Straightforward synthesis, spectroscopic characterizations and comprehensive DFT calculations of novel 1-ester 4-sulfonamide-1,2,3-triazole scaffolds

Article abstract of DOI:10.1016/j.molstruc.2019.127405

For the first time, an efficient click azide?alkyne [3 + 2] cycloaddition reaction for synthesis of new 1-ester 4-sulfonamide-1,2,3-triazole derivatives was developed via a three-component reaction of N-propargylsulfonamides, sodium azide, and α-haloesters in a one pot method. The mild reaction conditions, avoiding the isolation of hazardous organic azides, good yields (65–78%), and commercially available and inexpensive starting materials are advantages of this cycloaddition reaction for synthesis of fine chemicals. The all desired products were characterized by FT-IR, ¹H and ¹³C NMR spectroscopy. The HOMO-LUMO analysis (electrophilicity index), vibrational frequencies (FT-IR), ¹H and ¹³C chemical shift values and Li⁺ and Na⁺ ion affinities of a desired product have been also calculated by density functional theory (DFT). Lithium ion affinity of the product was determined as 80.78 kJ/mol higher than its sodium ion affinity. The NICS index was used to confirm of the cation π interaction in complex of the synthesized product with Li⁺ and Na⁺ ions.

Full text of DOI:10.1016/j.molstruc.2019.127405

Journal Pre-proof
Straightforward synthesis, spectroscopic characterizations and comprehensive DFT
calculations of novel 1-ester 4-sulfonamide-1,2,3-triazole scaffolds
Maryam Alizadeh, Zohreh Mirjafary, Hamid Saeidian
PII:
S0022-2860(19)31514-5
DOI:
https://doi.org/10.1016/j.molstruc.2019.127405
MOLSTR 127405
Reference:
To appear in: Journal of Molecular Structure
Received Date: 4 June 2019
Revised Date: 24 October 2019
Accepted Date: 11 November 2019
Please cite this article as: M. Alizadeh, Z. Mirjafary, H. Saeidian, Straightforward synthesis,
spectroscopic characterizations and comprehensive DFT calculations of novel 1-ester 4-
sulfonamide-1,2,3-triazole scaffolds, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/
j.molstruc.2019.127405.
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Straightforward synthesis, spectroscopic characterizations and comprehensive
DFT calculations of novel 1-ester 4-sulfonamide-1,2,3-triazole scaffolds
Maryam Alizadeh, Zohreh Mirjafary, Hamid Saeidian
OMe
O
p-Ts
MeO
Furyl-H C
2
Furyl-H C N
2
CuAAC
Br
N
N
N
+
NaN3 +
O
p-Ts
N
3
c
+ Na+
Li+
+

Straightforward synthesis, spectroscopic characterizations and comprehensive
DFT calculations of novel 1-ester 4-sulfonamide-1,2,3-triazole scaffolds
a
a, *
b
Maryam Alizadeh , Zohreh Mirjafary , Hamid Saeidian
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: For the first time, an efficient click azide‒alkyne [3 + 2] cycloaddition reaction for
synthesis of new 1-ester 4-sulfonamide-1,2,3-triazole derivatives was developed via a three-
component reaction of N-propargylsulfonamides, sodium azide, and α-haloesters in a one pot
method. The mild reaction conditions, avoiding the isolation of hazardous organic azides, good
yields (65-78%), and commercially available and inexpensive starting materials are advantages of
this cycloaddition reaction for synthesis of fine chemicals. The all desired products were
1
13
characterized by FT-IR, H and C NMR spectroscopy. The HOMO-LUMO analysis
1
13
+
(
electrophilicity index), vibrational frequencies (FT-IR), H and C chemical shift values and Li
+
and Na ion affinities of a desired product have been also calculated by density functional theory
(DFT). Lithium ion affinity of the product was determined as 80.78 kJ/mol higher than its sodium
ion affinity. The NICS index was used to confirm of the cation π interaction in complex of the
+
+
synthesized product with Li and Na ions.
Keywords: CuAAC reaction; 1,2,3-triazole; N-propargylsulfonamide; α-haloester; DFT
calculations; cation π interaction.
1. Introduction
1,2,3-Triazoles are important heterocycles, because of their pharmaceuticals and biological
activities such as anticancer, antiviral, antibacterials, anticonvulsant, antifungal, HIV protease
inhibitors, etc [1-6]. Design and preparation of novel 1,4-disubstituted 1,2,3-triazole derivatives
are of great importance in organic and medicinal chemistry. The ‘‘click” chemistry protocol,
1

developed by Sharpless and Meldal, was utilized for regioselective synthesis of 1,4-disubstituted
,2,3-triazole [7-10]. In this protocol a reactant bearing an azide motif reacts with a terminal
1
alkyne via a concerted [3 + 2] cycloaddition of [4πs + 2πs] type in a thermally allowed copper (I)-
calalyzed azide alkyne cycloaddition (CuAAC) in the presence of Cu (I) as a catalyst [11-17].
A lot of scientific reports describing the synthetic potencies of the CuAAC reaction have been
published. However, there is no example in which this robust method is applied for synthesis of
triazole scaffolds containing sulfonamide and ester groups. The ester and sulfonamide groups are
key motifs in chemistry and biology [18-20]. Organic molecules that contain triazole, sulfonamide
and carbonyl subunits possess various interesting biological activities, such as antiaromatase,
carbonic anhydrase isozymes inhibitors, potassium channel activators, antiviral agent and
thrombin inhibitors [21–29]. Some examples of biological active triazoles bearing sulfonamide
and carbonyl group are shown in Scheme 1.
Scheme 1. Some biologically active 1,2,3-triazole scaffolds containing sulfonamide and carbonyl
groups.
Recently, we devised highly efficient copper-catalyzed click reaction for synthesis of different
type of triazole derivatives, in which a terminal alkyne such as N-propargylsulfonamides and bis-
(N-propargyl) benzodiazepines react with a wide range of alkyl halides and epoxide derivatives in
the presence of different sources of copper (I) [30-35]. In the context of our general interest in the
2

synthesis of heterocycle compounds and following our research on triazole chemistry, for the first
time we propose an efficient synthesis for a new series of 1-ester 4-sulfonamide-1,2,3-triazole
scaffolds via the CuAAC reaction in the presence of CuI as a catalyst (Scheme 2). The structural
1
13
assignment of the desired products was based on H and C NMR and FT-IR spectral data.
To make a reasonable assignment of vibrational bands and chemical shifts, density functional
theory (DFT) geometry optimization and molecular orbital calculations were performed on the
structure of 3c. 1-Ester 4-sulfonamide-1,2,3-triazole derivatives can be considered as ligand for
+
+
metal ions, giving a variety of complexes. The Li and Na ion affinities of 3c have been also
studied by DFT calculations to find the applicability of these synthesized products for
complexation with metal ions.
Scheme 2. The efficient method for synthesis of novel 1-ester 4- sulfonamide-1,2,3-triazole
scaffolds 3 by the click reaction.
2
2
. Experimental
. 1. General information
All the chemicals required for the synthesis of 1,2,3-triazoles 3 were purchased from Sigma-
Aldrich (St. Louis, MO, USA), Fluka (Neu-Ulm, Germany) and Merck (Darmstadt, Germany)
companies and were used as received. The all synthesized compounds gave satisfactory
1
13
spectroscopic data. A Bruker (DRX-400 Avance) NMR was used to record the H and C NMR
spectra in DMSO at room temperature. FT-IR spectra were taken by a Nicolet spectrometer
3

(
Magna 550), using KBr pellets. All the reactions are monitored by thin layer chromatography
TLC) carried out on silica gel with UV light and iodine, as detecting agents.
(
2. 2. Computational details
All geometry optimizations and frequency calculations of the desired product 3c were carried out
using the Gaussian 09 software [36]. Density functional theory with the Becke three parameters
hybrid functional (DFT-B3LYP/6-31G(d)) calculations were performed for all atoms of 3c.
Vibrational frequencies were calculated at the same level to ensure that each stationary point was a
true minimum. After geometry optimization and frequency calculations, zero-point energies
(ZPEs) and thermal corrections are obtained at 298 K.
2. 3. General synthesis process for 1,2,3-triazole derivatives 3
α-Haloesters 2 (1 mmol) was dissolved into EtOH/H O (1:1, 5 mL). After dissolving, sodium
2
azide (1.2 mmol) was added, and the solution was stirred at room temperature for 1 h then CuI
(
10% mmol) and N-propargylsulfonamide 1 (1 mmol) were added, and the resulted mixture was
stirred at 60 ºC until the reaction was over by TLC monitoring. After completion of the reaction,
0 mL of water was added and the mixture was extracted with ethyl acetate. The organic layers
1
were dried over anhydrous sodium sulfate, filtrated and evaporated under vacuum to provide the
crude product which was purified by flash column chromatography (silica gel) using ethyl
acetate/hexane (1:1) to obtain the desired product 3.
2
3
2
=
.4. Spectral data of the 1-ester 4-sulfonamide-1,2,3-triazole 3
1
a: HNMR (400 MHz, DMSO): δ = 1.23 (t, J = 7.2 Hz, 3H), 2.40 (s, 3H), 4.17 (q, J = 7.2 Hz,
H), 4.36 (s, 2H), 4.39 (s, 2H), 5.33 (s, 2H), 7.23-7.35 (m, 5H), 7.38 (d, J = 8.0 Hz, 2H), 7.73 (d, J
1
3
8.0 Hz, 2H), 7.87 (s, 1H); CNMR (100 MHz, DMSO): δ = 14.42, 21.45, 31.12, 41.93, 50.72,
1.95, 126.08, 127.56, 128.01, 128.69, 128.87, 130.19, 136.60, 136.97, 142.37, 143.68, 167.53
6
-1
1
ppm; FT-IR (KBr) : 3138, 2951,1755, 1599, 1447, 1336, 1222, 1157 cm . 3b. HNMR (400 MHz,
DMSO): δ = 2.39 (s, 3H), 3.73 (s, 3H), 4.37 (s, 2H), 4.39 (s, 2H), 5.36 (s, 2H), 7.27-7.35 (m, 5H),
4

13
7
.38 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.88 (s, 1H); CNMR (100 MHz, DMSO): δ =
21.45, 41.96, 49.62, 50.61, 52.97, 126.08, 127.56, 128.01, 128.69, 128.87, 130.20, 135.97, 136.60,
-1
1
42.40, 143.71, 168.03 ppm; FT-IR (KBr) : 3137, 1755, 1599, 1447, 1336, 1222, 1157 cm . 3c:
1
HNMR (400 MHz, DMSO): δ = 2.39 (s, 3H), 3.73 (s, 3H), 4.40 (m, 4H), 5.39 (s, 2H), 6.28 (m,
H), 6.35-6.36 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.53 (m, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.95 (s,
1
1
3
1
1
1
H); CNMR (100 MHz, DMSO): δ = 21.44, 42.15, 43.66, 50.66, 52.98, 110.30, 110.94, 125.87,
27.52, 130.09, 136.79, 142.75, 143.49, 143.66, 149.51, 168.10 ppm; FT-IR (KBr) : 3330, 1750,
-1
1
508, 1468, 1417, 1371, 1185, 1026 cm . 3d: HNMR (400 MHz, DMSO): δ = 2.41 (s, 3H), 3.69
(
s, 3H), 3.72 (s, 3H), 4.87 (s, 2H), 5.37 (s, 2H), 6.84 (d, J = 8.8 Hz 2H), 6.96 (d, J = 8.8 Hz, 2H),
,
1
3
7
2
1
1
.40 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz 2H), 7.97 (s, 1H); CNMR (100 MHz, DMSO): δ =
,
1.50, 50.69, 52.93, 55.38, 55.68, 114.50, 125.92, 127.88, 130.17, 130.43, 131.56, 135.59, 143.17,
43.96, 159.00, 168.09 ppm; FT-IR (KBr): 3138, 2954, 1763, 1602, 1508, 1455, 1342, 1218,
-1
1
155, 1091 cm . 3e: HNMR (400 MHz, DMSO): δ = 1.24 (t, J = 8.0 Hz, 3H), 2.39 (s, 3H), 4.20
(q, J = 8.0 Hz, 2H), 4.38 (s, 2H), 4.39 (s, 2H), 5.36 (s, 2H), 6.27 (m, 1H), 6.3 (m, 1H), 7.37 (d, J =
1
3
8
.0 Hz, 2H), 7.52 (m, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.93 (s, 1H); CNMR (100 MHz, DMSO): δ
14.43, 21.46, 42.35, 43.60, 50.75, 61.95, 110.28, 110.93, 125.87, 127.52, 130.09, 136.81, 142.69,
43.50, 143.64, 149.50, 167.59 ppm; FT-IR (KBr): 3330, 2985, 1750, 1508, 1468, 1417, 1371,
=
1
1
4
2
-1
1
185 cm . 3f: HNMR (400 MHz, DMSO): δ =1.21 (t, J = 8.0 Hz, 3H), 2.41 (s, 3H), 3.72 (s, 3H),
.16 (q, J = 8.0 Hz, 2H), 4.87 (s, 2H), 5.34 (s, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz,
1
3
H), 7.40 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.96 (s, 1H); CNMR (100 MHz, DMSO):
δ = 14.38, 21.50, 46.71, 50.81, 55.68, 61.90, 114.50, 125.88, 127.88, 130.16, 130.41, 131.59,
1
1
2
35.65, 143.16, 143.94, 159.01, 167.55 ppm; FT-IR (KBr): 3287, 2951, 1755, 1599, 1441, 1337,
-1
1
156 cm . 4: HNMR (400 MHz, DMSO): δ = 2.14 (s, 3H), 2.42 (s, 3H), 4.91 (s, 2H), 5.39 (s,
H), 7.09 (d, J = 8.0 Hz, 2H), 7.30 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H),
5

1
3
7
1
3
.81 (s, 1H); CNMR (100 MHz, DMSO): δ = 21.51, 27.37, 46.42, 58.61, 125.85, 127.84,
28.22, 128.86, 129.34, 130.19, 135.53, 139.26, 142.88, 144.05, 201.22 ppm.
. Results and discussion
N-propargylsulfonamides 1 are readily prepared from the commercial available materials.
Reaction of p-toluenesulfonyl chloride with an amine in pyridine for two hours at room
temperature gives the corresponding sulfonamide in excellent yield. Treatment of the synthesized
sulfonamide with propargyl bromide in the presence of K CO in CH CN at 80 °C affords the N-
2
3
3
propargylsulfonamides 1.
With the N-propargylsulfonamides 1 and α-haloester 2 in hand, we turned our attention to the
CuAAC reaction. To find the optimal conditions, the reaction of ethyl 2-bromoacetate 2a, sodium
azide and N-propargylsulfonamide 1a was used as a model reaction. A mixture of 2a (1 mmol),
sodium azide (1.2 mmol) and solvent (5 mL) was stirred at room temperature for 1 h and then N-
propargylsulfonamide 1a was added to the mixture and was stirred under various reaction
conditions (Table 1). In the absence of catalyst the product was not produced even after 10 h
(entry 1). Using organic solvents such as ethanol and methanol decrease the reaction yield.
Sodium azide is not very soluble in organic solvents (entries 3 and 4). In the mixture of
water/ethanol (1:1), the yield of the reaction increased to 68% (entry 5). The effect of temperature
was also investigated by carrying out the model reaction at 80 °C. The yield of 3a was not affected
more as the reaction temperature was raised (entry 6). The model reaction was accomplished by
using Sharpless catalytic system which moderate yield of the desired product 3a was obtained
°
(
Table 1, entry 7). Thus, as shown in Table 1 heating of 1a with 2a and NaN at 60 C in the
3
presence of CuI (10 mol%) in the mixture of ethanol/water (1:1) were determined as optimal
reaction conditions which resulted the desired triazole derivative 3a in good yield (75%).
6

Table 1. Optimization conditions of the model reaction for synthesis of 3a.
a
Entry
Catalyst
-
Solvent
Yield (%)
1
2
3
4
5
6
H O/EtOH
2
-
CuI
CuI
CuI
CuI
H O
2
42
39
27
75
67
EtOH
MeOH
H O/EtOH
2
b
CuI
H O/EtOH
2
CuSO / sodium ascorbate
4
7
H O/EtOH
2
51
(
20 mol%)
a
Reaction conditions: Solvent (5 mL, 1:1), N-propargylsulfonamide 1a (1 mmol), ethyl 2-bromoacetate 2a (1 mmol),
b
NaN (1.2 mmol), catalyst (10 mol%), 60 °C and reaction time 10 h; at 80 °C.
3
With the optimized conditions in hand, various N-propargylsulfonamides 1 were allowed to react
with α-haloesters 2 and sodium azide in the presence of CuI in water/ethanol. All the substrates
efficiently proceed to give the corresponding 1,2,3-triazole derivatives 3 in good yields (Scheme
1
13
3
). The results of H, C NMR and FT-IR spectral data reflected the assigned structure of the
1
13
synthesized products. As a representative example, H NMR, C NMR and FT-IR spectral data of
the compound 3c are discussed in following section (computation section) and compared with
DFT calculated data.
7

Scheme 3. The synthesis of novel 1-ester 4-sulfonamide-1,2,3-triazole derivatives 3.
Interestingly, when 2-chloromethylacetoacetate was used as a substrate, the cycloaddition reaction
takes place along with the decarboxylation of the 1,2,3-triazole product, leading to 1-acetyl 4-
sulfonamide-1,2,3-triazole 4 (Scheme 4).
Scheme 4. Efficient synthesis of 1-acetyl 4-sulfonamide-1,2,3-triazole derivative 4.
A plausible mechanism for the preparation of 1,2,3-tiazole derivatives 3 was suggested in Scheme
5. First, N-propargylsulfonamide interacts with CuI to form intermediate A, as a copper acetylide,
followed by coordination of α-azidoester B to the copper of the acetylide initiates a thermally
allowed [4πs + 2πs] cycloaddition reaction. Removal of copper from intermediate C, leads to the
desired product 3. It should be mentioned that formation of α-azidoester proceeds via a SN2
mechanism. Direct substitution reaction of azide ion take place rapidly in α-azidoester or α-
azidoamide systems. The π-LUMO of the carbonyl group in these substrates provide extended
8

conjugation, which can be stabilized the transition state in the S mechanism [37], so α-haloesters
N2
compounds afforded the corresponding 1,2,3-triazoles in good yields, as shown in Scheme 3.
O
X
OR3
SN2
NaN3
+
R1
N
Cu
O
_
S
N
N
N
O
A
+
O
OR3
Me
B
Cu+
R1
N
Me
O
O
S
R1
O
OR3
O
Cu
S
H O
2
N
O
N
N N
C
1
Me
N
N
O
O
S
N
Me
N
OR3
R1
O
3
Scheme 5. Proposed mechanism for synthesis of 1,2,3-triazole derivatives 3.
With the encouraging experimental data of 1-ester 4-sulfonamide-1,2,3-triazole derivatives 3, our
attention was turned on DFT calculations for investigation of physicochemical properties of 3c
such as electrophilicity index (HOMO-LUMO analysis), spectral data (FT-IR and NMR), and its
+
+
interaction with Li and Na . It should be noted that the computational methods have become a
very useful and trustable tool for chemists. Moreover, DFT-B3LYP computational method is
utilized by organic chemists as a straightforward and fast method for a variety of chemical
calculations [38-47]. This method has been utilized here for performing the computations.
Optimized structure for the B3LYP/6-31G(d) of 3c is shown in Fig. 1. The obtained DFT data of
3c is listed in the Table 2.
9

Fig. 1. Optimized geometry for the B3LYP/6-31G(d) of 3c.
Table 2. The obtained DFT data of molecule 3c at B3LYP/6-31G(d) level.
Parameter
Energy (Hartree)
ꢀD (Debye)
Value
-1691.146
9.376
-0.221
-0.021
0.2
EHOMO (eV)
ELUMO (eV)
Eg (eV)
Chemical potential (ꢀ) (eV)
Chemical hardness (η) (eV)
Electrophilicity (ω) (eV)
-0.121
0.1
0.073
Dipole moment (ꢀ ) for 3c is 9.37 which demonstrates it has high dipolar properties. One reason
D
for this dipolar value is the presence of polar functional motifs, carbonyl and sulfonamide, in its
structure. ELUMO is the energy of the lowest unoccupied molecular orbital and EHOMO is the energy
1
0

of the highest occupied molecular orbital. The HOMO reveals the ability to donate an electron,
while the LUMO reveals the ability to accept an electron. EHOMO and ELUMO of 3c are -0.221 eV
and -0.021 eV, respectively (Table 1). Fig. 2 shows the graphical sketches of HOMO and LUMO
orbitals of the molecule 3c.
Fig. 2. Calculated HOMO and LUMO for 3c at B3LYP/6-31G(d).
As shown in Fig. 2 the HOMO orbital is localized on furyl ring, while the LUMO orbital is mainly
located on ester motif, due to bearing an electron withdrawing carbonyl group.
Electrophilicity is a fundamental object of organic compounds, which involves some adequate
information regarding structure, reactivity, aromaticity, and toxicity, etc. [48-50]. Parr and
coworkers defined electrophilicity (ω) as [51]:
2
ω = ꢀ /2η
(1)
ꢀ
= (ELUMO + EHOMO)/2
and
η = (ELUMO – EHOMO)/2
(2)
where ꢀ and η are the chemical potential and chemical hardness, respectively given by equation
2). The electrophilicity index of 3c, equals to 0.073 eV.
(
One of the main important goals of the DFT calculations is to properly assign the experimental
frequencies to the computed vibrational modes of optimized structure of 3c. The scaling factors
-1
-1
0
.98 for below 1800 cm and 0.99 for above 1800 cm were applied for calculated frequencies
1
1

[
52]. In general, there was a good agreement between experimental and calculated IR data.
-1
Triazole ring C-C stretching band for 3c in simulated IR spectrum appears at 1597 cm . The S=O
-1
stretching band for sulfonamide motif was appeared at 1304 cm and its calculated counterpart
-1
appears at 1292 cm . The characterized C=O stretching band for ester group were observed at
-1
-1
1
751 cm , while the corresponding calculated one appear at 1801 cm .
1
The experimental H NMR spectrum of 3c consisted of two singlet signals at δ = 2.39 and 3.72
ppm for -CH and -OCH group, respectively, a multiplet signal at δ = 4.40 for two methylene
3
3
groups (-CH ), a sharp singlet peak at δ = 5.39 for the –CH CO group, two multiplet lines for furyl
2
2
protons at δ = 6.27 and 7.36 ppm, five signals for furyl and phenyl protons at δ = 7.32–7.70 ppm,
1
13
and one characteristic singlet peak for triazole proton at δ = 7.95 ppm. The H–decoupled C
NMR spectrum of 3c showed 16 resonances, which is in agreement with the proposed structure,
with the ester carbon appearing at δ = 168.10 ppm, 10 distinct resonances for the aromatic carbons
of phenyl, furyl and triazole groups between δ = 110.30-149.51 ppm, a peak at δ = 52.98 ppm for
carbon of methoxy group, a line at δ = 50.66 ppm for CH CO and three distinct resonances at δ =
3
21.44-43.66 ppm for carbon of methylenes.
1
13
Representative B3LYP computed H and C chemical shifts for 3c with experimental data are
inserted in Table 3. It should be mentioned that the NMR calculations were done by using the
gauge-independent atomic orbital (GIAO) method [53]. It should be mentioned that NMR
calculations are sensitive for polarization function. The 6-31G(d) basis set is too small and cannot
provide reliable results. Therefore 6-31+G(d, p) basis set was used for NMR calculations. On the
other hand, since the experimental NMR spectra have been carried out in DMSO as solvent, the
data of NMR chemical shifts for 6-31+G(d, p) optimized geometry 5c in DMSO were also
obtained in same basis set and solvent (Table 3).
1
2

1
13
a
Table 3. Representative 6-31+G(d, p) calculated and experimental H and C chemical shifts of
c.
δ 6-31+(d, p) in the gas δ 6-31+(d, p) in DMSO
3
b
Atom
H45
H30
H25
H20
H5
δ exp.
2.39
2.37
3.91
2.26
3.85
3.72
5.39
4.65
4.86
7.94
7.40
7.68
5.39
4.60
4.51
H8
4.40
3.96
4.24
C44
C24
C28
C27
C11
C13
21.44
50.66
52.98
168.10
110.94
110.30
22.63
51.50
53.67
165.59
108.51
107.03
23.14
52.86
55.27
167.95
110.42
108.68
a
b
In ppm; For numbering of atoms refer Fig. 1.
1
13
The correlations of H and C NMR data in DMSO for 6-31+(d, p) basis set are presented in Fig.
1
13
3
. The correlation coefficients for the H and CNMR data in the gas phase for 6-31+G(d, p) are
1
13
also available in supporting information. The calculated H and C chemical shifts are in good
agreement with the experimental data (Fig. 3).
1
3

1H NMR in DMSO
9
8
7
6
5
4
3
2
1
0
y = 0.9275x + 0.0482
R² = 0.9662
0
2
4
6
8
10
Experimental
13C NMR in DMSO
1
80
1
1
1
1
60
40
20
00
y = 0.9774x + 2.5873
R² = 0.9996
80
60
40
20
0
0
50
100
150
200
Experimental
1
13
Fig. 3. The linear regression between experimental and 6-31+G(d, p) calculated H and C NMR
data for 3c.
It should be mentioned that chemical shifts were reported in parts per million relative to
1
13
tetramethylsilane (TMS) for H and C NMR spectra. Relative chemical shifts were calculated by
using the corresponding TMS shielding calculated at the same theoretical level and conditions as
the reference.
In most of biological processes such as the stabilization of biomolecular conformations, osmotic
balance, and information transfer via ion pumps, metal ions have vital rules. Sodium cation is the
+
+
most important electrolyte in biological systems [54, 55]. Understanding of Li and Na ion
interactions with the synthesized compounds 3, and to obtain some information about the intrinsic
binding poses of these ions to 3c, can be useful. Cation affinity (CA) of 3c can be determined in
1
4

the gas phase as the negative value of the enthalpy variation (ꢁH) in the following reaction
Scheme 6) by using equation (3) [56].
(
Scheme 6. Chemical process for cation affinity calculation of 3c.
+
+
CA(ꢀꢁ)ꢂ=ꢂ−∆Hꢂ =ꢂ−∆Eꢂ −ꢂ∆(pv)ꢂ=ꢂ−E(ꢀꢁ―M )ꢂ+ ꢂE(ꢀꢁ)ꢂ+ ꢂE(M )ꢂ+ ꢂRTꢂꢂꢂꢂꢂꢂꢂꢂ(3)
In equation (3) E is the total energy calculated for the optimized structures of both 3c and
metalated 3c in the gas phase [57].
DFT calculations were done on structure of 3c, metalated in its active sites. The cation can interact
with 3c at different positions: (1) with a nitrogen atom of triazole ring; (2) as a tetra-coordinated
ligand with two nitrogen atoms of triazole ring, oxygen atom of furyl ring, and oxygen atom of
O=C group, and (3) as a tri-coordinated ligand with oxygen atom of furyl ring, oxygen atom of
O=S group, and nitrogen atom of sulfonamide motif. As shown in Fig. 4, the structure of 3c is
significantly changed during metalation.
1
5

Fig. 4. Optimized structures of lithiated and sodiated 3c at the B3LYP/6-31G(d) level and their
relative energies in kJ/mol.
The tetra-coordinated complexes (Li (2) and Na (2)), are the most stable lithiated and sodiated
+
structure of 3c, in which M has attractive electrostatic interaction with the nitrogen atoms of
triazole group, oxygen atom of furyl ring, and O=C group (Fig. 4). DFT calculations show that the
lithiation of 3c is more exothermic than the sodiation. Difference in energies (80.78 kJ/mol)
+
+
between Li (2) and Na (2) shows that in interaction of M with the face a π system, Li is in close
+
proximity to aromatic rings in comparing of Na , due to its longer radius, positive charge is spread
+
over large space than Li . Atomic charge in molecules has been used to describe the processes of
electronegativity equalization and charge transfer in chemical reactions. Atomic polar tensor
(APT) charges [58] affect electronic structure, dipole moment, and molecular polarizability. The
ATP charge distribution structure of Li(1) and Na(1) are shown in Fig. 5. Most of the hydrogen
atoms exhibit a net positive charge between 0.01-0.13 in APT analysis. All nitrogen atoms show
negative charge in the range of -1.10 to -0.70. The Li and Na atoms in these complexes exhibit
positive charge 0.602 and 0.762, respectively.
1
6

Fig. 5. The Atomic polar tensor charge distribution for Li (1) and Na (1).
It is interesting to note that in complexes Li (1) and Na (1), the cation can be interacted with π
system of phenyl group (cation π interaction) [59, 60]. First evidence of this kind interaction in the
gas phase was mentioned by Kebarle in 1981 [61]. The cation π interaction arises from the
+
+
+
electrostatic interaction of M with the face of a π system. Comparing of Na , Li is in close
proximity to aromatic rings, follows the classical electrostatic interaction (Fig. 4. In comparing
with other structures of the complexes, Li (1) and Na (1) have not lowest energies. Heteroatom-
cation interactions (the complexes Li (2), Li (3), Na (2) and Na (3)) are stronger that the cation π
interaction (Fig. 4).
+
Comparison of aromaticity index of phenyl group in 3c, after metalation with M , is also
informative for cation π interaction. Aromaticity deals with the induced ring currents, therefore the
magnetic susceptibility becomes more prominent for the aromaticity determination [62]. The
nucleus–independent chemical shift (NICS) estimates the absolute magnetic shielding at the center
of a ring [63, 64]. It should be noted that the more negative value of NICS, the more aromatic is
the ring. It is expected that after metalation the aromaticity of phenyl group decreases. As shown
in Fig. 6, in both lithiated Li (1) and sodiated Na (1) structures of 3c, the aromaticity of phenyl
1
7

+
was decreased in comparing to unmetalated 3c or complex Li (2), in which Li is coordinated with
other sites of the molecule.
Fig. 6. The cation π interaction in complexes of Li (1) and Na (1) of 3c. The bond distances are in
Å. The NICS values are calculated at GIAO-B3LYP/6-31G(d) level and in ppm. The atom in
center of phenyl group is a Bq atom as a probe.
It should be mentioned that the NICS values for phenyl group in 3c and Li (2) are the same. The
cation π interaction was also observed in furyl ring of complexes Li (2) and Na (2) of 3c (Fig. 7).
1
8

Fig. 7. The cation π interaction in complexes of Li (2) and Na (2) of 3c. The bond distances are in
Å. The NICS values are calculated at GIAO-B3LYP/6-31G(d) level and in ppm. The atom in
center of furyl group is a Bq atom as a probe.
4. Conclusions
We have developed an efficient and practical protocol for the synthesis of 1-ester 4-sulfonamide-
1,2,3-triazole derivatives as novel privileged scaffolds. The method is based on azidation of α-
haloesters with sodium azide following by click azide‒alkyne [3 + 2] cycloaddition reaction using
H O/EtOH as a green reaction medium in the presence of 10 mol % of CuI. This click reaction
2
takes place under mild and green conditions. Further work is in progress to synthesis of 1-ketone
4-sulfonamide-1,2,3-triazole derivatives. The HOMO-LUMO analysis, NMR and FT-IR studies of
3c have been also studied using DFT calculations. The DFT results show that in some metalated
structures of 3c, there are some cation π interactions which for the first time, the NICS index was
used to prove this kind of interaction.
Conflicts of interest
There are no conflicts to declare.
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2
3

1
2
. The novel 1,2,3-triazole scaffolds were synthesized by using a CuAAC reaction.
. DFT calculations were used to obtain physicochemical properties of the product
3
c.
3
. Lithium ion affinity of 3c was determined as 80.78 kJ/mol higher than its sodium
affinity.

Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: