 7H), 7.51-7.60 (m, 2H), 10.67 (s, 1H). 13CNMR (100 MHz, DMSO): δ = 21.55,
45.44, 51.57, 55.69, 114.44, 114.51, 119.67, 119.88, 124.43, 127.81, 127.88, 127.96, 129.28, 129.37,
131.55, 131.65, 138.56, 144.09, 164.60 ppm. FT-IR (KBr): 3419, 1633, 1456, 1031, 873 Cm-1. (3e).
1HNMR (400 MHz, DMSO): δ = 2.39 (s, 3H), 4.34 (s, 2H), 4.35 (s, 2H), 4.36 (s, 2H), 5.10 (s, 2H), 7.26-
7.37 (m, 12H), 7.70 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H), 8.89 (m, 1H). 13CNMR (100 MHz, DMSO): δ = 21.48,
41.88, 42.84, 50.66, 51.93, 126.16, 127.37, 127.50, 127.58, 127.77, 127.88, 128.71, 128.82, 128.85, 130.18,
136.65, 136.97, 141.94, 143.63, 165.78 ppm. FT-IR (KBr): 3322, 2856, 1681, 1526, 1447, 1331, 1153 Cm-
1. (3f). 1HNMR (400 MHz, DMSO): δ = 2.38 (s, 3H), 3.75 (s, 3H), 4.41 (s, 4H), 5.28 (s, 2H), 6.30 (m, 1H),
5

ACCEPTED MANUSCRIPT
6.36 (m, 1H), 6.93 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 7.6 Hz, 2H), 7.54-7.56 (m, 3H), 7.68 (d, J = 7.2 Hz,
2H), 7.93 (s, 1H), 10.45 (s, 1H). 13CNMR (100 MHz, DMSO): δ = 21.46, 42.08, 43.55, 52.57, 55.64, 110.29,
110.94, 114.49, 121.25, 126.01, 127.52, 130.07, 132.06, 136.91, 142.35, 143.49, 143.58, 149.57, 156.02,
164.02 ppm. (3g). 1HNMR (400 MHz, DMSO): δ = 2.38 (s, 3H), 4.38 (s, 2H), 4.41 (s, 2H), 5.31 (s, 2H),
7.17 (d, J = 7.6 Hz, 1H), 7.30-7.41 (m, 8H), 7.50 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.86 (s, 1H),
7.89 (s, 1H), 10.72 (s, 1H). 13CNMR (100 MHz, DMSO): δ = 21.46, 41.88, 50.67, 52.59, 118.10, 119.24,
124.00, 126.27, 127.57, 127.99, 128.73, 128.86, 130.18, 131.08, 133.74, 136.65, 137.06, 140.35, 142.13,
1
143.59, 164.97 ppm. (3h). HNMR (400 MHz, DMSO): δ = 0.80 (t, J = 7.6 Hz, 3H), 1.12-1.22 (m, 2H),
1.38-1.45 (m, 2H), 3.13 (t, J = 7.2 Hz, 2H), 4.47 (s, 2H), 5.34 (s, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.39 (t, J =
7.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.58-7.69 (m, 3H), 7.82-7.84 (m, 3H), 8.03 (s, 1H), 10.70 (s, 1H).
13CNMR (100 MHz, DMSO): δ = 13.93, 19.61, 30.63, 42.81, 47.77, 52.63, 118.11, 119.21, 123.98, 126.18,
127.39, 129.78, 131.13, 133.18, 133.69, 139.78, 140.34, 142.05, 165.07 ppm.
3. Results and discussion
3.1 Synthesis and spectroscopic characterization of 1-amide 4-sulfonamide-1,2,3-triazoles 3
The starting N-propargyl-4-toluenesulfonamides 1 and α-chloroamides 2 were easily synthesized in-house.
With N-propargyl-4-toluenesulfonamides 1 and α-chloroamides 2 in hand, attention focused on the
azide‒alkyne [3 + 2] cycloaddition reaction to produce the desired 1-amide 4-sulfonamide-1,2,3-triazoles
3. SN2 reaction of sodium azide with α-chloroamides 2 generated in situ organic azides, which reacted in
different conditions with 1 in the presence of copper (I) as a catalyst to prepare the desired products 3. To
find the optimal conditions, the effect of the solvent, catalyst, and temperature on the model reaction of N-
propargyl-4-toluenesulfonamide 1b and α-chloroamide 2b was collected in Table 1.
6

ACCEPTED MANUSCRIPT
Table 1. Optimization conditions of the model reaction for synthesis of 3b.
Me
O
NH
O
O
H
O
S
N
O
Different conditions
N
S
Cl
N
+
NaN3
+
O
N
O
2b
1b
O
N
3b
N
Me
Entry
Catalyst
-
Solvent
Yield (%)a
1
2
3
4
5
6
7
8
H2O/EtOH
H2O
-
CuI
CuI
CuI
CuI
37
31
28
68
43
37
67
EtOH
MeOH
H2O/EtOH
CuSO4/ sodium ascorbate (20 mol%) H2O/EtOH
CuSO4/ sodium ascorbate (20 mol%) H2O
CuI b
H2O/EtOH
a Reaction conditions: Solvent (5 mL, 1:1), 1b (1 mmol), 2b (1 mmol), NaN3 (1.2 mmol), catalyst (10 mol%), 60 °C and reaction
time 10 h; b at 80 °C.
As shown in Table 1, the optimal reaction conditions were determined to be CuI (10 mol%) as a catalyst,
in the mixture of H2O and EtOH (1:1) at 60 °C for 10 hours (entry 5, Table 1). To explore the scope of the
click reaction, various N-propargyl-4-toluenesulfonamides 1 and α-chloroamides 2 were used to afford the
functionalized 1,2,3-triazole derivatives (Scheme 2). All reaction proceeded smoothly to achieve the
corresponding 1-amide 4-sulfonamide-1,2,3-triazoles 3 in moderate to good yields under the optimized
conditions. All of the products 3a-h were confirmed by FT-IR, 1H NMR, and 13C NMR analysis.
7

ACCEPTED MANUSCRIPT
H
H
Me
N
O
N
N
H
N
O
N
N
O
O
N
N
N
N
N
N
N
N
N
N
N
O
S
O
S
O
O
Me
Me
N
N
S
Me
N
S
Me
O
O
O
O
O
3a
, 75%
3c
, 61%
3b
, 63%
3d
, 71%
MeO
Cl
H
H
N
O
O
H
N
O
H
N
O
N
Cl
N
N
N
N
N
N
N
OMe
N
N
N
N
N
N
O
O
S
O
O
Me
N
S
Me
N
S
Me
N
S
O
O
O
O
O
3g
, 61%
3f
, 65%
3e
, 74%
3h
, 45%
Scheme 2. The structure of synthesized 1-amide 4-sulfonamide-1,2,3-triazole derivatives 3.
3.2. Theoretical studies on the 1-amide 4-sulfonamide-1,2,3-triazole 3b
With the encouraging experimental data, attention was turned on DFT calculations for investigation of
physicochemical properties of 3b. The DFT methods have become a trustable, cost-effective and standard
tool for many chemical applications such as electrophilicity index, spectral data, and cation affinity. It is
worth highlighting that DFT-B3LPY method is a straightforward method with significant increment in the
computational accuracy without increasing of computing time for such calculations [38-42]. This method
has been utilized here for performing the computations.
3.2.1. Electronic characterization of 3b
The optimized geometry and electronic data of 3b are inserted in Fig. 1 and Table 1, respectively. Dipole
moment of 3b is 11.24 (μD), which demonstrates its medium dipolar properties. ELUMO is the energy of the
lowest unoccupied molecular orbital (LUMO), and EHOMO is the energy of the highest occupied molecular
orbital (HOMO). The HOMO reveals the ability to donate an electron, while the LUMO reveals the ability
8

ACCEPTED MANUSCRIPT
to accept an electron. The HOMO and LUMO are the frontier orbitals most likely to be involved in chemical
reactivity. EHOMO and ELUMO of 3b are -0.217 eV and -0.0385 eV, respectively (Table 1). The difference
between energy levels of the HOMO and LUMO (Eg) is 0.178 eV. As can be seen from Fig. 2, the LUMO
orbital is localized mainly on amide motif, due to bearing a carbonyl group as an electron withdrawing
group, while the HOMO orbital is located on furyl ring.
Fig. 1. B3LYP/6-31G(d) optimized geometry of 3b.
Table 1. The electronic data of 3b at B3LYP/6-31G(d) level.
Parameter
Value
Energy (Hartree)
μD (Deby)
-1863.019
11.24
EHOMO (eV)
-0.217
9

ACCEPTED MANUSCRIPT
ELUMO (eV)
Eg (eV)
-0.0385
0.178
Chemical potential (μ) (eV) -0.127
Chemical hardness (η) (eV) 0.089
Electrophilicity (ω) (eV)
0.092
Fig. 2. Frontier orbitals (HOMO and LUMO) for 3b calculated at B3LYP/6-31G(d) level.
Global electrophilicity index (GEI) is a measure of the molecule ability to take up electrons. This index is
a fundamental property of the molecule, which has been used extensively to predict some adequate
information on structure, reactivity, dynamics, aromaticity, Lewis acidity, and toxicity, etc. [43-45]. In
1999, Parr and co-workers defined the GEI (ω) as [46]:
ω = μ2/2η
(1)
μ = (ELUMO + EHOMO)/2 and η = (ELUMO – EHOMO)/2
(2)
10

ACCEPTED MANUSCRIPT
where μ and η are the chemical potential and chemical hardness, respectively given by equation (2). The
GEI of 3b was calculated by using eq. 1 as 0.092 eV.
3.2.2. Experimental and Simulated 1H, 13CNMR, and FT-IR spectra of 3b
The experimental 1H NMR spectrum of 3b consisted of three singlet lines at δ = 2.38 (3 H) for methyl, 4.39
(4 H), and 5.30 (2 H) ppm for three methylene groups, two distinct signals for furyl protons at δ = 6.29 (1
H) and 6.36 (1 H) ppm, 10 protons for furyl and phenyl rings at δ = 7.10–7.67 ppm, a characteristic signal
at δ = 7.93 ppm for hydrogen on triazole ring, and a resonance at δ = 10.48 ppm correlating to the NH of
1
amide group. An intramolecular hydrogen bonding results in deshielding of the NH proton. The H–
decoupled 13C NMR spectrum of 3b showed 19 resonances, which is in agreement with the proposed
structure, while the amide carbon appearing at δ = 164.56 ppm, 14 distinct resonances for the aromatic
carbons of phenyl, furyl and triazole rings between δ = 110.30-149.51 ppm and four resonances at δ =
21.47-52.61 ppm for aliphatic carbons.
The NMR analysis of 3b was carried out at B3LYP/6-31G(d) level with the aid of Gauss View software
1
13
[47]. Representative computed H, and C chemical shifts of 3b with experimental data are inserted in
Table 2. The chemical shifts were reported in parts per million (ppm) relative to tetramethylsilane as the
reference, which its corresponding shifts were calculated at the same theoretical level.
Table 2. Representative B3LYP/6-31G(d) calculated and experimental 1H and 13C shifts of 3b.
Atoma
H20
δ B3LYP (ppm)
8.18
δ exp (ppm)
7.93
׀δexp-δB3LYP
׀
0.25
H14
7.26
7.36
0.10
H40
2.91
2.38
0.53
H16
6.77
6.27
0.50
11

ACCEPTED MANUSCRIPT
H25
C27
C11
C39
C24
C4
5.15
5.30
0.15
5.65
0.29
3.45
1.24
0.05
158.91
110.01
24.92
51.37
42.11
164.56
110.30
21.47
52.61
42.06
a For numbering of atoms refer Fig. 1.
1
The calculated H and 13C chemical shifts are in excellent agreement with the experimental data. The
correlation between the experimental chemical shifts and calculated data are better for 1H than 13C atoms.
The calculated and experimental chemical shifts for hydrogen on the triazole ring (H20) are 8.18 and 7.93
ppm, respectively. The most mismatch is observed in the 13C chemical shift of the amidic carbon (C27). The
experimental chemical shift of the C27 is 164.56 ppm, whereas it was calculated as 158.91 ppm.
The FT-IR spectrum of 3b revealed a band at 3429 arising from the stretching adsorption band of the N-H
group. It can be declared that the distinguishing peaks formed at 2922 and 2858 cm-1 are attributed to the
stretching aromatic C-H bonds. Amidic C=O adsorption of 3b observed in 1684 cm-1. Characteristic strong
peaks at 1332 and 1153 cm-1 can be related to the asymmetric and symmetric stretching of S=O bond,
respectively. FT-IR spectrum of 3b is also simulated by the DFT method at the B3LYP/6-31G(d). There
was a good agreement between experimental and calculated frequencies. The aromatic C–H stretching
vibrations are presented in the region 3317–3043 cm-1. The calculated value of amidic C=O mode was
somewhat shifted to the lower frequencies appearing at 1657 cm−1. Asymmetric and symmetric S=O
stretching band for sulfonamide group in the simulated IR spectrum were observed at 1339 and 1155 cm-1,
respectively.
12

ACCEPTED MANUSCRIPT
3.2.3. Cation (Li+ and Na+) affinity of 3b
The alkali cations play a vital role in many biological processes such as DNA duplexing, sequence-specific
recognition of nucleic acids by enzymes, the stabilization of DNA triple and quadruple helices [48, 49].
Investigation of Li+ and Na+ interactions with 3b, and obtaining some information about its intrinsic binding
properties, can be useful. Cation affinity (CA) of 3b can be defined in the gas phase as the negative value
of the enthalpy variation (ΔH) in the following reaction (Scheme 3) according to the equation (3) [50].
H
H
O
O
N
N
N
N
+
M
N
N
N
N
+
+
M
O
O
N
S
Me
N
+
S
Me
O
O
O
O
[3b + M]+
3b
+
+
M = Li and Na
Scheme 3. Chemical reaction for cation affinity calculation of 3b.
CA(ퟑ퐛) = ― ∆H = ― ∆E ― ∆(pv) = ― E(ퟑ퐛 ―M+) + E(ퟑ퐛) + E(M+) + RT (3)
In equation (3), E is the total energy calculated for the optimized structures of both 3b and [3b+M]+ in the
gas phase, where M+ is the alkali cation. The M+ can interact with 3b at different sites: (1) with oxygen
atom of furyl ring and oxygen atom of O=S group ([3b1+M]+); (2) with a nitrogen atom of triazole ring and
oxygen atom of amide group ([3b2+M]+) and (3) with a nitrogen atom of triazole and π system of aryl group
([3b3+M]+). The structure of 3b is significantly changed during complexation (Fig. 3). It should be
higlighted that all of these structures were optimized using DFT /B3LYP/6-31G(d) method.
As can be seen in the Fig. 3, the [3b2+Li]+ and [3b1+Na]+ complexes are the most stable lithiated and
sodiated structure of 3b, and their cation affinities in the gas phase, were calculated to be 372.45 and 268.35
kJ mol-1, respectively. The results show that the interaction of the Li+ with 3b is more exothermic than Na+.
13

ACCEPTED MANUSCRIPT
The difference in energies (104.1 kJ/mol) between lithiation and sodiation shows that the cation affinity
strongly depends on the coordination mode of the cation to 3b and the charge‐to‐size ratio of the cation.
Due to the longer radius of Na+, the positive charge is spread over large space than Li+.
Fig. 3. Optimized structures of [3b+M]+ at the B3LYP/6-31G(d) level and their relative energies in
kJ/mol.
It is worth to mention that in complexes [3b3+Li]+ and [3b3+Na]+, the cation can be interacted with π
system of aryl group (cation π interaction) [51, 52]. Cation–π interactions are noncovalent interactions
which in many cases they are stronger than hydrogen bondings and van der Waals interactions [53]. They
play an important role in cation complexes with proteins, DNA, chemical catalysis, and drug receptors [54,
55]. The cation π interaction arises from the electrostatic interaction of M+ with π electrons of aromatic
rings. Comparing of Na+, Li+ is near aromatic ring in [3b3+Li]+, follows the classical electrostatic
interaction (Fig. 4). Comparison of aromaticity index of phenyl on the sulfonamide group in 3b, after
interaction with M+, is a good hint to support the cation π interaction in [3b3+Li]+ and [3b3+Na]+ structures.
14

ACCEPTED MANUSCRIPT
Aromaticity is evaluated based on some energetic, geometric, and electronic criteria. Magnetic
susceptibility becomes more prominent for assessment of the aromaticity [56]. The most widely used index
is the Nucleus-Independent Chemical Shift (NICS), which estimates the absolute magnetic shielding in a
given point of the molecule [57]. NICS decrement of the phenyl is expected after metalation. As shown in
Fig. 4, in both [3b3+Li]+ and [3b3+Na]+ structures, NICS of the phenyl was decreased in comparing to
unmetalated 3b or complex [3b1+Li]+, in which Li+ is coordinated with other sites of the molecule.
Fig. 4. The cation π interaction in [3b3+Li]+ and [3b3+Na]+ (bond distances in Å). The NICS values are
calculated at GIAO-B3LYP/6-31G(d) level and in ppm (The Bq atom in center of phenyl as a probe).
15

ACCEPTED MANUSCRIPT
4. Conclusion
A practical and environmentally friendly procedure was developed for the synthesis of 1-amide 4-
sulfonamide-1,2,3-triazole derivatives through azide-alkyne [3 + 2] Huisgen cycloaddition reaction. Full
structural analysis such as electronic characterizations, HOMO and LUMO energies, NMR and IR data and
cation affinity for the synthesized compound 3b have also been studied at B3LYP/6-31G(d) level. The DFT
calculated results show that in some metalated structures of 3b, a cation π interaction can be observed. The
NICS criteria were used to prove the cation π interaction.
References
[1] D. Astruc, L. Liang, A. Rapakousiou, J. Ruiz, Click dendrimers and triazole-related aspects: catalysts,
mechanism, synthesis, and functions. A bridge between dendritic architectures and nanomaterials, Acc.
Chem. Res. 45 (2012) 630-640.
[2] W. Brittain, B. Buckley, J. Fossey, Asymmetric copper-catalyzed azide–alkyne cycloadditions, ACS
Catal. 6 (2016) 3629-3636.
[3] H.C. Kolb, M.G. Finn, K.B. Sharpless, Light-induced copper (I)-catalyzed click chemistry, Angew.
Chem. Int. Ed. 40 (2001) 2004-2021.
[4] Q. Wang, T.R. Chan, R. Hilgraf, V.V. Fokin, K.B. Sharpless, M.G. Finn, Bioconjugation by copper(I)-
catalyzed azide-alkyne [3 + 2] cycloaddition, J. Am. Chem. Soc. 125 (2003) 3192-3193.
[5] J. Han, J.X. Ran, X.P. Chen, Z.H. Wang, F.H. Wu, Study on the green click-chemistry synthesis of 4-
trifluoroacetyl-1,2,3-triazoles. Tetrahedron, 74 (2018) 6985-6992.
[6] O. Dimroth, Ueber eine Synthese von Derivaten des 1.2.3‐Triazols, Ber. Dtsch. Chem. Ges. 35 (1902)
4041-4060.
[7] R. Huisgen, R. Knorr, L. Möbius, G. Szeimies, 1.3‐Dipolare cycloadditionen, XXIII. Einige
beobachtungen zur addition organischer azide an CC‐dreifachbindungen, Chem. Ber. 98 (1965) 4014-4021.
16

ACCEPTED MANUSCRIPT
[8] R. Huisgen, 1,3‐Dipolar cycloadditions. Past and Future, Angew. Chem., Int. Ed. Engl. 2 (1963) 565–
598.
[9] E.J. Yoo, M.A. Ahlquist, S.H. Kim, I. Bae, V.V. Folkin, K.B. Sharpless, S. Chang, Copper-catalyzed
synthesis of N-sulfonyl-1,2,3-triazoles: controlling selectivity, Angew. Chem. Int. Ed. 46 (2007) 1730–
1733.
[10] M. Meldal, C.W. Tornøe, Cu-catalyzed Azide−Alkyne Cycloaddition, Chem. Rev. 108 (2008) 2952–
3015.
[11] Y. Belay, L.C. Coetzee, D.B.G. Williams, A. Muller, Synthesis of novel 1,2,3-triazole based
polycarboxylic acid functionalised ligands for MOF systems ,Tetrahedron Lett. 60 (2019) 501–503.
[12] H.C. Kolb, K.B. Sharpless, The growing impact of click chemistry on drug discovery, Drug Discov.
Today 8 (2003) 1128-1137.
[13] B. Zhang, Comprehensive review on the anti-bacterial activity of 1,2,3-triazole hybrids, Eur. J. Med.
Chem. 168 (2019) 357-372.
[14] G. Singh, J. Singh, A. Singh, J. Singh, M. Kumar, K. Gupta, S. Chhibber, Synthesis, characterization
and antibacterial studies of schiff based 1,2,3-triazole bridged silatranes, J. Organomet. Chem. 871 (2018)
21-27.
[15] N. Fu, S. Wang, Y. Zhang, C. Zhang, D. Yang, L. Weng, B. Zhao, L. Wang, Efficient click chemistry
towards fatty acids containing 1,2,3-triazole: Design and synthesis as potential antifungal drugs for Candida
albicans, Eur. J. Med. Chem 136 (2018) 596-602.
[16] A.A Ali, D. Gogoi, A.K. Chaliha, A.K. Buragohain, P. Trivedi, P.J. Saikia, P.S. Gehlot, A. Kumar, V.
Chaturvedi, D. Sarma, Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-
tubercular agents, Bioorg. Med. Chem. Lett. 27 (2017) 3698-3703.
17

ACCEPTED MANUSCRIPT
[17] M.J. Wu, D.M. Wu, J.B. Chen, J.F. Zhao, L. Gong, Y.X. Gong, Y. Li, X.D. Yang, H. Zhang, Synthesis
and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore,
Bioorg. Med. Chem. Lett. 28 (2018) 2543-2549.
[18] F. Naaz, M.C.P. Pallavi, S. Shafi, N. Mulakayala, M. Shahar Yar, H.M.S. Kumar, 1,2,3-triazole tethered
Indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX, COX-2 & tubulin: Their anti-
proliferative & anti-inflammatory activity, Bioorg. Chem. 81 (2018) 1-20.
[19] K. Maji, M.A. Debasish Podder, R. Datta, D. Haldar, Potential antileishmanial activity of a
triazole‐based hybrid peptide against Leishmania major, Chemistryselect 3 (2018) 10220-10225.
[20] D. Dheer, V. Singh, R. Shankar, Medicinal attributes of 1,2,3-triazoles: Current developments, Bioorg.
Chem. 71 (2017) 30–54.
[21] G.C. Brand, F.C.R. Missias, L.M. Arantes, L.F. Soares, K.K. Roy, R.J. Doerksen, A.B. Oliveira, G.R.
Pereira, Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to
PfDHODH and SAR of lapachol-based compounds, Eur. J. Med. Chem. 145 (2018) 191-205.
[22] D. Rai, W. Chen, P. Zhan, H. Liu, Y. Tian, X. Liang, E.D. Clercq, C. Pannecouque, J. Balzarini, X. Liu,
Synthesis and anti-HIV activity of 4-(naphthalen-1-yl)-1,2,5-thiadiazol-3-hydroxyl derivatives, Chem.
Biol. Drug Des. 84 (2014) 420-430.
[23] D.R. Rocha, W.C. Santos, E.S. Lima, V.F. Ferreira, Synthesis of 1,2,3-triazole glycoconjugates as
inhibitors of α-glucosidases, Carbohydr. Res. 350 (2012) 14-19.
[24] D.R. Buckle, D.J. Outred, C.J.M. Rockell, H. Smith, B.A. Spicer, Studies on triazoles. Antiallergic 9-
oxo-1H,9H-benzopyrano[2,3-d]-v-triazoles, J. Med. Chem. 26 (1983) 251-254.
[25] F.M. Moghaddam, Z. Mirjafary, H. Saeidian, S. Taheri, B. Soltanzadeh, Synthesis of eight-membered
hydroquinolines related to alkaloid skeletons via addition of 4-hydroxycoumarin or 4-hydroxypyran-2-one
to quinolinium salts, Tetrahedron 66 (2010) 3678-3681.
18

ACCEPTED MANUSCRIPT
[26] M. Abdoli, A. Angeli, M. Bozdag, F. Carta, A. Kakanejadifard, H. Saeidian, C.T. Supuranc, Synthesis
and carbonic anhydrase I, II, VII, and IX inhibition studies with a series of benzo [d] thiazole-5-and 6-
sulfonamides, J. Enzyme Inhib. Med. Chem. 32 (2017) 1071-1078.
[27] H. Paghandeh, H. Saeidian, Expedient and click synthesis, spectroscopic characterizations and DFT
calculations of novel 1,5-bis(N-substituted 1,2,3‒triazole) benzodiazepinedione scaffolds, J. Mol. Struct.
1157 (2018) 560-566.
[28] E. Taheri, Z. Mirjafary, H. Saeidian, Highly efficient regioselective synthesis, spectroscopic
characterizations and DFT calculations of novel hydroxymethylated 1,4-disubstituted-1,2,3-triazole-based
sulfonamides, J. Mol. Struct. 1157 (2018) 418-424.
[29] H. Paghandeh, H. Saeidian, E. Saeedian Moghadam, Z. Mirjafary, M. Ghaffarzadeh, One-pot, clean and
energy efficient synthesis of dibenzo[b,f][1,4]oxazepine derivatives promoted by ultrasound, Asian J.
Green Chem. 2 (2018) 1-10.
[30] F.M. Moghaddam, M. Kiamehr, M.R. Khodabakhshi, Z. Mirjafary, Sh. Fathi, H. Saeidian, A new
domino Knoevenagel-hetero-Diels–Alder reaction: an efficient catalyst-free synthesis of novel
thiochromone-annulated thiopyranocoumarin derivatives in aqueous medium, Tetrahedron 66 (2010) 8615-
8622.
[31] F.M. Moghaddam, Z. Mirjafary, H. saeidian, S. Taheri, M.R. Khodabakhshi, A new and convenient
approach to heterotetracyclic benzoxazocines through addition of 1,3-dicarbonyl compounds to
quinolinium salts, Tetrahedron Lett. 51 (2010) 2704-2707.
[32] Z. Mirjafary, L. Ahmadi, M. Moradi, H. Saeidian, A copper(II)–thioamide combination as a robust
heterogeneous catalytic system for green synthesis of 1,4-disubstituted-1,2,3-triazoles under click
conditions, RSC Adv. 5 (2015) 78038-78046.
19

ACCEPTED MANUSCRIPT
[33] Z. Mirjafary, H. Saeidian, F.M. Moghaddam, Microwave-assisted synthesis of 3-substituted coumarins
using ZrOCl2.8H2O as an effective catalyst, Scientia Iranica, 16 (2009) 12-16.
[34] H. Saeidian, H. sadighian, M. Abdoli, M. Sahandi, Versatile and green synthesis, spectroscopic
characterizations, crystal structure and DFT calculations of 1,2,3‒triazole‒based sulfonamides, J. Mol.
Struct. 1131 (2017) 73-78.
[35] H. Saeidian, H. Sadighian, M. Arabgari, Z. Mirjafary, S.E. Ayati, E. Najafi, F.M. Moghaddam,
Organocopper-based magnetically recoverable and reusable nanocatalyst for efficient synthesis of novel 1,
2, 3-triazole-based sulfonamides in green medium, Res. Chem. Intermediate, 44 (2018) 601-612.
[36] J. M. Frisch, et al., Gaussian, Inc., Wallingford CT, Gaussian 09, Gaussian, Inc, (2013).
[37] K. Wolinski, J.F. Hilton, P. Pulay, Efficient implementation of the gauge-independent atomic orbital
method for NMR chemical shift calculations, J. Am. Chem. Soc. 112 (1990) 8251-8260.
[38] M. Ghiasi, A.A. Oskouie, H. Saeidian, Dynamic stereochemistry of Topiramate (anticonvulsant drug)
in solution: theoretical approaches and experimental validation, Carbohydr. Res. 348 (2012) 47-54.
[39] R.O. Jones, Density functional theory: Its origins, rise to prominence, and future, Rev. Mod. Phys. 87
(2015) 897-923.
[40] H. Saeidian, M. Sahandi, Comprehensive DFT study on molecular structures of Lewisites in support of
the Chemical Weapons Convention, J. Mol. Struct. Chem. 1100 (2015) 486-495.
[41] A.J. Cohen, P. Mori-Sánchez, W. Yang, Challenges for Density Functional Theory, Chem. Rev. 112
(2012) 289-320.
[42] B. Shams, H. Saeidian, Design of the novel neutral organic superacids by comprehensive DFT study on
organic fluorosulfuric acids, Comput. Theor. Chem.1135 (2018) 48-55.
[43] L.R. Domingo, P. Pérez, Global and local reactivity indices for electrophilic/nucleophilic free radicals,
Org. Biomol. Chem. 11 (2013) 4350-4358.
20

ACCEPTED MANUSCRIPT
[44] P.K. Chattaraj, U. Sarkar, D. Roy, Electrophilicity Index, Chem. Rev. 106 (2006) 2065-2091.
[45] A. R. Jupp, T.C. Johnstonea, D.W. Stephan, The global electrophilicity index as a metric for Lewis
acidity, Dalton Trans. 47 (2018) 7029-7035.
[46] R.G. Parr, L.v. Szentpály, S. Liu, Electrophilicity Index, J. Am. Chem. Soc. 121 (1999) 1922-1924.
[47] R.I.I. Dennington, T. Keith, J. Millam, GaussView Version 4.1.2, Semichem Inc., Shawnee Mission,
KS, (2007).
[48] A. Sigel, H. Sigel, Interactions of metal ions with nucleotides, nucleic acids and their constituents. Metal
ions in biological systems. Marcel Dekker, New York, (1996).
[49] A.Sigel, H, Sigel Probing of nucleic acids by metal ion complexes of small molecules. Metal ions in
biological systems. Marcel Dekker, New York, (1996).
[50] M.S. Ahmadi, M. Shakourian-Fard, A. Fattahi, Molecular structure and character of bonding of mono
and divalent metal cations (Li+, Na+, K+, Mg2+, Ca2+, Zn2+, and Cu+) with guanosine: AIM and NBO
analysis, Struct. Chem. 23 (2012) 613-626.
[51] D.A. Dougherty, The cation−π interaction. Acc. Chem. Res. 46 (2013) 885-893.
[52] D.Kim, Sh. Hu, P. Tarakeshwar, K.S. Kim, J.M. Lisy, Cation−π Interactions:ꢀ A Theoretical
Investigation of the Interaction of Metallic and Organic Cations with Alkenes, Arenes, and Heteroarenes,
J. Phys. Chem. A, 107 (2003) 1228-1238.
[53] J.C. Ma, D.A. Dougherty, The cation–π interactions. Chem. Rev. 97 (1997) 1303-1324.
[54] J.P. Gallivan, D.A. Dougherty DA, Cation–π interactions in structural biology. Proc. Natl. Acad. Sci.
USA. 96 (1999) 9459-9464.
[55] D.L. Beene, G.S. Brandt, W.G. Zhong, N.M. Zacharias, H.A. Lester, D.A. Dougherty, Cation—pi
interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the
anomalous binding properties of nicotine, Biochem. 41 (2002) 10262.
21

ACCEPTED MANUSCRIPT
[56] R. Gershoni-Poranne, A. Stanger, Magnetic criteria of aromaticity, Chem. Soc. Rev. 44 (2015) 6597-
6615.
[57] P.v.R. Schleyer, C. Maerker, A. Dransfeld, H. Jiao, N.J.R.v.E. Hommes, Nucleus-Independent Chemical
Shifts:ꢀ A Simple and Efficient Aromaticity Probe, J. Am. Chem. Soc. 118 (1996) 6317-6318.
22

ACCEPTED MANUSCRIPT
1. The novel 1,2,3-triazole derivatives were synthesized in good yields.
2. To compute physicochemical properties of a product, DFT calculations were
used.
3. NICS index was used to confirm the cation π interaction of 3b.