Synthesis of 1-aroyl-3-methylsulfanyl-5-amino-1,2,4-triazoles and their analysis by spectroscopy, X-ray crystallography and theoretical calculations

Article abstract of DOI:10.1016/j.molstruc.2020.129317

N-Aroyl-1,2,4-triazoles TAM and TACl were regioselectively synthesized in excellent yields through an efficient N-acylation reaction of 3-amino-5-methylsulfanyl-1H-1,2,4-triazole with aroyl chlorides. Structures of N-aroyl-1,2,4-triazoles were studied by

Full text of DOI:10.1016/j.molstruc.2020.129317

Journal of Molecular Structure 1226 (2021) 129317
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis of 1-aroyl-3-methylsulfanyl-5-amino-1,2,4-triazoles and their
analysis by spectroscopy, X-ray crystallography and theoretical
calculations
Rodolfo Moreno-Fuquena,∗, María Mercedes Hincapié-Oteroa, Diana Becerrab,
Juan-Carlos Castillob,c, Jaime Portillac, Mario A. Macíasd,∗
a Grupo de Cristalografía, Departamento de Química, Universidad del Valle, A.A. 25360, Santiago de Cali, Colombia
b Escuela de Ciencias Química, Universidad Pedagógica y Tecnológica de Colombia, Avenida Central del Norte 39-115, Tunja, Colombia
c Bioorganic Compounds Research Group, Department of Chemistry, Universidad de los Andes, Carrera 1 No. 18A-10, Bogotá, Colombia
d Department of Chemistry, Universidad de los Andes, Carrera 1 No. 18A-10, Bogotá, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Aroyl-1,2,4-triazoles TAM and TACl were regioselectively synthesized in excellent yields through an
efficient N-acylation reaction of 3-amino-5-methylsulfanyl-1H-1,2,4-triazole with aroyl chlorides. Struc-
tures of N-aroyl-1,2,4-triazoles were studied by single-crystal X-ray diffraction, observing that their crys-
tal structures are characterized by the formation of dimers through N–H···N bonds. The supramolecu-
lar assembly depends on the sort of connections between dimers, which notably change with the para-
substituent on the aroyl group. The directly calculated ionization potential (IP), electron affinity (EA),
electronegativity (χ), electrophilicity index (ω), hardness (η), and chemical potential (μ) are correlated
with the HOMO and LUMO orbital energies. Moreover, molecular electrostatic potential maps of both
molecules have been calculated showing a negative region at N2 atom of the 1,2,4-triazole ring instead
of exocyclic amino group. The vibrational spectral analysis was carried out using infrared spectroscopy
in the range 4000–400 cm−1 for N-aroyl-1,2,4-triazoles TAM and TACl. The experimental spectra were
recorded in the solid state. The fundamental vibrational frequencies and intensity of vibrational bands
were evaluated using density functional theory (DFT) with the standard B3LYP/6–31G(d,p) method and
basis set yielding fairly good agreement between observed and calculated frequencies. Simulation of in-
frared spectra utilizing the results of these calculations led to an excellent overall agreement with the
observed spectral patterns.
Received 8 July 2020
Revised 19 September 2020
Accepted 20 September 2020
Available online 22 September 2020
Keywords:
N-aroyl-1,2,4-triazole
DFT quantum-chemical studies
Hirshfeld surface maps
Regioselectivity
X-ray crystallography
Structural energy
© 2020 Published by Elsevier B.V.
1. Introduction
Among the broad range of privileged structures, 1,2,4-triazole
represents one of the most prominent classes of N-heterocyclic
Amide group is one of the most important chemical building
blocks found in nature and is also part of a vast number of syn-
thetic structures. This structural unit constitutes the backbone of
peptides, proteins, bioactive compounds, commercial drugs, agro-
chemicals, and polymers [1,2]. The classical amide moiety forma-
tion is among the most executed procedures in the chemistry
and pharmaceutical industry. From the viewpoint of atom econ-
omy and environmental sustainability, the amide bond construc-
tion by operationally simple, efficient, eco-friendly, and chemose-
lective methodologies is still in great demand [1–4].
scaffolds for drug discovery due to its wide range of biological and
pharmacological properties such as analgesic [5], antiviral [6,7], an-
timicrobial [8], antifungal [9,10], antihypertensive [11], and anti-
cancer [12]. Furthermore, the use of 1,2,4-triazole derivatives con-
taining an amine group enables the preparation of highly function-
alized triazole-based compounds with interesting biological activ-
ities [13,14]. For example, amino-1,2,4-triazoles are amenable to
further derivatization via palladium-catalyzed Buchwald-Hartwig
amination [15,16], and N-acylation reaction [17]. Particularly, N-
acyl-1,2,4-triazoles are still highly desirable due to their high se-
lectivity towards pharmacological targets, including cells infected
with the rubella virus [18,19], inhibitors of CDK1 and CDK2 [20],
and Microsomal Triglyceride Transfer Protein (MTP) inhibitors use-
ful in the treatment of atherosclerosis [21]. Although diverse syn-
thetic methods have been developed for the synthesis of amide-
∗
Corresponding authors.
E-mail addresses: rodolfo.moreno@correounivalle.edu.co (R. Moreno-Fuquen),
ma.maciasl@uniandes.edu.co (M.A. Macías).
https://doi.org/10.1016/j.molstruc.2020.129317
0022-2860/© 2020 Published by Elsevier B.V.

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
Scheme 1. Chemo and regioselective acylation reaction of 3-amino-5-methylsulfanyl-1H-1,2,4-triazole (1) with aroyl chlorides (2).
containing 1,2,4-triazoles, there remains a great need to find oper-
ationally simple and sustainable methodologies for the chemo- and
regioselective N-acylation reaction of 3-amino-5-methylsulfanyl-
1H-1,2,4-triazole.
IR spectra of the 1,2,4-triazole-based amides were measured in
the region 4000–600 cm−1 using a SHIMADZU IR Affinity-1 spec-
trophotometer (equipped with an ATR accessory). Spectra are re-
ported in wavenumber (cm−1) and only selected resonances are
reported. Mass spectra were recorded on a Shimadzu-GCMS 2010-
DI-2010 spectrometer (equipped with a direct inlet probe) operat-
ing at 70 eV. UV–Vis absorption spectra were recorded in methanol
(50 μM) at 298.15 K on a Thermo Scientific Evolution 220 UV–
Vis spectrophotometer using a peltier control and a cooling unit
PCCU1. The X-ray intensity data were measured at room tempera-
In connection with the ongoing development of efficient
protocols for amide bond construction [17], and our contin-
uing interest in the search of simple and greener methods
for the synthesis of biologically active N-heterocycles [22–25],
we envisioned that the chemo- and regioselective N-acylation
of 3-amino-5-methylsulfanyl-1H-1,2,4-triazole (1) with aroyl
chlorides 2a-b would provide the 5-amino-3-(methylthio)−2,5-
dihydro-1H-1,2,4-triazol-1-yl)(p-tolyl)methanone (3a, TAM) and
5-amino-3-(methylthio)−2,5-dihydro-1H-1,2,4-triazol-1-yl)(4-
chlorophenyl)methanone (3b, TACl) using triethylamine as a base
in the absence of any additive or catalyst (Scheme 1). In this work,
the structures of N-aroyl-1,2,4-triazoles TAM and TACl (Scheme 1)
were investigated using X-ray crystallography and both theoretical
and spectroscopic studies.
˚
ture, 298 (2) K, using MoKα radiation (λ = 0.71073 A) in an Ag-
ilent SuperNova, Dual, Cu at Zero, Atlas four-circle diffractometer
equipped with a CCD plate detector. The collected frames were in-
tegrated with the CrysAlis PRO software package [26]. Data were
corrected for the absorption effect using the CrysAlis PRO soft-
ware package by the empirical absorption correction using spheri-
cal harmonics, implemented in the SCALE3 ABSPACK scaling algo-
rithm [26]. The structures of TAM (3a) and TACl (3b) were solved
using an iterative algorithm [27], and then completed by difference
Fourier map.
2. Experimental
2.1. General information
2.2. Synthesis
All reagents were purchased from commercial sources and
used without further purification unless otherwise noted. All start-
ing materials were weighed and handled in air at room tem-
perature. The reactions were monitored by TLC visualized by UV
lamp (254 nm or 365 nm). Flash chromatography was performed
on silica gel (particle size 0.040−0.063 mm). NMR spectra were
recorded at 400 MHz (1H) and 101 MHz (13C) at 298 K using
tetramethylsilane (0 ppm) as the internal reference. NMR spectro-
scopic data were recorded in CDCl3 using as internal standards
the residual non-deuterated signal for 1H NMR and the deuter-
ated solvent signal for 13C NMR spectroscopy. DEPT spectra were
used for the assignment of carbon signals. Chemical shifts (δ)
are given in ppm and coupling constants (J) are given in Hz.
The following abbreviations are used for multiplicities: s = sin-
glet, d = doublet, t = triplet, q = quartet, dd = doublet of dou-
blets, and m = multiplet. Melting points were determined using
a capillary melting point apparatus and are uncorrected. The FT-
2.2.1. Regioselective synthesis of
1-(aroyl)−3-methylsulfanyl-5-amino-1,2,4-triazole 3a-b
The corresponding aroyl chloride 2a-b (2.0 mmol) was
added dropwise to a solution of 3-amino-5-methylsulfanyl-1H-
1,2,4-triazole (1) (2.0 mmol) and triethylamine (2.4 mmol) in
dichloromethane (5.0 mL) (Scheme 2). The mixture was stirred
at 298 K for 1 h until the starting materials were no longer de-
tected by thin-layer chromatography. After the solvent was re-
moved under reduced pressure, water (5.0 mL) was added, and the
aqueous solution was extracted with ethyl acetate (2 × 5.0 mL).
The combined organic layers were dried with anhydrous magne-
sium sulfate, and the solvent was removed under reduced pres-
sure to afford the crude compound. Ultimately, the crude prod-
uct was purified by flash column chromatography on silica gel
using CH2Cl2/MeOH (30:1, v/v) as eluent to afford pure N-aroyl-
1,2,4-triazoles 3a-b. Single crystals of both compounds suitable
for diffraction analysis were grown via slow evaporation from
Scheme 2. Synthesis of 1-(aroyl)−3-methylsulfanyl-5-amino-1,2,4-triazoles 3a-b.
2

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
methanol at room temperature under ambient atmosphere. Al-
though N-aroyl-1,2,4-triazoles 3a-b were synthesized three decades
ago [19,28]; the structural and electronic information obtained
from spectroscopic, crystallographic, and DFT quantum-chemical
analysis has not been reported.
(μ), electronegativity (χ) and hardness (η). The molecular elec-
trostatic potential analysis is presented as a powerful tool for the
knowledge of charge distribution and its results can be useful in
determining how molecules interact with each other. The multi-
wfn algorithm was used for these calculations [35]. The electronic
absorption spectra were obtained from TD-DFT calculations using
the same method and level of theory used to estimate the vibra-
tional frequencies and the integrated integral equation formalism
for the polarizable continuum model (IEFPCM) was applied to con-
sider solvent effects in the calculation.
2.2.2. 1-(4-Methylbenzoyl)−3-methylsulfanyl-5-amino-1,2,4-triazole
(3a, TAM)
Following the general procedure, the reaction of 1 (260 mg)
with 4-methylbenzoyl chloride (2a) (264 μL) and triethylamine
(334 μL) afforded amide TAM (3a) as a white solid [462 mg,
93% yield, m.p. 461–462 K (amorphous)]. Lit. 459–461 K [19]. Rf
(CH2Cl2/MeOH: 30/1) = 0.36. Recrystallization of TAM (3a) from
methanol afforded crystalline white prisms suitable for single-
crystal X-ray diffraction analysis. 1H NMR (400 MHz, CDCl3):
δ = 2.43 (s, 3H, CH3), 2.53 (s, 3H, SCH3), 6.91 (br s, 2H, NH2),
7.28 (d, J = 8.0 Hz, 2H, Ar–H), 8.15 (d, J = 8.0 Hz, 2H, Ar–H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ = 13.7 (SCH3), 21.8 (CH3), 128.9
(CH), 131.6 (Cq), 131.6 (CH), 144.4 (Cq), 158.9 (Cq), 162.5 (Cq), 167.5
(Cq) ppm. The UV−Vis spectra of 3a (50 μM) was obtained in
methanol with a λmax at 248 nm and 289 nm. MS (70 eV) m/z (%):
248 (12, M+), 119 (100), 91 (91), 74 (29), 65 (52) (see Supporting
Information).
2.4. Refinement and data collection strategy
Crystal data, data collection, and structure refinement details
are summarized in Table 1. The X-ray intensity data were mea-
sured at room temperature [298 (2) K] using CuKα radiation
˚
(λ = 1.54184 A), and ω scans, in an Agilent SuperNova, Dual, Cu at
Zero, Atlas four-circle diffractometer equipped with a CCD plate de-
tector. The collected frames were integrated with the CrysAlis PRO
software package (CrysAlisPro 1.171.39.46e, Rigaku Oxford Diffrac-
tion, 2018). Data were corrected for the absorption effect using the
CrysAlis PRO software package by the empirical absorption correc-
tion using spherical harmonics, implemented in the SCALE3 AB-
SPACK scaling algorithm. The final anisotropic full-matrix least-
squares refinements on F2 with 163, and 161 variables converged
at R1 = 5.3%, and 3.5% for the observed data, and R2 = 13.7%
and 9.2% for all data. The goodness-of-fit was 1.07 and 1.04 for
TAM (3a) and TACI (3b), respectively. The largest peaks in the fi-
2.2.3. 1-(4-Chlorobenzoyl)−3-methylsulfanyl-5-amino-1,2,4-triazole
(3b, TACl)
Following the general procedure, the reaction of 1 (260 mg), 4-
chlorobenzoyl chloride (2b) (256 μL) and triethylamine (334 μL)
afforded compound TACl (3b) as a white solid [520 mg, 97% yield,
m.p. 458 K (amorphous)]. Lit. 448–450 K [28]. Rf (CH2Cl2/MeOH:
30/1) = 0.28. Recrystallization of TACl (3b) from methanol afforded
crystalline white prisms suitable for single-crystal X-ray diffraction
analysis. 1H NMR (400 MHz, CDCl3): δ = 2.53 (s, 3H, SCH3), 6.84
(br s, 2H, NH2), 7.46 (d, J = 8.4 Hz, 2H, Ar–H), 8.21 (d, J = 8.4 Hz,
2H, Ar–H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ = 13.7 (SCH3),
128.5 (CH), 130.0 (Cq), 132.9 (CH), 140.0 (Cq), 159.0 (Cq), 163.2
(Cq), 166.5 (Cq) ppm. The UV−Vis spectra of 3b (50 μM) was ob-
tained in methanol with a λmax at 248 nm and 304 nm. MS (70 eV)
m/z (%): 270/268 (9/24, M+), 141/139 (32/100), 113/111 (34/94), 85
(27), 75 (67) (see Supporting Information).
−
3
˚
nal difference electron density synthesis were 0.253/0.304 e /A ,
−
3
˚
and the largest holes were −0.248/−0.271 e /A with RMS devi-
−
3
˚
ations of 0.05/0.04 e /A , respectively. Table 1 shows the num-
ber of measured reflections (the total number of intensities, ex-
cluding reflections that are classed as systematically absent aris-
ing from translational symmetry), independent reflections (include
Friedel-equivalent reflections, i.e. symmetry-equivalent under Laue
symmetry but inequivalent under crystal class), and observed re-
flections (significantly intense, satisfying the criterion specified by
I > 2\σ(I) and may include Friedel-equivalent reflections) (see dic-
tionary at enCIFer version1.51.).
All the non-hydrogen atoms were refined anisotropically, while
the hydrogen atoms were generated geometrically, placed in calcu-
˚
–
lated positions (C H = 0.93−0.96 A), and included as riding con-
tributions with isotropic displacement parameters set at 1.2 − 1.5
times the Ueq value of the parent atom. H atoms belonging to N—
H groups were located in difference density maps and were re-
fined freely. The crystal structures were refined using the program
SHELXL2014 [36]. Molecular and supramolecular graphics were car-
ried out using the software Mercury [37]. Single crystals of N-
aroyl-1,2,4-triazoles 3 suitable for diffraction analysis were grown
via slow evaporation from methanol at room temperature under
ambient atmosphere.
2.3. Computational study
The geometry optimization of the 1-(aroyl)−3-methylsulfanyl-
5-amino-1,2,4-triazoles 3a-3b was performed using Density Func-
tional Theory (DFT) Becke’s three-parameter hybrid function with
the non-local correlation of Lee-Yang-Parr (B3LYP) method at 6–
31G(d,p) basis set [29–31]. A linear regression analysis using re-
sults from two basis sets 6–31G(d,p) and 6–311+G(d,p) showed
that the base 6–31G(d,p) achieved a better behavior in the analysis
of the properties of these compounds with a minor computational
cost (see Supporting Information). The corresponding harmonic vi-
brational frequencies were computed at the same level of theory to
characterize them as minima (no imaginary frequencies) using the
Gaussian09 package program [32], and the zero-point energy (ZPE)
corrections were also performed at the same level of theory. The
assignment of the calculated frequencies was carried out based on
potential energy distribution (PED) analysis, using the “Vibrational
Energy Distribution Analysis” (VEDA4) program [33], and the vibra-
tions were visualized with the program Gauss View 5.0.8 [34]. The
DFT calculations have sought to establish the stability of synthe-
sized 1,2,4-triazole-based amides with the help of quantum chem-
ical descriptors such as Frontier molecular orbitals, HOMO-LUMO
energy gap, and global reactivity descriptors such as potential (IP),
electron affinity (EA), electrophilicity index (ω), chemical potential
3. Results and discussion
3.1. Synthesis of 1-(aroyl)−3-methylsulfanyl-5-amino-1,2,4-triazole
3a-b
The synthesis of amide-containing N-heterocyclic compounds
has received augmented interest over the past decades due to their
broad range of applications in medicinal chemistry, drug design,
and the pharmaceutical industry. The most traditional and sim-
ple procedure for the synthesis of an amide consists of a nucle-
ophilic acyl substitution between an aroyl chloride and an amine
in the presence of a base [17,22]. Applying this procedure to the
stirring of an equimolar mixture of the NH-1,2,4-triazole 1 and 4-
methylbenzoyl chloride (2a) in dichloromethane as solvent and tri-
3

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
Table 1
Crystallographic data of TAM (3a) and TACl (3b).
Crystal Data
TAM (3a)
11H12N4OS
TACl (3b)
Chemical Formula
Mr
C
C10H9ClN4OS
248.31
268.72
Melting point, K
461
458
Solvent for Crystallization
Crystalline system, space group
Methanol
Methanol
P21/n
P-1
˚
a, b, c (A)
5.3866(10), 9.0145(17), 24.833(5)
7.0207(8), 7.6989(9), 12.2124(11)
α, β, γ (°)
90, 92.427(19),90
86.682(9), 87.439(8), 64.728(11)
3
˚
Volume, (A )
ρ, kg m−3
1204.7(4)
1.369
4
595.77(12)
1.498
2
Z
Temperature, (K)
Radiation type
298
298
Mo K
Mo K
α
α
μ (mm−1
)
0.258
0.484
Crystal size (mm)
Theta range for data collection
Index range
0.38, 0.31, 0.29
0.35, 0.28, 0.24
3.254 to 27.564
3.210 to 27.093
−6<=h<=6, −11<=k<=11, −31<=l<=31
−8<=h<=8, −9<=k<=9, −15<=l<=15
Data collection
Diffractometer
Agilent SuperNova Dual Source diffractometer with
an Atlas detector
Agilent SuperNova Dual Source diffractometer with
an Atlas detector
Absorption correction
Tmin, Tmax
Multi-scan (CrysAlis PRO; Agilent, 2014)
0.298, 1.000
Multi-scan (CrysAlis PRO; Agilent, 2014)
0.711, 1.000
No. of measured, independent and observed
reflections [I>2σ(I)]
Rint
13,397, 2643, 2189
12,964, 2615, 2290
0.072
0.031
Refinement
R[F2 > 2σ(F2)], wR(F2), S
0.053, 0.137, 1.07
0.035, 0.092, 1.04
No. of reflections
2189
2290
Refined parameters
H-atoms treatment
163
161
H atoms treated by constrained refinement
H atoms treated by constrained refinement
−3
˚
ꢀρmax, ꢀρmin (e A
)
0.253, −0.248
0.304, −0.271
ethylamine (1.2 equiv) as base at 298 K for 1 h, regioselectively af-
forded the amide TAM (3a) in 93% isolated yield. Rewardingly, the
scope of aroyl chloride substrates was extended to 4-chlorobenzoyl
chloride (2b) leading to the expected amide TACl (3b) in 97% iso-
lated yield. This chemo- and regioselective synthesis of 3a-b was
distinguished by its operational simplicity, high yielding, and the
absence of any drying agent under normal atmospheric conditions.
Albeit these 1,2,4-triazole-based amides 3a-b were previously syn-
thesized three decades ago [19,28], the structural and electronic
information obtained from spectroscopic, crystallographic, and DFT
quantum-chemical analysis has not been reported. For that reason,
TAM (3a) and TACl (3b) were initially characterized by spectro-
scopic techniques (NMR, FT-IR, and UV–Vis) and mass spectrom-
etry (see Experimental section and Supporting Information).
The presence of two absorption bands in the range of 3419–
3431 cm−1 and 3275–3278 cm−1 assigned to the –NH2 function-
ality, and one absorption band in the range of 1674–1680 cm−1
are characterized by two main planes that constitute the com-
plete molecular structures (Fig. 1). The dihedral angles between
the weighted least-squares mean planes that contain the phenyl
and triazole rings are 31.94 ° and 32.59 ° for TAM (3a) and TACl
(3b), respectively (Fig. 1), showing a slight difference in their con-
formations. The different substituting groups in the phenyl ring, –
CH3 and –Cl, have no structural effects over the molecules. Bond
˚
˚
distances such as C10–C8 (~1.48 A), C8–N4 (~1.39 A), and N7–C5
˚
(~1.32 A) are equivalents in both structures. A complete report of
the bond lengths and bond/valence angles for TAM (3a) and TACl
(3b) is shown in the Supporting Information.
In order to obtain a better understanding of the crystal packing,
the crystallographic analysis was complemented with calculations
using CE-B3LYP energy model based on B3LYP/6–31G(d,p) quantum
mechanical charge distribution for unperturbed monomers which
was applied to the molecular crystals. This model is implemented
in CrystalExplorer. In these calculations, the total interaction en-
ergy was modeled as the sum of the electrostatic (Eele), polariza-
tion (Epol), dispersion (Edis), and exchange–repulsion (Erep) terms
based on molecular wavefunctions calculated applying the crys-
tal symmetry obtained from X-ray crystallographic results [38–40].
The electrostatic term corresponds to the classical electrostatic en-
ergy of interaction between monomer charge distributions, and re-
pulsion term the exchange–repulsion energy, both of them are ob-
tained from the antisymmetric product of the monomer spin or-
bitals. The polarization energy is estimated as a sum over atoms
with terms of the kind −1/2α|F|2, with F being the electric field
and α the isotropic atomic polarizabilities. The dispersion energy
term is Grimme’s D2 dispersion correction [38–40].
=
assigned to the newly NC O functionality, are the most relevant
features of the FT-IR spectra. The absence of the triazolic NH pro-
ton and the presence of a broad singlet at 6.91 ppm and 6.84 ppm
for TAM (3a) and TACl (3b), respectively, assigned to the –NH2 pro-
1
=
ton in the H NMR spectra, and the presence of the newly NC
O
functionality at 167.5 ppm and 166.5 ppm for TAM (3a) and TACl
(3b), respectively, in the 13C NMR spectra, suggest that the nu-
cleophilic acyl substitution occurred chemo- and regioselectively
on the N2 atom of the 1,2,4-triazole ring instead of the exocyclic
amino group (–NH2). The most relevant feature in the EI-MS spec-
tra for the 1,2,4-triazole-based amides TAM (3a) and TACl (3b) cor-
respond to a base peak assigned to the respective stable acylium
ions (see Supporting Information).
The supramolecular assembly presented in TAM (3a) and TACl
(3b) systems is different as they crystallize in space groups P21/n
and P-1, respectively. However, from a short distance perspec-
tive, equivalent pairs of N7–H71ꢀN6i,ii hydrogen bonds (symme-
try codes (i): −1-x,2-y,1-z and (ii): 1-x,-y,1-z for TAM (3a) and
TACI (3b), respectively) connect inversion-related molecules form-
ing R22(8) centrosymmetric rings (Figs. 2a and 3a) (Table 2). It is
3.2. X-ray crystallographic analysis
The collected crystal data and structure refinement details of
TAM (3a) and TACl (3b) are summarized in Table 1, and the re-
spective molecular structures are shown in Fig. 1. Both molecules
4

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
Fig. 1. Molecular structures and dihedral angles of (a) TAM and (b) TACl with anisotropic thermal vibration ellipsoids drawn at the 50% probability level. The hydrogen
atoms are shown as spheres of arbitrary radius.
–
Fig. 2. (a). Inversion related molecules of TAM (3a) showing the N HꢀN hydrogen-bond interactions to form dimers. (b) Further connection of dimers through C–HꢀO
hydrogen-bond interactions. (c) and d) π···π stacking interactions between centroids of triazole and phenyl rings. The pairwise interaction energies were calculated based
on references [38–40].
Table 2
are dominated by electrostatic forces compared with other terms
Selected hydrogen-bond geometry (A, o) for TAM (3a) and TACl (3b).
˚
as shown in Table 3. The difference in the packing emerges in
TAM (3a)
the mode in which the molecular dimers are connected. In TAM
(3a), the methyl group substituted in the phenyl ring participates
in the connection of the dimers through C16–H16ꢀO9iii (symmetry
code (iii): –x+1/2,y+1/2,-z+3/2) hydrogen bonds with O···H dis-
D-HꢀA
D-H
HꢀA
DꢀA
D-HꢀA
N7-H71ꢀN6i
C16-H16ꢀO9iii
TACI (3b)
0.860(19)
0.96
2.10(2)
2.62
2.957(3)
3.567(3)
172(2)
169
˚
tances of ~2.62 A (Fig. 2b) (Table 2). The pairwise interaction en-
N7-H71ꢀN6ii
0.859(19)
0.93
2.100(19)
2.68
2.955(2)
3.369(3)
174(2)
131
ergy for this contact is −27.6 kJ/mol but in this case, dispersion
forces are the principal contributors to the total energy (Table 3).
Important πꢀπiv staking interactions are present to connect the
C12-H12ꢀO9v
Symmetry codes: (i) −1-x, 2-y, 1-z; (ii) 1-x, -y, 1-z; (iii) –x+1/2,
y+1/2, -z+3/2; (v) 1+x, y, z.
˚
centroids of triazole rings (3.8244(14) A, symmetry code (iv): -
x,2-y,1-z) with total interaction energy of −20.8 kJ/mol with an
obvious dominance of the dispersion energies (Fig. 2c). These in-
teractions allow the molecules to have their molecular centers of
noteworthy that N···H distances are equivalents in both systems
˚
˚
˚
˚
˚
–
–
mass relatively close, 9.30 A, 7.48 A and 6.63 A for N HꢀN, C HꢀO
and π···π (connecting the centroids of triazole rings), respectively
(Table 3). However, π···π stacking of molecules along [100] di-
rection involving the triazole and phenyl rings simultaneously al-
(2.10(2) A and 2.100(19) A for TAM (3a) and TACI (3b), respec-
tively). This equivalence is observed in the pairwise interaction en-
ergies in these N7–H71ꢀN6i,ii hydrogen bonds, −66.2 kJ/mol, and
−65.9 kJ/mol, respectively. The intermolecular N–HꢀN interactions
5

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
–
–
Fig. 3. (a). Inversion related molecules of TACI (3b) showing the N HꢀN hydrogen-bond interactions to form dimers. (b) Further connection of dimers through C HꢀO
hydrogen-bond interactions. (c) π···π stacking interactions between centroids of phenyl rings. (d) C–ClꢀC halogen interactions along [−101] direction. The pairwise interac-
tion energies were calculated based on references [38–40].
Table 3
Selected CrystalExplorer CE-B3LYP interaction energies (kJ/mol) for TAM (3a) and TACI (3b). N is
the number of molecules with a molecular centroid-to-centroid distance R (A˚). Electron density
was calculated using B3LYP/6–31G(d,p) model energies. Symop is the symmetry operation.
TAM (3a)
N
Symop
R
Eele
Epol
Edis
Erep
Etot
2
1
1
2
x, y, z
5.39
9.30
6.63
7.48
−6.5
−1.5
−19.9
−2.5
−2.2
−42.7
−17.1
−31.5
−30.5
21.7
89.2
14.6
20.7
−31.8
−66.2
−20.8
−27.6
-x, -y, -z
−86.8
−0.5
-x, –y, -z
-x+1/2, y+1/2, -z+1/2
−11.6
TACI (3b)
N
2
1
1
1
1
Symop
R
Eele
Epol
Edis
Erep
Etot
x, y, z
7.02
10.19
4.83
7.63
8.28
−4.4
−86.3
−7.9
−9.5
−5.9
−1.4
−19.4
−1.7
−2.9
−0.5
−21.2
−17.0
−59.7
−33.6
−21.4
11.4
88.1
34.3
21.5
16.7
−17.1
−65.9
−40.4
−28.2
−14.9
-x, –y, -z
-x, –y, -z
-x, –y, -z
-x, –y, -z
Note: scale factors used to determine Etot: Eele = 1.057; Epol = 0.740; Edis = 0.871; Erep = 0.618.
low the molecules to have their centers of mass as close as pos-
action energy higher (Table 3). Interestingly, the molecular dis-
position in the crystal allows imagining the formation of weak
C13–Cl16ꢀC17vii halogen interactions (symmetry code (vii): 3–x,-
˚
sible in the crystal, 5.39 A, with pairwise interaction energy of
−31.8 kJ/mol (Fig. 2d). In this last case, the dispersion term domi-
nates the contact (Table 3). The combination of these interactions
and van der Waals forces act to build the three dimensions assem-
ble.
In TACI (3b), C12–H12ꢀO9v (symmetry code (v): 1+x,y,z) hydro-
gen interactions connect the dimers along [100] direction (Fig. 3b
and Table 2) with an pairwise interaction energy of −17.1 kJ/mol.
In this contact, dispersion energy is the main term that contributes
to the total energy (Table 3). These chains are further connected
˚
y,-z) with Cl···C distances of ~3.43 A, between pairs of molecules
related by inversion centers and running along [−101] (Fig. 3d).
The pairwise interaction energy for this interaction was found to
be −14.9 kJ/mol with the main contribution of dispersion forces
(Table 3).
Computed energies between molecular pairs are represented
using cylinders joining the centroids (molecular center of mass) of
the molecules, with a radius proportional to the magnitude of the
interaction managing a minimal cut-off of 15.0 kJ/mol. Figs. 4a and
4b show the energy framework diagrams for pairs of molecules for
separate electrostatic (red) and dispersion (green) contributions to
the total nearest-neighbor pairwise interaction energies (blue). In
TAM (3a) and TACI (3b), the electrostatic energy is observed mainly
in the N7–H71ꢀN6i,ii hydrogen bonds to connect inversion-related
molecules. However, the three-dimensional assembly is due to dis-
persion forces having in both structures topologies with isotropic
tendencies, certainly more structured in TACI (3b). This detailed
structuration of the total interaction energy framework of TACI
(3b) is reflected in the total structural energy, −95.3 kJ/mol and
by two different π···πvi (3.8607(12) A and 3.9422(12) A; symme-
try code (vi): 2-x,-y,-z) interactions along [001] direction (Fig. 3c)
(Table 2). As it can be observed, this π···πvi stacking occurs along
[010] and involves molecules that have their molecular center of
˚
˚
˚
˚
˚
mass within a distance of 4.83 A and 7.63 A (3.8607(12) A and
˚
3.9422(12) A between centroids, respectively) with pairwise inter-
action energies of −40.4 kJ/mol and −28.2 kJ/mol, in each case
(Fig. 3c). Despite that this π···πvi stacking allows the molecules
to be closer compared with the N–HꢀN hydrogen interactions
˚
(10.19 A between molecular centers of mass), in the last case, the
high contribution from electrostatic forces makes the total inter-
6

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
Fig. 4. Energy framework diagrams for electrostatic (red) and dispersion (green) contributions to the total interaction energies (blue) in (a) TAM (3a) and (b) TACI (3b). (For
interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Table 4
Table 5
CE-B3LYP structural energy components E for TAM (3a) and TACI
(3b) (kJ/mol).
Participation percentages involving intermolecular contacts on the Hirsh-
feld surfaces.
∗
Eele
Epol
Edis
Erep
Etot
NꢀH
CꢀH
OꢀH
CꢀCl
HꢀH
SꢀH
Other
TAM (3a)
TACI (3b)
−62.1
−64.5
−15.0
−15.1
−86.1
91.1
−95.3
TAM (3a)
TACl (3b)
14.3
13.8
18.9
6.8
8.4
8.7
–
39.8
27.4
11.2
7.3
7.4
−118.6
108.7
−115.6
5.3
30.7
∗
The total structural energy is the sum of scaled terms:
The NꢀH intermolecular contacts are similar for the two compounds; how-
ever, the CꢀCl and ClꢀH interactions contribute to the TACl (3b) com-
pound with 18.7% of all intermolecular contacts on the Hirshfeld surface.
C–Hꢀπ/πꢀH–C interactions become more frequent in the compound TAM
(3a) (almost 3 times more) due to the involvement of the methyl group in
this kind of interactions.
Estructural = 1.057Eele + 0.740Epol + 0.871Edis + 0.618 Erep, as de-
scribed in [39].
−115.6 kJ/mol for TAM (3a) and TACI (3b), respectively, calculated
based on the estimation of the interaction energies for selected
˚
molecular pairs in a coordination sphere of 10.0 A around the
These sorts of intermolecular contacts are also observed in some
organic conducting materials and proteins [46]. In TACI (3b), N7–
H71ꢀN6ii hydrogen bonds are observed while the remaining inter-
actions present longer distances not highlighted as red spots in the
dnorm maps (Fig. 5b).
asymmetric unit (Table 4). CE-B3LYP structural energies were then
calculated by direct summation of total interaction energies over
the asymmetric unit [41]. These values suggest a more stable crys-
tal structure in TACI (3b) compared with TAM (3a) (Table 4).
Hydrogen bonds and other interactions enhance the stability of
the supramolecular structure, and this behavior can be observed
through Hirshfeld surface analysis, using the CrystalExplorer pro-
gram [40–42], which allows the visualization of interactions within
the crystalline structure, including N–HꢀN, C–HꢀO and CꢀCl in-
teractions. Assigning de and di as the external and internal dis-
tances of an atom to the Hirshfeld surface and normalizing these
pairs of values to the van der Waals (Vdw) radii of the correspond-
ing atoms results in the so-called dnorm surface. Contacts smaller
than the sum of the Vdw radii of the two atoms result in a neg-
ative value highlighted on the surface in red. Contacts close to
the limit of the Vdw radii are shown in white, and those contacts
greater than the sum of the Vdw radii are highlighted on the sur-
face in blue [43,44]. Hirshfeld surfaces (HFs) mapped over dnorm
were calculated using TONTO [45], a Fortran-based object-oriented
system for quantum chemistry and crystallography, by the B3LYP
method using the 6–31G(d,p) basis set implemented in CrystalEx-
plorer [40]. Fig. 5a shows that N7–H71ꢀN6i and C16–H16ꢀO9iii hy-
drogen interactions are observed in the HFs mapped over dnorm for
TAM (3a). However, a new contact no observed previously was de-
tected. Weak nonbonding SꢀS interactions are contributing to the
The Hirshfeld surfaces mapped over dnorm indicates the lo-
cations of the strongest intermolecular contacts (red spots). e.g.,
the N–HꢀN hydrogen bonds, which are the most important in-
teractions in the crystal considering their intermolecular distances.
When mapping de and di on this surface, these two values are as-
sociated; resulting in relations that are combined in intervals of
˚
0.01 A, providing the so-called fingerprint plots (Fig. 6). Table 5
summarizes the main intermolecular contacts and their percent-
age distributions on the Hirshfeld surface for the two compounds.
An additional and relevant component of the TACl (3b) system that
does not appear in Table 5 corresponds to the interaction ClꢀH
that comprises 12.3% of this surface.
A search in the CSD database version 5.41 (November 2019
with 2 updates May 2020) through the ConQuest software ver-
sion 2020.1.1 for molecules with the same core, phenyl(1H-1,2,4-
triazol-1-yl)methanone, gave as result no coincidence. However, re-
cently, the crystallographic analysis of (5-amino-3-methylsulfanyl-
1H-1,2,4-triazol-1-yl)(2-fluorophenyl)methanone was reported [17].
Considering that methanol was also used as a crystallization sol-
vent, this compound crystallized in a Triclinic P-1 space group,
with cell parameters a = 7.6599(9), b = 7.8079(8), c = 10.0140(12),
α=94.487(9), β = 108.668 (11), and γ = 97.565 (9). In this case,
˚
supramolecular assembly with a distance of 3.402 (1) A (Fig. 5a).
7

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
Fig. 5. (a). Packing diagram of dnorm surfaces displaying the NꢀH. OꢀH. and S···S pairwise interactions TAM (3a). (b) Packing diagram of dnorm surfaces displaying the NꢀH.
and CꢀCl pairwise interactions for TACl (3b).
Fig. 6. Two-dimensional fingerprint plots for (a) TAM (3a) and (b) TACl (3b) compounds and relative contributions of the atom pairs to the Hirshfeld surface.
the most related compound is TACI (3b), sharing similar interac-
tions such as N–H····N hydrogen bonds to form inversion-related
molecules, also observed in TAM (3a), C–H···O and π···π stak-
ing interactions involving the same groups. However, the struc-
tural difference appears due to the C–ClꢀC halogen interactions
along [−101] direction observed in TACI (3b) that change the
packing.
3.3. Molecular comparison by crystallographic and theoretical studies
In order to study the electronic behavior of TAM (3a) and TACI
(3b), geometric optimization was performed using Density Func-
tional Theory (DFT) Becke’s three-parameter hybrid function with
the non-local correlation of Lee-Yang-Parr (B3LYP) method at 6–
31G(d,p) basis set [29–31]. The conformational comparison be-
tween the optimized molecules and the crystal structure is shown
in Fig. 7 and Table 6. The dihedral angles between the weighted
Fig. 7. Molecular structures of TAM (3a) and TACI (3b) obtained from (a) optimiza-
least-squares mean planes that contain the phenyl and triazole
tion by DFT and (b) X-ray crystal structure.
rings are 64.82 °/65.32 ° and 31.94 °/32.59 ° for TAM (3a)/TACI (3b)
8

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
Table 6
˚
Optimized and experimental bond lengths (A), bond angles (°) and torsion angles (°) of TAM (3a) and TACI (3b).
TAM (3a)
TACI (3b)
Parametersa
Experimental (X-ray)
DFT/B3LYP 6–31G(d,p)b
Parametersa
Experimental (X-ray)
DFT/B3LYP 6–31G(d,p)b
Bond Lengths
S(1) - C(2)
1.735(3)
1.792(3)
1.223(3)
1.406(2)
1.309(3)
1.385(3)
1.398(3)
1.370(3)
1.321(3)
1.322(3)
1.481(3)
1.398(3)
1.392(3)
1.380(3)
1.387(3)
1.507(3)
1.386(3)
1.377(3)
1.765
1.827
1.211
1.393
1.313
1.318
1.428
1.385
1.375
1.367
1.492
1.403
1.403
1.395
1.401
1.509
1.404
1.395
Cl(16) - C(13)
S(1) - C(2)
1.741(2)
1.7401(17)
1.793(2)
1.217(2)
1.367(3)
1.314(2)
1.401(2)
1.391(2)
1.392(2)
1.302(2)
1.326(2)
1.488(2)
1.391(2)
1.387(3)
1.380(3)
1.370(3)
1.373(3)
1.383(3)
1.752
1.764
1.828
1.210
1.313
1.317
1.393
1.387
1.424
1.376
1.367
1.495
1.402
1.394
1.390
1.397
1.395
1.394
S(1) - C(17)
O(9) - C(8)
S(1) - C(17)
O(9) - C(8)
N(3) - C(2)
N(6) - C(5)
N(4) - N(3)
N(4) - C(5)
N(4) - C(8)
N(6) - C(2)
N(7) - C(5)
C(8) > C(10)
C(10) - C(15)
C(10) - C(11)
C(15) - C(14)
C(14) - C(13)
C(13) - C(12)
C(11) - C(12)
N(3) - N(4)
N(3) - C(2)
N(4) - C(5)
N(4) - C(8)
N(6) - C(2)
N(6) - C(5)
N(7) - C(5)
C(8) > C(10)
C(10) - C(11)
C(10) - C(15)
C(11) - C(12)
C(12) - C(13)
C(13) - C(16)
C(13) - C(14)
C(14) - C(15)
Bond Angles
C(2)-S(1)-C(17)
S(1)-C(2)-N(3)
N(4)-N(3)-C(2)
N(4)-C(8)-C(10)
C(5)-N(4)-C(8)
C(2)-N(6)-C(5)
Torsion Angles
C(17)S(1)C(2)N(3)
C(10)C(8)N(4)N(3)
N(6)C(5)N(4)C(8)
N(4)C(8)C(10)C(11)
100.74(12)
124.69(18)
101.70(17)
120.15(16)
126.45(17)
103.92(18)
100.19
123.17
102.00
116.60
131.05
102.72
C(2)-S(1)-C(17)
S(1)-C(2)-N(6)
N(6)-N(5)-C(7)
N(5)-C(7)-C(9)
C(4)-N(5)-C(7)
C(2)-N(3)-C(4)
99.68(10)
100.24
120.38
118.97
116.66
131.11
102.80
123.11(16)
124.26(15)
119.86(16)
126.76(16)
103.26(14)
9.3(2)
−117.61
−152.71
167.83
C(17)S(1)C(2)N(6)
C(9)C(7)N(5)N(6)
N(3)C(4)N(5)C(7)
N(5)C(7)C(9)C(15)
7.58(17)
−2.9(2)
−178.39
−152.82
167.62
1.1(3)
175.04(19)
−31.5(3)
173.08(15)
−30.3(2)
−149.82
−149.60
a
The atom numbering scheme of the molecular structure is given in Fig. 1.
b
Deviation from experimental and calculated data. a) Bond lengths. TAM: y = 1.0412x – 0.0466 (R² = 0.9697), TACI: y = 1.0208x – 0.0163
(R² = 0.9756). b) Bond angles. TAM: y = 1.0451x – 5.4095 (R² = 0.957), TACI: y = 0.9545x + 4.1625 (R² = 0.9168).
Fig. 8. Molecular electrostatic potential mapped for a) TAM (3a) and b) TACl (3b).
molecules, optimized and crystal structure, respectively. This result
establishes a clear conformational difference between them.
ditions. Regions with negative potentials have a high probability
of performing nucleophilic attacks or undergoing protonation re-
actions. Theoretical calculations of MEP for 1-(2-fluorophenyl)−3-
methylsulfanyl-5-amino-1,2,4-triazole (TAF) indicates that N2 atom
contains a minimum potential value of −38.898 kcal/mol [17]. The-
oretical calculations reported under the same reaction conditions
with the NH-1,2,4-triazole 1, confirmed a prototropic behavior fa-
vored by its 1H-form tautomer with higher energetic stability [17].
MEP studies performed on the most stable tautomer showed con-
sistent results with a maximum potential value over the N4–H re-
gion, which would confirm the formation of covalent bonds in this
region in case of an acylation reaction with the presence of an acy-
lating agent [17]. The acylation reaction between NH-1,2,4-triazole
1 and aroyl chlorides in the presence of triethylamine showed
high chemo- and regioselectivity towards the formation of the
1,2,4-triazole-based amides TAM (3a) and TACl (3b), whose MEP
values appear in Fig. 8. The MEP total density of the molecules
3.4. Molecular electrostatic potential mapped (MEP)
The molecular electrostatic potential mapped (MEP) is
a
stratagem of electrostatic potential mapping onto the iso-electron
density surface simultaneously displays molecular shape, size, and
electrostatic potential values and it has been plotted for molecule
under investigation using B3LYP method. The color scheme for the
MEP surface is red, electron rich; blue, electron deficient; light
blue, slightly electron deficient region; yellow, slightly electron rich
region, respectively [47]. The MEP calculations were performed to
find the charge distribution on the surface of the 1,2,4-triazole-
based amides TAM (3a) and TACl (3b), as well as to determine
the regions of that surface with higher or lower potential, which
may assure an anchoring with other molecules in synthesis con-
9

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
Fig. 9. HOMO-LUMO transitions obtained from the calculated spectra (isovalue = 0.02) of TAM (3a) from (a) crystal structure (b) optimized from DFT, and TACI (3b) from
(c) optimized from DFT (d) crystal structure.
Table 7
(3a) and (3b) clearly shows the presence of more electron den-
HOMO and LUMO orbital energies (in eV) and global reac-
sity characterized by red color around the N2 atom of the 1,2,4-
tivity descriptors (in eV) for TAM (3a) and TACl (3b).
triazole with minimum potential values of −52.553 kcal/mol and
Parameters
TAM (3a)
TACl (3b)
−49.137 kcal/mol, respectively. The predominance of green regions
in the MEP surfaces corresponds to a potential halfway between
the two extremes red and dark blue color. The results suggest that
1,2,4-triazole-based amides were found to be useful to both bond
metallically and interact intermolecularly.
HOMO energy
–6.04
–1.84
4.20
6.04
1.84
1.84
3.94
3.94
4.20
5.94
2.00
7.94
–6.08
–2.05
4.03
6.08
2.05
2.05
4.07
4.07
4.03
6.40
2.33
8.73
LUMO energy
HOMO-LUMO energy gap
Ionization Potential (IP)
Electron Affinity (EA)
Electrophilicity Index (ω)
Chemical Potential (μ)
Electronegativity (χ)
Hardness (η)
3.5. Frontier orbitals and global reactivity descriptors
The energy levels of the HOMO (highest occupied molecular or-
bital) and LUMO (lowest unoccupied molecular orbital) for TAM
(3a) and TACI (3b) were computed using DFT for the optimized
molecules, and the B3LYP method using the 6–31 G (d,p) basis
set implemented in CrystalExplorer using TONTO, a Fortran-based
object-oriented system for quantum chemistry and crystallography.
Fig. 9 shows the results from both calculations. It is possible to
conclude that DFT calculations from the molecules optimized and
the crystal structures are comparable between them. The measured
maximum wavelengths as well as the computed data are summa-
rized in Table S3 (see Supporting Information). The LUMO as an
electron acceptor represents the ability to obtain an electron while
HOMO represents the ability to donate an electron. It is important
to mention that electron-withdrawing groups (i.e. chlorine and
bromine) would decrease the energy of the LUMO, while electron-
donating groups (i.e. methyl, methoxy, and hydroxyl) would in-
crease its energy. Indeed, the energy gap between the HOMO and
LUMO molecular orbitals is an important parameter in determining
molecular electrical transport properties and the chemical reactiv-
Electrodonating power (ω−
Electroaccepting power (ω+
)
)
Net electrophilicity (ꢀω
)
gies is related to the electronegativity (χ), as χ = (IP + EA)/2
[49]. The HOMO-LUMO gap is related to the hardness (η) [48,49].
The electrophilicity is a descriptor of reactivity that allows the
quantitative classification of the global electrophilic nature of a
molecule within a relative scale. Parr et al. [50,51] suggested the
term electrophilicity index (ω), as ω = μ2/2η where μ is the
chemical potential taking the average value μ = – (IP + EA)/2
[52–54]. In addition, Gázquez et al. represented the local elec-
trodonating power ω− = [(3IP + EA)2/16(IP − EA)], electroaccept-
ing power ω+ = [(IP + 3EA)2/16(IP − EA)], and net electrophilicity
ꢀω = ω+ + ω− [52–54].
–
A small HOMO LUMO gap means small excitation energies to
the manifold of excited states. Therefore, soft molecules, with a
small gap, will have their electron density changed more easily
than a hard molecule. In terms of chemical reactivity, we can
conclude that soft molecule TACl (3b) would be more reactive
–
ity of the molecule. As shown in Fig. 9, the HOMO LUMO energy
gap values are 4.20 eV and 4.03 eV for TAM (3a) and TACl (3b), re-
spectively. As expected, the slightly lower value in the energy gap
of TACl (3b) explains the eventual charge transfer interactions tak-
ing place within the molecule because of the presence of a chlorine
atom on the benzene ring which may decrease the energy of the
LUMO.
–
than hard molecule TAM (3a) due to its smaller HOMO LUMO gap
(4.03 eV). It is important to mention that the presence of a chlo-
rine atom on the benzene ring would decrease the energy of the
LUMO orbital. Moreover, when IP is small and EA is large and pos-
itive, the molecule should be soft. Once again, these global reac-
tivity descriptors confirm that TACl (η = 4.03) is softer than TAM
(η = 4.20).
The calculated Ionization Potential (IP), Electron Affinity (EA),
Electrophilicity Index (ω), Chemical Potential (μ), Electronegativ-
ity (χ), Hardness (η), Electrodonating Power (ω−), Electroaccept-
ing Power (ω+), and Net Electrophilicity (ꢀω ) for TAM (3a)
and TACl (3b) are presented in Table 7. In simple molecular or-
bital theory approaches, the HOMO energy (εHOMO) is correlated
to the ionization potential (IP) by Koopmann’s theorem and the
LUMO energy (εLUMO) has been used to calculate the electron affin-
ity (EA) [46]. The average value of the HOMO and LUMO ener-
The electrophilicity (ω) index encompasses the balance be-
tween the tendency of an electrophile to acquire electron den-
sity and the resistance of
a molecule to exchange electron
density. Interestingly, Domingo et al. [55] established an elec-
trophilicity (ω) scale for the classification of organic molecules
as strong electrophiles with ω > 1.5 eV, moderate electrophiles
10

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
Table 8
Most relevant assignments of the calculated and experimental vibrational frequencies in terms of PED analysis.
TAM (3a)
TACl (3b)
Assignment
Experimental (cm−1
)
Scaled DFT (B3LYP) Calc.(cm−1) PED%
Assignment
Experimental (cm−1
)
Scaled DFT (B3LYP) Calc. (cm−1) PED%
–
–
H
νas
νs
N
H
3419.79
3561.71
3447.06
1475.05
1368.08
3012.23
2983.52
2924.25
3054.28
3046.33
2955.54
1732.19
100
100
75
46
93
93
95
99
94
95
90
νas
νs
N
3431.24
3275.03
1498.62
1377.05
–
3567.51
3453.12
1474.14
1365.70
–
100
100
69
–
–
–
H
N
H
3278.99
N
=
=
ν C Ntriazole
1496.76
ν C Ntriazole
1381.03
νas CH3
–
νas CH3
–
–
–
–
–
νs CH3
–
νs CH3
–
–
–
νas S-CH3
–
νas S-CH3
3051.26
2993.40
2933.70
1674.21
3055.01
3047.00
2956.08
1732.01
99
94
95
90
–
νs S-CH3
–
νs S-CH3
=
=
ν C
O
1680.00
ν C
O
υ. Stretching; δ. Bending; ω. Wagging; τ. Twisting; s. Symmetric; as. Asymmetric.
Fig. 10. Superposition of observed and DFT (B3LYP)/6–31 G (d,p) calculated FT-IR spectra of a) TAM (3a), and b) TACl (3b).
with 0.8 < ω < 1.5 eV, and marginal electrophiles with ω <
it is well known, vibrational frequencies from DFT calculations are
often overestimated and are commonly scaled by empirical factors.
The main reasons because of this are necessary are: first, the the-
oretical model does not consider the vibrational anharmonicity of
the real system, and second, the incomplete treatment of electron
correlation. A scaling factor of 0.9613 was used in this study to fit
the calculated frequencies to the experimental ones [56].
0.8 eV. As shown in Table 7, N-aroyl-1,2,4-triazoles (3) consid-
ered in this study can be regarded as strong electrophiles, which
is in agreement with the net electrophilicity index (ꢀω ). As ex-
pected from the molecular structure of TAM (3a) and TACl (3b),
their electron-donating ability (ω−) is more important than their
electron-accepting character (ω+).
3.6. Vibrational analysis
3.6.1. N–H stretching
Primary amines present two medium to weak intensity bands
in the region around 3520–3420 cm−1 and 3420–3340 cm−1 due
to the asymmetric and symmetric N–H stretching vibrations, re-
spectively [57]. In the experimental IR spectrum, absorption bands
at 3419.79 cm−1 (νas N–H) and 3278.99 cm−1 (νs N–H) were
observed for TAM (3a), while absorption bands at 3431.24 cm−1
The detailed vibrational assignments of fundamental modes in
terms of PED% are reported in Tables S1 and S2 (see Supporting In-
formation), but Table 8 lists the most relevant theoretical and ex-
perimental wavenumbers. For visual comparison, a superposition
of observed and simulated FT-IR spectra is presented in Fig. 10. As
11

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
−1
2995.33 cm−1, and 2933.70 cm−1 for the compound TACl (3b). For
–
–
(νs N H) were observed for TACl
(νas N H) and 3275.03 cm
–
(3b) (Table 8). Moreover, the calculated scaled vibrations were
3561.71 cm−1 and 3447.06 cm−1 for TAM (3a), and 3567.51 cm−1
and 3453.12 cm−1 for TACl (3b), respectively. The downshifting of
the experimental values related to the calculated ones responds to
each case, we assigned the last two bands to aliphatic C H vibra-
tions. Unfortunately, we could not determine if the aliphatic vi-
brations observed for TAM (3a) corresponding to –CH3 or –SCH3
stretching vibrations. Despite that, our results are in good agree-
ment with the calculated values and also the literature data.
–
the intermolecular interactions in the solid-state involving N HꢀO
hydrogen bonds; interactions that are not observed in the opti-
mized molecules by DFT.
=
–
3.6.4. C N and C N vibrations
The –NH2 bending vibrations appear in the region around
1700–1600 cm−1 for scissoring, and 1150–900 cm−1 for rocking.
Theoretical studies show that computed –NH2 bending−1vibrations
appear at 1604.12 cm−1, 1524.29 cm−1, and 1061.40 cm for TAM
(3a), and 1605.15 cm−1, 1525.23 cm−1, and 1058.74 cm−1 for TACl
(3b); nonetheless, all bands appear as mixed vibrations. Experi-
The interpretation of vibrational spectra of triazoles in the fin-
gerprint region is difficult due to the mixing of several bands
[62,63], but by making use of the GaussView graphical inter-
=
face was possible to identify C N stretching assignments. For
the TAM (3a), the most relevant computed scaled frequencies at-
−1
=
tributed to C N stretching vibrations were 1475.05 cm
1368.08 cm−1, while for the TACl (3b) the computed scaled band at
1474.14 cm−1 is due to C–N stretching vibration and 1365.70 cm−1
and
mental frequencies were observed at 1639.49 cm−1, 1606.70 cm−1
and 1089.78 cm−1 for TAM (3a), and 1637.51 cm−1, 1587.34 cm−1
,
,
and 1087.76 cm−1 for TACl (3b), respectively. It is important to note
arises from the C N stretching vibration. Mentioned vibrations
=
that calculated and experimental values are in good agreement.
were assigned at 1496.76 cm−1 and 1379.10 cm−1 for TAM (3a),
while 1498.62 cm−1 and 1377.05 cm−1 for TACl (3b).
=
3.6.2. C O stretching
–
Carbonyl group of the amide functionality shows a very strong
3.6.5. C Cl vibrations
=
band due to the C O stretching vibration. Albeit the carbonyl ab-
Chlorine compounds absorb strongly in the region 760–
395 cm−1 due to C Cl stretching vibrations [64]. However, the
–
sorption band of tertiary amides often appears in the region 1680–
1630 cm−1 [58], it probably shifted to higher frequencies because
the nitrogen atom belongs to triazole ring [59]. As depicted in
Table 8, computed scaled frequencies appeared at 1732.19 cm−1 for
TAM (3a), and 1732.01 cm−1 for the TACl (3b), which is accord-
ing to previously reported data [60]. From experimental results,
PED% assignment of the IR spectrum of TACl (3b) indicated the
–
absence of a pure C Cl stretching vibration band. The calculated
band at 452.91 cm−1 represents a mixed-mode involving wagging
–
of ClCCC moiety, stretching of C N bond, and torsion around the
carbon skeleton of the benzene ring. Moreover, the calculated band
at 436.01 cm−1 also involves a mixed-mode with a minor contri-
bution of the bending vibration of the CCCl group (see Supporting
Information).
−1
=
the C O stretching vibration was assigned at 1680.00 cm
and
1674.21 cm−1 for TAM (3a) and TACl (3b), respectively. Once again,
the difference between experimental and computed values arises
from the intermolecular interactions previously mentioned.
4. Conclusions
–
3.6.3. C H vibrations
The presence of weak intensity bands in the region above
–
a remarkable
In summary, we have synthesized functionalized N-aroyl-1,2,4-
triazoles (3a) and (3b) in excellent yields via a high chemo- and
regioselective acylation reaction from NH-1,2,4-triazole and aroyl
chlorides in the presence of triethylamine in air. This straightfor-
ward and efficient method is distinguished by its reduced reac-
tion time, high yielding, and operational simplicity, allowing a sub-
stantial improvement over other previously described methods for
the synthesis of N-aroyl-1,2,4-triazole analogs. The crystal struc-
tures of TAM (3a) and TACl (3b) are characterized by the for-
mation of molecular dimers which are further connected by dif-
ferent sorts of intermolecular interactions inducing crystallization
in the P21/n and P-1 space groups, respectively. Hirshfeld surface
maps over dnorm allowed to identify weak nonbonding S···S in-
teractions contributing to the supramolecular assembly. The in-
3000 cm−1 due to C H stretching vibrations is
feature of the presence of an aromatic ring [61]. As shown in
Table 8, the calculated frequencies appeared at 3094.12 cm−1
,
3078.65 cm−1, 3062.11 cm−1, and 3060.50 cm−1 for TAM (3a), and
at 3104.05 cm−1, 3100.45 cm−1, 3091.78 cm−1, and 3078.35 cm−1
for TACl (3b), which is in good agreement with the literature data.
Methyl group bonded to the aromatic ring absorbs in the range
of 3010–2905 cm−1 and 2945–2845 cm−1 due to asymmetric and
symmetric C–H stretching vibrations, respectively [62]. It is im-
portant to note that compound TAM (3a) has one –CH3 group
bonded to the phenyl ring, and one –SCH3 bonded to the triazole
ring, while the compound TACl (3b) only has the –SCH3 group.
Gratifyingly, the computed C–H(CH3) scaled asymmetric stretch-
ing vibrations were observed at 3012.23 cm−1 and 2983.52 cm−1
,
teraction of inversion-related molecules (dimers) by N HꢀN hy-
–
–
while the C H(CH3) symmetric stretching vibration was observed
at 2924.25 cm−1 for the compound TAM (3a). As expected, these
vibrations are absent for the compound TACl (3b). On the other
hand, the methyl group directly bonded to electron-withdrawing
heteroatoms absorbs at slightly higher energies than these previ-
drogen bonds constitutes the stronger force acting between pairs
–
of molecules. Despite that N HꢀN interactions are mainly rep-
resented by electrostatic energies, the three-dimensional crystal
structures are dominated by dispersion forces. The MEP total den-
sity of TAM (3a) and TACl (3b) clearly shows the presence of
more electron density around the N2 atom of the 1,2,4-triazole
ring with minimum potential values of −52.553 kcal/mol and
−49.137 kcal/mol, respectively. The calculated frontier molecular
orbital energies and global reactivity descriptors showed that soft
molecule TACl is more reactive than hard molecule TAM due to its
–
ously discussed. For example, asymmetric and symmetric (S–)C H
stretching vibrations are observed in the region 3040–2980 cm−1
and 3030–2935 cm−1, respectively [59]. The computed (S–)C–H
scaled asymmetric stretching vibrations values were 3054.28 cm−1
and 3046.33 cm−1 for TAM (3a), while at 3055.01 cm−1 and
3047.00 cm−1 for TACl (3b). Ultimately, the computed (S–)C H
smaller HOMO LUMO gap (4.03 eV); thus, the presence of a chlo-
–
–
scaled symmetric stretching vibrations values were 2955.54 cm−1
and 2956.08 cm−1 for compounds TAM (3a) and TACl (3b), respec-
tively.
rine atom on benzene ring would decrease the energy of the LUMO
orbital. Vibration frequency assignments of triazole-based amides
3 were performed using energy distribution analysis (PED) with
VEDA4 software. A statistical study showed similar results with the
use of both basis set 6–31G(d,p) and 6–311+G(d,p). Thus, funda-
mental vibrational frequencies and intensity of vibrational bands
–
The experimental C H stretching vibrations mainly appear at
3174.83 cm−1, 3088.03 cm−1, 2997.38 cm−1, and 2929.87 cm−1
for the compound TAM (3a), and at 3172.85 cm−1, 3086.07 cm−1
,
12

R. Moreno-Fuquen, M.M. Hincapié-Otero, D. Becerra et al.
Journal of Molecular Structure 1226 (2021) 129317
were evaluated using density functional theory (DFT) with the
B3LYP/6–31G(d,p) method and basis set, yielding fairly good agree-
ment between observed and calculated frequencies. Ultimately, ex-
ocyclic amine and thiomethyl moieties into N-aroyl-1,2,4-triazoles
3 would be susceptible to functionalization reactions for obtaining
biologically active 1,2,4-triazole derivatives of great interest in both
drug discovery and pharmaceutical industry.
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The authors declare that they have no known competing finan-
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The authors declare the following financial interests/personal
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