An investigation of supramolecular synthons in 1,2,4-triazole-3(4H)-thione compounds. X-ray crystal structures, energetic and Hirshfeld surface analysis

Article abstract of DOI:10.1016/j.molstruc.2019.06.049

A series of four closely related 1,2,4-triazole-3-thione (1-4) compounds was obtained by heterocyclization of thiosemicarbazides under basic catalytic conditions. The crystal structures of the 4-alkyl-5-(substituted-phenyl)-2H-1,2,4-triazole-3(4H)-thione

Full text of DOI:10.1016/j.molstruc.2019.06.049

Accepted Manuscript
An investigation of supramolecular synthons in 1,2,4-triazole-3(4H)-thione
compounds. X-ray crystal structures, energetic and hirshfeld surface analysis
Aamer Saeed, Zaman Ashraf, Humaira Nadeem, Jim Simpson, Hiram Pérez,
Mauricio F. Erben
PII:
S0022-2860(19)30773-2
DOI:
https://doi.org/10.1016/j.molstruc.2019.06.049
MOLSTR 26691
Reference:
To appear in: Journal of Molecular Structure
Received Date: 13 March 2019
Revised Date: 30 May 2019
Accepted Date: 12 June 2019
Please cite this article as: A. Saeed, Z. Ashraf, H. Nadeem, J. Simpson, H. Pérez, M.F. Erben, An
investigation of supramolecular synthons in 1,2,4-triazole-3(4H)-thione compounds. X-ray crystal
structures, energetic and hirshfeld surface analysis, Journal of Molecular Structure (2019), doi: https://
doi.org/10.1016/j.molstruc.2019.06.049.
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ACCEPTED MANUSCRIPT
An Investigation of Supramolecular Synthons in 1,2,4-Triazole-3(4H)-
thione Compounds. X-ray Crystal Structures, Energetic and Hirshfeld
Surface Analysis
a,
b
c
d,
e
Aamer Saeed, * Zaman Ashraf, Humaira Nadeem, Jim Simpson, * Hiram Pérez, Mauricio
f,
F. Erben *
a
Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
b
Department of Chemistry, Allama Iqbal University, Islamabad, Pakistan.
c
Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences,
Riphah International University, Islamabad.
d
Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand.
e
Departamento de Química General e Inorgánica, Facultad de Química, Universidad de la
Habana, Habana 10400, Cuba.
f
CEQUINOR (UNLP, CONICET-CCT La Plata), Departamento de Química, Facultad de
Ciencias Exactas, Universidad Nacional de La Plata, Bv. 120 1465, La Plata (1900),
República Argentina.
*
Corresponding authors:
(AS) E-mail: aamersaeed@yahoo.com, Tel: +92 51 9064-2128, Fax: +92 51 9064 2241.
(JS) E-mail: jsimpson@alkali.otago.ac.nz, Tel: +64 3 479 7914, Fax: +64 3 479 7906.
(MFE) E-mail: erben@quimica.unlp.edu.ar, Tel/Fax: +54 221 445 4393.

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Abstract
A series of four closely related 1,2,4-triazole-3-thione (1-4) compounds was obtained by
heterocyclization of thiosemicarbazides under basic catalytic conditions. The crystal
structures of the 4-alkyl-5-(substituted-phenyl)-2H-1,2,4-triazole-3(4H)-thione derivatives [4-
alkyl = 4-ethyl-5-phenyl (1), 4-hexyl-5-phenyl (2), 4-hexyl-5-p-tolyl (3), and 4-ethyl-5-(2,4,6-
trimethoxyphenyl) (4)] have been determined. PIXEL lattice energy calculations revealed that
dispersion components make the major contributions, with the coulombic terms also
contributing significantly to the total energy. Interaction energies for the inversion dimers
involving N–H···S=C hydrogen bonds indicate a dominant contribution to packing
stabilization coming from the coulombic energy component. Hirshfeld surfaces and 2D-
fingerprint plots allowed us to visualize different intermolecular contacts and their relative
contributions to the total surface in each compound. The comprehensive analysis of the
crystal packing and the energetic features demonstrate the key role of the
supramolecular synthon of the type (···HNCS) in the solid state structures of these 1,2,4-
2
triazole-3-thiones.
Keywords: triazole; crystal structure; supramolecular synthons; Pixel energy; Hirshfeld
surface analysis.

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1
-Introduction
Among the N-heterocyclic family, 1,2,4-triazoles are the most widely used compounds
1, 2]. Triazoles have gained considerable attention due to their wide potential in the treatment
[
of various diseases as they are used as antibacterial, antifungal, anti-tubercular, anticancer,
anti-inflammatory and anti-convulsant agents and in other medicinal drugs [3, 4]. An
extensive series of triazole-based drugs, including Fluconazole (2-(2,4-Difluorophenyl)-1,3-
bis(1H-1,2,4-triazol-1-yl)propan-2-ol) and Itraconazole ((±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-
[
[(2R,4S)-rel-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
2
yl]methoxy]phenyl]-1-piperazinyl]phenyl]-ꢀ -1,2,4-triazolin-5-one), which were shown to
target the P450-dependent sterol 14a-demethylase, have been successfully marketed and are
widely used in clinical practice [5].
Among the azoles, 1,2,4-triazole derivatives receive a great deal of attention due to
their low toxicity, favorable safety profile and beneficial pharmacokinetic characteristics [6-
9
]. In recent years, some novel 1,2,4-triazoles have been shown to demonstrate remarkable
antibacterial properties, especially against Methicillin-Resistant Staphylococcus aureus [10].
Moreover, the potential of 1,2,4-triazole compounds as versatile precursors in the synthesis of
heterocycles has been recognized [11-13].
The introduction of a sulfur atom into the triazole ring efficiently improves the
bioactivities of the resulting compounds [14]. The presence of the sulfur atom, which is an
electron rich center, improves the lipophilicity and modulates the electron density in the
triazole ring. These characteristics increase the transmembrane diffusion ability of the
molecules as well as their interaction with macromolecular targets. Recent efforts have
therefore focused on the preparation of 1,2,4-triazole-3-thione compounds with promising
antibacterial [15, 16] and anticancer activities [17, 18].

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From the structural point of view, thiol/thione tautomeric equilibrium is feasible for
1
,2,4-triazole-3-thiol/thione compounds, the thione tautomer being the most stable one
observed in solid phase [19-21]. The resulting structural properties make these derivatives
ideal agents to act as chemosensors for selective and sensitive recognition of toxic organic
substances such as anilines [22].
Recent studies also highlighted the relevance of intermolecular interactions, especially
the tendency to form dimers, on the spectroscopic and physicochemical properties of 1,2,4-
triazole-3-thione species [23]. It has been recognized that dimeric aggregates are formed in
the crystal structures of 1,2,4-triazole-3-thiones through pairs of N–H···S=C hydrogen bonds
that form of eight-membered,
[24] synthons of the type (···HNCS) (Scheme 1) [25].
2
In this sense, the thioamide functional group is characterized as a strong hydrogen-bond donor
and moderate acceptor[26, 27] and the robustness of the thioamide dimer synthon has been
recognized as a building block in several organosulfur compounds, including
thiosemicarbazones [28], dihydropyrimidine-2(1H)-thione [29], and thioureas [30]. Chopra
and coworkers reported a complete structural study on four molecules belonging to a family
of substituted 4-(benzylideneamino)-3-(4-fluoro-3-phenoxyphenyl)-1H-1,2,4-triazole-5-(4H)-
thione derivatives and the formation of N−H···S=C hydrogen bonds was clearly determined
to be the primary structural motif in terms of both topological and Hirshfeld surface analysis
[
31]. However, in a study based on crystal structures deposited in the Cambridge Structural
Database, Wawrzycka-Gorczyca concluded that the N–H···S=C structural motif is
…common (centrosymmetric or pseudo-centrosymmetric) in the crystals of 1,2,4-triazole-5-
thione derivatives; in 77 (=52.4%) of the 147 crystals, which means it is not so much
“
predominant”. Furthermore, no clear correlation between the graph set
motif and the
substituents on the triazole rings can be found from a statistical analysis [32].

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Scheme 1. The
synthon in 1,2,4-triazole-3-thiones.
R1
N
N
H
S
H
N
R2
R2
N
N
N
R1
S
Prompted by this seeming controversy and to shed further light on the role of the N–
H···S=C intermolecular interaction, in this work the crystal structures of four novel 4-alkyl-5-
(substituted-phenyl)-2H-1,2,4-triazole-3(4H)-thione derivatives (see Scheme 2) have been
determined using single-crystal X-ray analysis. The aim of this article is threefold: (1) to
analyze the structural features of the 1,2,4-triazole-3-thione derivatives by varying the
substitution at the N4-position; (2) to determine variations in the intermolecular interactions
that accompany the placement of benzene rings carrying various substituents at the C5-
position and finally, (3) to characterize the occurrence and predominance of N–H···S=C
interactions formed by the central 1,2,4-triazole-3-thione cores of the different molecules. To
this end, in this work molecular conformation analyses and detailed characterizations of the
intermolecular contacts were carried out for these four compounds. The calculation of lattice
energies and intermolecular interaction energies associated with different molecular pairs
enabled determination of the energy components contributing to crystal stabilization [33, 34].
Moreover, Hirshfeld surface based tools, such as dnorm, shape index and curvedness surface
properties [35, 36], and fingerprint plots [30, 37] have been used to explore the packing
modes and to visualize the intermolecular interactions.

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Entry
R1
R2
R1
N
R2
1
2
3
4
CH -CH -
H
3
3
3
3
2
CH
CH
CH
-(CH
)
)
- H
2
5
S
-(CH
- 4-CH
N
2
5
3
N
-CH
-
3,4,5-tri-(OCH )
3
2
H
Scheme 2. General structures of the 4-alkyl-5-(substituted-phenyl)-2H-1,2,4-triazole-3(4H)-
thione derivatives studied in this work.
2
-Experimental
2
.1-General Instrumentation. Melting points were recorded using a digital Gallenkamp
1
13
(
SANYO) model MPD.BM 3.5 apparatus and are uncorrected. H and C NMR spectra were
determined in CDCl at 300 MHz and 75.5 MHz respectively using a Bruker spectrometer.
3
FTIR spectra were recorded on an FTS 3000 MX spectrophotometer. Mass Spectra (EI,
7
0eV) were obtained on a GC-MS instrument Agilent technologies 6890N (GC) and an inert
mass selective detector 5973 mass spectrometer. Elemental analyses were conducted using a
LECO-183 CHNS analyzer. Thin layer chromatography (TLC) was conducted on 0.25 mm
silica gel plates (60 F254, Merck). Visualization was achieved with ultraviolet light. Reagents
were obtained commercially and used as received.
2
.2-Synthesis of 2,4-Dihydro-4,5-disubstituteD-3H-1,2,4-triazole-3-thiones, General
Procedure and Characterization. The synthesis pathway leading to the title compounds is
shown in Scheme 3. The thiosemicarbazide intermediates were synthesized by reacting
equimolar amounts of the corresponding alkyl (R = ethyl and hexyl) isocyanate with phenyl-
1
substituted acyl hydrazides in absolute ethanol [38]. The reaction mixtures were refluxed for
2
h, concentrated and the precipitated thiosemicarbazides were filtered off. They were then

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treated separately with aqueous 4M sodium hydroxide to obtain the triazoles 1-4 [39]. The
reaction mixtures were refluxed and progress of the reactions was checked by TLC. After
completion of the reactions, the reaction mixtures were cooled, filtered and the filtrates were
acidified to pH 4-5, with 4M hydrochloric acid. The solid products were filtered off, washed
thoroughly with water and recrystallised from aqueous ethanol. Yields of the compounds
were close to 70% in all cases.
Scheme 3. Method of synthesis for the 1,2,4-triazole-3-thiones 1-4 involving
thiosemicarbazide derivatives as intermediates [R and R groups are CH CH and H for 1,
1
2
3
2
CH (CH ) and H for 2, CH (CH ) and 4-CH for 3 and CH CH and 3,4,5-tri-(OCH ) for 4].
3
2 5
3
2 5
3
3
2
3
O
O
H
H
N
NH2
N
N
H
R NCS
N
H
R1
+
1
S
R2
R2
NaOH 4M
R1
N
R2
S
N
N
H
1
-4
4
-Ethyl-2,4-dihydro-5-phenyl-3H-1,2,4-triazole-3-thione (1). Reaction time required = 3.0
o
−1
hours, yield = 70.2%, m.p. = 172 C. IR (ν , KBr, cm ): 3175 (νN−H), 1585 (νC=N), 1250
max
1
(
νC=S). H-NMR (CDCl , 300 MHz) δ (ppm): 1.32 (t, 3H, J = 7.3 Hz, CH ), 5.20 (q, 2H, J =
3
3

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1
3
7
4
1
.2 Hz, CH ), 7.30-7.48 (s, 4H, Ar−H). C-NMR (CDCl , 75 MHz) δ (ppm): 13.6 (CH ),
2
3
3
0.9 (CH –N), 122.0 (C−1’), 123.9 (C-3’,5’), 136.4 (C-2’,6’), 148.9 (C-4’), 152.2 (C-5),
2
+
70.6 (C-3). EI-MS, m/z (%): 205(M , 80), 177(8), 173(3), 103(2).
4
-Hexyl-2,4-dihydro-5-phenyl-3H-1,2,4-triazole -3-thione (2). Reaction time required = 6.0
o
−1
hours, yield = 76.3%, m.p. = 110 C. IR (ν , KBr, cm ): 3260 (νN−H), 1585 (νC=N), 1270
max
1
(
νC=S). H-NMR (CDCl , 400 MHz) δ (ppm): 0.79 (t, 3H, J = 6.0 Hz, CH ), 1.19 (m, 6H, 3 x
3
3
CH ), 1.67 (m, 2H, CH ), 4.06 (t, 2H, J = 7.8 Hz, CH – N), 7.47-7.54 (m, 5H, Ar H), 12.42
2
2
2
13
(
s, 1H, NH/SH). C-NMR (CDCl , 75 MHz) δ (ppm): 13.9 (CH ), 22.4, 26.1, 28.0, 31.1, (4 x
3
3
CH ), 46.6 (CH -N), 122.4 (C-1’), 124.1 (C-3’,5’), 137.2 (C-2’-6’), 146.9 (C-4’), 149.6 (C-5),
2
2
+
1
70.7 (C-3). ). EI-MS, m/z (%): 261(M , 73), 229(11), 228(5), 201(6). 69(1)
4
-Hexyl-2,4-dihydro-5-(p-methylphenyl)-3H-1,2,4-triazole-3-thione (3). Reaction time
o
−1
required = 4.0 hours, yield = 67.4%, m.p. = 90 C. IR (ν , KBr, cm ): 3242 (νN−H), 1590
max
1
(
νC=N), 1270 (νC=S). H-NMR (CDCl , 400 MHz) δ (ppm): 0.85 (t, 3H, J = 5.8 Hz, CH ), 1.52
3
3
(
m, 6H, 3 x CH ), 1.70 (m, 2H, CH ), 2.4 (s, 3H, CH −Ar), 4.41 (t, 2H, J = 6.8 Hz, CH −N),
2
2
3
2
1
3
7
3
1
2
.38-7.42 (m, 4H, Aryl H). C-NMR (CDCl , 75 MHz) δ (ppm): 13.2 (CH ), 21.4, 24.8, 27.5,
3
3
0.7, (4 x CH ), 21.6 (CH -Ar), 43.8 (CH -N), 123.2 (C-1’), 129.6 (C-2’,6’), 128.9 (C-3’,5’),
2
3
2
+
33.5 (C-4’), 150.4 (C-5), 171.2 (C-3). EI-MS, m/z (%): 275(M , 70), 247(4), 243(14),
15(3), 69(2).
4
-Ethyl-2,4-dihydro-5-(3,4,5-trimethoxyphenyl)-3H-1,2,4-triazole-3-thione (4). Reaction
o
−1
time required = 7.5 hours, yield = 70.0%, m.p. = 155 C. IR (ν , KBr, cm ): 3180 (νN−H),
max
1
1
590 (νC=N), 1409 (νC=C), 1284 (νC=S). H NMR (CDCl , 300 MHz) δ(ppm): 1.37 (t, 3H, J =
3
1
3
6
.8 Hz, CH ), 4.60 (q, 2H, J = 6.8 Hz, CH −), 3.78 (s, 9H, 3-CH ), 6.98 (s, 2H, A H). C-
3
2
3
’
NMR (CDCl , 75 MHz) δ (ppm): 13.8 (CH ), 41.9 (CH –N), 57.2 (OCH ), 104.0 (C-1 ),
3
3
2
3

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’
’
’
’
1
2
17.3 (C-2 ,6 ), 139.1 (C-4 ), 153.2 (C-3’,5 ), 159.1 (C-5), 176.9 (C-3). EI-MS, m/z(%):
+
95(M , 86), 262(6), 234(5), 69(2).
2
.3- X-ray data collection and structure refinement. Diffraction data were collected on single
crystals of 1-4 using a Bruker APEXII CCD diffractometer with graphite-monochromated
Mo-Kα radiation (λ = 0.71073 Å) at 91(2) or 92(2)K. Data collections were controlled by
APEX2 [40] software with cell refinement and data reduction performed using SAINT [40].
Multi-scan absorption corrections were applied using SADABS [40]. The structures were all
2
solved with SHELXS [41] and refined by full-matrix least-squares on F using SHELXL-2014
[
42] and TITAN2000 [43]. All non-hydrogen atoms were assigned anisotropic displacement
parameters. The C41 and C42 atoms of ethyl group of one of the unique molecules of 1 are
disordered over two sites. Occupancies were refined to sum to unity and converged with a
0
.554(8):0.446(8) occupancy ratio. For all molecules, the hydrogen atoms of the NH groups
were located in an electron density map and their coordinates refined with U = 1.2U (N).
iso
eq
All H-atoms bound to carbon were refined using a riding model with d(C-H) = 0.95 Å U =
iso
1
.2U (C) for aromatic, 0.99Å, U = 1.2U (C) for methylene, 0.98Å U = 1.5U (C) for
eq iso eq iso eq
methyl hydrogen atoms. Molecular plots and packing diagrams were drawn using Mercury
44]. Other calculations were performed using PLATON [45] and tabular material was
[
produced using WINGX [46].
Crystallographic data for the structures reported in this paper are shown in Table 1 and the
CIF files have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. 1871333-1871336 for compounds 1-4, respectively. Copies of
available material can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif,
by e-mailing data_request@ccdc.cam.ac.uk, or contacting the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Table 1. Crystal data and structure refinement for compounds 1-4.
1
2
3
4
Empirical formula
Formula weight
Temperature / K
Crystal system
C
20
H
22
N S
6
2
C
14
H
19
N
3
S
C
15
H
21
N S
3
C H N O S
13 17 3 3
295.35
92(2)
triclinic
P-1
410.55
92(2)
triclinic
P-1
261.38
92(2)
Monoclinic
275.41
91(2)
triclinic
P-1
Space group
P2 /n
1
Unit cell dimensions
a = 10.788(5) Å
b = 11.060(5) Å
c = 11.391(5) Å
a =8.1455(3) Å
b =18.0921(6) Å
c =10.1306(3)Å
a =8.4096(4)Å
b =9.3468(4)Å
c =9.9766(4)Å
a =7.8362(4)Å
b =8.3191(4)Å
c =12.2056(5)Å
o
o
α
β
γ
= 92.291(5)
α
β
γ
= 105.899(2)
α
β
γ
= 81.505(3)
o
o
o
o
= 117.485(5)
β
= 109.5600(10)
= 90.298(2)
= 72.349(2)
=75.313(3)
o
o
=117.930(5)
=97.336(2)
3
Volume / Å
1006.8(8)
2
1.354
0.283
432
1406.78(8)
4
1.234
0.217
560
747.35(6)
2
1.224
0.208
296
731.28(6)
2
1.341
0.232
312
Z
3
ρ calc. / mg mm‐
ꢀ
1
/ mm‐
F(000)
Crystal size / mm
3
0.79 x 0.32 x 0.29 0.67 x 0.19 x 0.14 0.73 x 0.20 x 0.20 0.41 x 0.23 x 0.11
Theta range for data collection 2.21 to 30.26°
2.41 to 33.51°
-12 ≤ h ≤ 12
-27 ≤ k ≤ 24
-14 ≤ l ≤ 15
25925
3.12 to 33.33°
-10 ≤ h ≤ 12
-13 ≤ k ≤ 13
-15 ≤ l ≤ 15
13642
2.97 to 27.10°
-10 ≤ h ≤ 10
-10 ≤ k ≤ 10
-15 ≤ l ≤ 15
10132
Index ranges
-15 ≤ h ≤ 15
-
-
15 ≤ k ≤ 15
16 ≤ l ≤ 16
Reflections collected
Independent reflections
17329
5962
5047
5155
3195
[
R(int) = 0.040]
[R(int) = 0.039]
5047/0/167
1.043
[R(int) = 0.036] [R(int) = 0.048]
Data/restraints/parameters
6406/0/282
1.103
5155/0/167
1.094
3195/0/188
1.065
2
Goodness-of-fit on F
Final R indexes [I >2σ (I)]
R1 = 0.0644
wR2 = 0.1612
0.669 / -1.289
R1 = 0.0363
wR2 = 0.0925
0.399 / -0.246
R1 = 0.0422
wR2 = 0.1201
0.450 / -0.351
R1 = 0.0419
wR2 = 0.0971
0.380 / -0.282
Largest diff. peak/hole / e Å‐3
2
.4- Lattice and interaction energies. For each crystal under consideration, lattice energy and
intermolecular interaction energies for specific molecular pairs were calculated using the CLP
Coulomb–London–Pauli) approach implemented in the CLP-PIXEL program package [47,
8], which enables partitioning of the total energy into the coulombic, polarization, dispersion
and repulsion contributions.
(
4

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2
.5- Hirshfeld surface calculations. Hirshfeld surfaces and their associated two-dimensional
fingerprint plots [49-52] were plotted using CrystalExplorer3.1 software [53]. The normalized
contact distance (dnorm) enables identification of the regions of particular importance to the
intermolecular interactions, with dnorm being a symmetric function of distances to the surface
from nuclei inside and outside the Hirshfeld surface (d and d , respectively), relative to their
i
e
respective van der Waals radii. Hirshfeld surfaces were also mapped with shape index and
curvedness properties. The 2D-fingerprint plots provide decompositions of the Hirshfeld
surfaces into relative contributions of the different intermolecular interactions present in
crystal structure. A color scale of red shorter than, white equal to and blue longer than the
vdW separations is used to visualize these intermolecular contacts [54]. The 3D dnorm surfaces
are mapped over a fixed color scale of -0.046 (red) to 1.058 (blue), shape index mapped in the
color range of -1.0 a.u. (concave)-1.0 a.u. (convex) Å, and curvedness in the range of -4.0 a.u.
(flat)- 4.0 a.u. (singular) Å. The 2D-fingerprint plots are displayed using the translated 0.6-2.8
Å range, including reciprocal contacts.
3
. Results and Discussion
3
.1- Chemical synthesis and characterization
Ethyl and hexyl isothiocyanates were refluxed with acyl hydrazides in ethanol to
afford the corresponding thiosemicarbazides. Completion of this reaction was clearly
evidenced in the FTIR spectra by the lack of an NH stretching absorption and the appearance
2
–
1
of two new intense bands at 3200-3372 and 3261-3295 cm for the NH stretching modes of
1
the thiosemicarbazide group. The analysis of the H NMR spectrum also reveals the formation
of thiosemicarbazide intermediates, with signals at δ 8.3-8.9 ppm and 2.3-2.4 ppm assigned to
the CONH and NH-NH protons, and at δ 7.4-7.9 for the CSNH proton.

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Further addition of NaOH catalyzed the intramolecular cyclization of the
thiosemicarbazides to afford the corresponding triazoles with global yields of ca. 70%. The
main changes in the infrared spectra of 1-4 involve the N–H stretching region, with a strong
–1
absorption near 3200 cm assigned to the NH group, and the appearance new bands at ca.
–
1
1
585 cm are assigned to the C=N stretching of the triazole ring. The occurrence of
–
1
distinctive bands in the 1250-1285 cm region is associated with the presence of the thione
–1
tautomer ν(C=S), and the absence of absorptions in the 2650-2500 cm region, assigned to
the characteristic ν(S–H) mode, is indicative of minor contributions of the thiol tautomer [55,
1
5
6]. In the H-NMR spectra, disappearance of signals for thiosemicarbazide NH groups and
the appearance of one singlet for the NH proton resonance at δ 8.87-11.30 ppm are also
1
3
indicative of the formation of the 1,2,4-triazole ring. In the C-NMR spectra of compounds
1
1
-4, the resonances at ca. 170 ppm are assigned with confidence to the C-3 carbon in the
,2,4-triazole ring, values that are typical for a C=S group. The mass spectra are dominated by
the molecular ions, with small contributions from daughter ions [57].
Thus, based on the NMR and infrared data, the preference for the thione form is
clearly determined for the series of 1,2,4-triazole here studies, i.e. for 4-alkyl-5-(substituted-
phenyl)-2H-1,2,4-triazole-3(4H)-thione compounds (see Scheme 3).
R1
R2
R1
N
R2
N
S
HS
N
N
N
N
H
Scheme 3. Tautomeric forms of 4-alkyl-5-(substituted-phenyl)-2H-1,2,4-triazole-3(4H)-
thione derivatives.

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3
.2- Description of the molecular structures and their conformations
Molecular structures with the atom labeling schemes for compounds 1-4 are shown in
Figure 1. Selected bond lengths and torsion angles are given in Table 2. The molecular
structures of the four molecules are sufficiently similar to be discussed together. Two
exceptions to this generalisation each concern 1. This compound crystallises with two unique
molecules in the asymmetric of the triclinic unit cell. These are identified in the numbering
scheme by leading 1 and 2 characters. They can be differentiated as molecule 1.1 and 1.2
respectively. Furthermore, both atoms of the ethyl substituent of 1.2 are disordered over two
sites with a 0.554(8):0.446(8) occupancy ratio.
A 4,5-dihydro-3H-1,2,4-triazole-3-thione ring system is the common factor to all four
molecules that differ in the substituents on the N4 and C5 atoms of the triazole ring. For
compounds 1 and 4 the N4 substituents are both ethyl groups while for 2 and 3 these are
replaced by nicely ordered n-hexyl chains. The C5 substituents are simple phenyl rings for 1
and 2, with a p-tolyl ring system for 3 and a 2,4,6-trimethoxyphenyl substituent for 4. None of
the molecules are planar with the triazole and benzene rings inclined at dihedral angles of
2
6.05(14)° and 58.6(6)° for the 1.1 and 1.2, 34.18(4)° for 2, 27.87(4)° for 3, and 36.66(6)° for
4
.
A search of the Cambridge structural database (Version 5.39 November 2017 with 3
updates, Aug 2018)[58, 59] reveals 54 discrete 1,2,4-triazole-3(4H)-thione derivatives with
phenyl or substituted benzene substituents at the 5-position. Only one of these has an ethyl
substituent at the 4-position, 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione [60,
6
1]. Derivatives with methyl [62], allyl [63], and phenyl [64-68] substituents at C4 and the
bond distances and angles observed for these structures are generally similar to those for the
molecules reported here, but a few points deserve further comment. The five-membered
triazolyl ring in all structures is planar with the maximum r.m.s. deviation being 0.0062(1) Å

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for the C5 atom in structure 3. The N1–N2 bond lengths around 1.37 Å are slightly shorte
r
than that expected for an N-N single bond (1.42 Å) [69], while the two C–N bond distances
involving the pyridine-like nitrogen atoms are between the characteristic single (1.46 ) and
double bond lengths (1.27 ) [70]. Similar differences have been observed in related
Å
Å
compounds [71], and can be explained by a degree of delocalization within the triazolyl ring,
which is also supported by the IR and NMR data. In contrast, we observe longer C–N bond
lengths near 1.47
Å involving the pyrrole-like nitrogen atom and the methylene carbon. The
C–S [1.681(1)-1.689(3) Å] bond distances are almost equal within experimental error [70],
and show considerable double-bond character according to the sum of covalent radii (1.70 Å)
[
69, 72].
o
Table 2. Selected geometric parameters (Å, ) for compounds 1-4.
Parameters
N1-N2
N1-C5
N2-C3
N4-C3
N4-C5
N4-C41
C3-S3
1.1
1.2
2
3
4
1.370(3)
1.314(3)
1.337(2)
1.370(3)
1.387(2)
1.472(3)
1.685(2)
84.0(1)
1.368(3)
1.303(3)
1.336(2)
1.369(4)
1.378(2)
1.495(4)
1.689(3)
91.4(1)
1.368(1)
1.310(1)
1.341(1)
1.370(1)
1.384(1)
1.468(1)
1.683(1)
84.5(1)
1.370(1)
1.316(1)
1.343(1)
1.371(2)
1.387(1)
1.470(1)
1.681(1)
-80.0(1)
1.371(2)
1.310(2)
1.335(2)
1.366(2)
1.380(2)
1.474(2)
1.687(2)
-83.6(1)
C3-N4-C41-C42
1.1 and 1.2
2

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3
4
Figure 1. The asymmetric unit of 1 and the molecular structures of 2-4 showing the atom
numbering, with ellipsoids drawn at the 50% probability level. For molecule 1.2 only the
major disorder components of the disordered ethyl substituent are shown.
3
.3- Description of the crystal packing
The intermolecular distances for compounds 1-4, including hydrogen bond, C-X···π(ring) and
···π contacts are displayed in the Table 3, while their molecular packing in the crystal
π
structures are described in the following subsections.
Table 3. Hydrogen bonds, C-X···π(ring) and π···π contacts for 1-4.
H-A (Å)
X-A (Å)
D···A/
D-X···A (˚)
Cg···Cg (Å)
Compound 1
1
i
C14'-H14'···S13
0.95
0.88(3)
0.89(3)
2.91
3.593(3)
3.269(2)
3.293(2)
4.137(3)
130
1
1
ii
ii
N12-H12N···S23
N22-H22N···S13
2.39(3)
2.42(3)
3.775(2)
174(2)
166(2)
90.06(9)
1
iii
C23=S23···Cg3
1
iv
3
3
.521(3)
.814(2)
Cg4···C42
Cg2···Cg3
Compound 2

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2
i
N2-H2N···S3
C5'-H5'···S3
0.868(14)
0.95
0.99
2.401(14)
3.00
2.93
3.2657(9
174.5(12)
151
131
2
ii
3.8572(10)
3.6611(10
3.9928(6)
2
iii
C42-H42A···Cg2
Cg1···Cg2
Compound 3
3
i
N2-H2N···S3
C45-H45A···S3
0.901(15)
0.99
0.98
2.332(15)
2.92
2.91
3.2320(10)
3.3659(12)
3.6041(15)
176.3(13)
133
129
3
ii
3
iii
C46-H46C···Cg1
Compound 4
4
i
N2-H2N···S3
0.85(2)
0.99
0.98
0.98
0.98
2.43(2)
2.46
2.56
2.72
3.00
3.2679(16)
3.402(2)
3.477(2)
3.355(2)
3.727(2)
3.525(2)
168.3(19)
160
155
129
132
4
ii
C41-H41A···O3'
C51'-H51B···O4'
C51'-H51B···O5'
C31'-H31B···O5'
C43-H32C···Cg1
4
4
4
iii
iii
iv
4
v
0.98
2.97
117
Symmetry transformations used to generate equivalent atoms:
i = 1+ x, 1+ y, z; 1ii =1-x,-y,1-z; 1iii = 1-x, -y, -z; 1iv = 2-x, 1-y, -z; Cg2, Cg3 and Cg4 are the
centroids of the C11'-C16', N21, N22, C23, N24, C25 and C11'-C16' rings respectively.
i = 1-x, -y, -z; 2ii = x, y, -1+z; 2iii = -1/2+x, -1/2-y, -1/2+z; Cg1 and Cg2 are the centroids of the N1,
N2, C3, N4, C5 and C11'-C16' rings respectively.
i = -x, 1-y, 2-z, 3ii = 1−x, 2−y, 2−z; 3iii = x, 1+y, z; Cg1 is the centroid of the N1, N2, C3, N4, C5
ring.
1
2
3
4
i = 1-x, -y, 1-z; 4ii = -x, 1-y, 2-z; 4iii = -x, 2-y, 2-z; 4iv = x, y, 1+z; 4v = 1-x, 1-y, 1-z; Cg1 and Cg2
are the centroids of the N1, N2, C3, N4, C5 and C11'-C16' rings respectively.
3
.3.1 Crystal packing for 1.
In the crystal packing of compound 1, C14'—H14'···S13 contacts form C(9) chains of
type 1 molecules along the b axis. These chains are further embellished by the addition of
type 2 molecules through N11—H12N···S23 and N22—H22N···S13 hydrogen bonds,
2
forming R (8) dimers, Figure 2a and arranging the two unique molecules into sheets parallel
2
to (-1,1,1). In addition, π···π stacking interactions between pairs of C21'···C26' phenyl rings,
[
Cg4···Cg4 = 3.521(3) Å], Table 3, and between the C11'···C16' phenyl rings and the N21,
N22, C23, N24, C25 triazole rings [Cg2···Cg3 = 3.814(3) Å] combine with N—H···S
2
generated R (8) dimers to form chains of molecules along the ac diagonal, Figure 2b.
2

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Packing for 1 is completed by unusual sulfur lone-pair – π interactions between the
S23 sulfur atom of type 2 molecules and a triazole ring of an adjacent type 2 molecule
(S···Cg1 = 3.775(2) Å), Table 3. These combine with the Cg4···Cg4 π-stacking interactions
mentioned previously to form double chains of type 2 molecules along the ab diagonal,
Figure 2c.
a
b

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c
Figure 2. a) Sheets of molecules of 1 formed from N—H···S dimers and C—H···S hydrogen
bonds. In this and subsequent Figures, hydrogen bonds are drawn as blue dashed lines. b)
Crystal packing showing π···π interactions linking N—H···S dimers into chains along the ac
diagonal. c) Double chains of type 1 molecules of 1 formed by C=S···π and π···π interactions.
(π···π and C=S···π contacts are shown as green dotted lines). Cg2 (red), Cg3 (green) and Cg4
(
yellow) are the centroids of the C11···C16, N21, N22, C23, N24, C25 and C21···C26 rings
respectively and are shown as coloured spheres.
3
.3.2 Crystal packing for 2.
Inversion dimers of molecules of compound 2 again form through N2—H2N···S3
2
hydrogen bonds and generate R (8) ring motifs. These dimers are linked by C5'—H5'···S3
2
2
contacts generating R (18) ring motifs and forming sheets of molecules in the bc plane,
4
Figure 3a. Edge to face C—H···π(ring) contacts between H42A in the hexyl chain and the
phenyl ring are bolstered somewhat by a weak Cg1···Cg2 π···π stacking interaction between
the triazole and phenyl rings with a centroid to centroid separation of 3.9928(6) Å (Figure

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3
b). These link adjacent atoms in a head to tail fashion into chains along a. A π···π contact at
this separation is close to the limit of approximately 4.0 Å recognised for such contacts. The
fact that the dihedral between the ring planes is 30.08(5)° further indicates that this is a weak
contact. These contacts combine to arrange the molecules in sweeping curves along b when
viewed along the c axis direction.
a

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b
Figure 3. a) Sheets of molecules of 2 viewed along a. b) Chains of molecules of compound 2
along a. C—S···π(ring) contacts are also shown as green dotted lines). Cg1 and Cg2 are the
centroids of the N1, N2, C3, N4, C5 and C1'···C6' rings respectively.
3
.3.3 Crystal packing for 3.
For compound 3 the ubiquitous inversion dimers again form through N2—H2N···S3
2
hydrogen bonds and generate the R (8) ring motifs. A second set of inversion dimers form
2
2
through C45—H45A···S3 hydrogen bonds building larger R (18) rings. These linked dimers
2
produce sheets of molecules parallel to (-110), Figure 4a. Weak C46—H46C···Cg1 contacts
to the five membered rings link molecules in a head to head fashion into chains along b,
Figure 4b.

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a
b
Figure 4. a) Sheets of molecules of 3 parallel to (-110). b) Chains of molecules of 3 along b.
Cg1 is the centroid of the N1, N2, C3, N4, C5 ring.
3
.3.4 Crystal packing for 4.
For compound 4, inversion dimers again form through N2—H2N···S3 hydrogen
2
bonds and generate R (8) ring motifs. These dimers are linked into chains along the bc
2
diagonal through a second set of inversion dimers that result from weak C—H···O contacts.
2
H51B acts as a bifurcated donor to the O4' and O5' methoxy O atoms generating R (5) and
1
2
2
R (6) ring motifs respectively, Figure 5a. H41A also acts as a bifurcated donor to the O3' and
2
2
2
2
O4' oxygen atoms, again forming inversion dimers and generating R (5), R (16) and R (18)
1
2
ring motifs. These dimers are further strengthened by a π···π stacking interaction between
adjacent benzene rings [Cg2···Cg2 = 3.525(2) Å]. As shown in Figure 5b, adjacent dimers are
linked by C31'—H31B···S3 contacts, propagating a double chain of molecules along c. The
final inversion dimer in the extensive catalogue for this molecule results from C42—
H42C···Cg1 contacts. These dimers are linked by the π···π contacts between two benzene
rings and the bifurcated C41—H41A···O3' and C41—H41A···O4' hydrogen bonds forming
chains along the ac diagonal, Figure 5c.

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a
b

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c
Figure 5. a) Chains of inversion dimers for 4 along the bc diagonal. b) Double chains along c
for 4. Cg2 is the centroid of the C1'···C6' benzene ring. c) Chains of molecules of 4 along the
ac diagonal. Cg1 is the centroid of the N1, N2, C3, N4, C5 ring.
3
.4- Lattice energies, structural motifs and interaction energies.
Lattice energy calculations (Table 4) show that the dispersion energy (Edisp) is the major
contributor towards the crystal stabilization for all of the structures as is generally expected
for organic compounds [34], with similar percentages ranging from 49.8 % in compound 2 to
5
5.5 % in compound 4. The coulombic component (Ecoul) is significant for all four structures
representing the second highest contributor in the range 27.0-32.0 %.
Structures 2 and 3 each have a hexyl substituent at the 4-position of the triazole ring, but
the lattice stability increases by 15.2 kJ/mol for 3, presumably due to the presence of the
methyl group in the para position of the benzene ring. Among the four structures, the most
energetically stable lattice is found for structure 4 (-183.4 kJ/mol) due to the presence of the
three methoxy groups on the benzene ring and the additional contacts that they generate.

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Table 4. Lattice energies (kJ/mol) partitioned into
coulombic (Ecoul), polarization (E ), dispersion (Edisp)
pol
and repulsion (E ) components for compounds 1–4.
rep
Compound
Ecoul Epol
Edisp
Erep ETOT
1
2
3
4
-78.4 -51.4 -139.1 128.7 -140.1
-90.5 -53.7 -173.8 156.6 -161.4
-91.4 -59.9 -187.0 161.9 -176.4
-109.8 -62.5 -170.6 159.5 -183.4
Intermolecular energy calculations for selected molecular pairs are shown in Table 5 in
the order of decreasing interaction energy. The geometry of the intermolecular interactions
involved in each molecular pair is summarized in column 4. The occurrence of N–H···S
hydrogen bonds forming centrosymmetric
motifs is a common factor for all of the
structures 1-4. These generate molecular pairs with the highest energy stabilization energies
in comparison to pairs involving other types of contacts with values ranging from -82.4
kJ/mol for compound 2 to -98.0 kJ/mol for compound 3. The computed values are in
agreement with that reported for
motifs found in related thiourea species [73, 74]. It
should be noted, however, that it is possible that the calculation scheme tends to overestimate
in some extent the strength of these N–H···S hydrogen bond interactions.
Crystal packing of structures 1-3 are also characterized by the presence of weaker C–
H···S hydrogen bonds, which form molecular pairs with much lower pairing energies (-11.7/-
1
8.8 kJ/mol). For structure 4, the oxygen atoms of the methoxy groups facilitate the formation
of C-H· ··O hydrogen bonds. In Table 4, the C41-H41A· ··O3' interaction energy for one of
such pairs is listed.
An offset π· ··π stacking interaction involving the benzene rings [centroid Cg4,
Cg4· · · Cg4 = 3.521(2) Å, slippage = 1.221(2) Å] forms a molecular pair of molecules for 1.2
with an interaction energy of -16.4 kJ/mol. Furthermore, an unusual and higher energy lone-
pair S(lp)· ··π(ring) interaction (-27.8 kJ/mol) which involves the thiocarbonyl sulfur S23 lone

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pair(s) and the triazole ring of molecule 1.2 (centroid Cg3). This C=S(lp)· · · π interaction is
characterized by a short S23· · · Cg1 distance of 3.775(2) Å, and a C23=S23· · · C g 3 a n g l e
o
o f 9 0 . 0 6 ( 9 ) ˚ . The deviation of this angle α from 120 of is approximately 30˚ a value
similar to the mean value of 30.6˚ reported for a variety of related C=O(lp)· ··π(ring) contacts
[
75, 76].
In addition to the N—H· ··S and C—H· ··
S
contacts, point-to-face C–H· ··π contacts
along with offset π· ··π stacking interactions are found in the supramolecular assembly of 2.
The former involves the benzene ring (centroid Cg2) and a hydrogen atom of the hexyl
substituent and provides a high energy contribution of -46.5 kJ/mol to the crystal packing.
The π· ··π contact connects adjacent triazole and benzene rings, Cg1· · · Cg2 = 3.9928(1) Å.
π
· ··π stacking is not significant for compound 3, but the packing here is reinforced by
two C-H· ··π(ring) contacts involving the triazole ring with C—H bonds from both the
benzene ring and the hexyl substituent. One of them (C2'-H2'· · ·Cg1) is associated to a
molecular pair with smaller inter-centroid distance (4.127 Å) and higher pixel energy (-59.2
kJ/mol) than those for compound 2.
In compound 4, the molecular pair involving the previously mentioned C41–
H41A· ··O3' hydrogen bond is further stabilized by an almost face-to-face π· ··π interaction
between adjacent benzene rings, with a short inter-centroid separation, Cg2· · · Cg2 =
3
.5400(2) Å, slippage = 1.158(2) Å, increasing the interaction energy to -66.5 kJ/mol for this
molecular pair.

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Table 5. Interaction energies (ETOT) partitioned into coulombic, polarization, dispersion and repulsion contributions (kJ/mol) for various
molecular pairs in compounds 1–4.
Involved
Interactions
N12-H12N· · ·S23
Cg2· · ·Cg3,
C142-H14C· · ·Cg2
C23=S23· · ·Cg3
Cg4· · ·Cg4
H14D· · ·H24'
H14A· · ·H25'
C14'-H14'· · ·S13
N2-H2N· · ·S3
C42-H42A· · ·Cg2,
Cg1· · ·Cg2
Distance, angle
Compound
1
Symmetry
Ecoul
Epol
Edisp
Erep
94.0
17.8
ETOT
-86.8
-31.2
1-x,-y,1-z
2.39(3), 174
-85.7
-66.6 -28.5
-3.3 -34.7
a
1-x,1-y,1-z
3.814 (2)
-10.9
c
2.94
3.775(2)
3.521(2)
2.356(1)
b
1
2
1
-x,-y,-z
-x,1-y,-z
-x,1-y,-z
-10.7
-10.8
-3.9
-8.1
-8.9
-9.7 -27.0
-4.1 -33.3
-6.2 -30.9
-6.4 -16.2
-3.9
-65.9 -28.1
19.5
31.8
26.9
17.5
10.9
97.9
-27.8
-16.4
-14.0
-13.2
-11.7
-82.4
a
d
d
-
1+x,-1+y,z
+x,1+y,z
1-x,-y,1-z
+x,½-y,½+z
2.319(1)
1
2.824(1), 128
2.40(1), 175
-9.8
2
3
-86.3
c
½
2.93
3.9928(1)
-19.8
-8.4 -62.4
44.1
-46.5
a
x,y,-1+z
-x,1-y,2-z
C5'-H5'· · ·S3
2.9995(4), 151
2.33(2), 176
-10.3
-96.0
-21.3
-4.0
-9.2
-90.2
-7.1 -25.4
-81.9 -29.3
-10.0 -77.1
-2.5 -25.5
-6.6 -19.4
-71.9 -30.4
24.0
109.1
49.3
17.4
21.8
97.0
-18.8
-98.0
-59.2
-14.6
-13.4
-95.4
N2-H2N· · ·S3
C2'-H2'· · ·Cg1
C46-H46C· · ·Cg1
C45-H45A· · ·S3
N2-H2N· · ·S3
C41-H41A· · ·O3',
Cg2· · ·Cg2
c
-
x,1-y,1-z
x,1+y,z
-x,2-y,2-z
1-x,-y,1-z
x,1-y,2-z
2.96
c
2.91
1
2.9188(3), 133
2.43(2), 169
4
-
2.457(1), 160
-38.6
-20.2 -84.3
-8.5 -41.3
76.7
32.2
-66.5
-40.2
a
3.5400(2)
c
1
-x,1-y,1-z
C42-H42C· · ·Cg1
2.97
-22.6
a
b
c
d
Inter-centroid distance; S· ··Cg distance; H· ··Cg distance; H· ··H distance. Compound 1: Cg2, Cg3 and Cg4 are the centroids of C11'-C16',
N21/N22/N24/C23/C25 and C21'-C26' rings, respectively. Compounds 2, 3 and 4: Cg1 and Cg2 are the centroids of N1/N2/N4/C3/C5 and C1'-
C6' rings, respectively.

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3
.5- Hirshfeld surface analysis
Hirshfeld surface analyses have been carried out in order to get further insight into the
packing motifs and the contributions of the main intermolecular interactions governing the
molecular architecture in the crystalline compounds 1-4. Figure 6 shows Hirshfeld surfaces
(HSs) mapped over the dnorm property in two orientations. The surfaces are displayed
transparently to allow visualization of the molecules within the surfaces. Contacts with
distances equal to the sum of the van der Waals radii are represented as white regions and the
contacts with distances shorter than and longer than van der Waals radii are shown as red and
blue colors, respectively. The corresponding full two-dimensional fingerprint plots (FPs) and
resolved to show C···H/H···C and C···C contacts are displayed in Figure 7.

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1
1
.1
.2
2
3
4
Figure 6. Views of the Hirshfeld surfaces mapped with dnorm in two orientations: front view
o
and back view (180 rotated around the vertical axis of the plot). Close contacts are labeled as
follows: (1) S···H, (2) C···H, (2) N···H, (4) O···H, (5) H···H and (6) C···C.

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1
.1
.2
1
2
3
4
Figure 7. 2D-fingerprint plots: full (left) and resolved into C···H/H···C (center) and C···C
right) intermolecular contacts for 1-4 showing percentage contributions to the total Hirshfeld
(
surface area of the molecules. Close contacts are labeled as shown in Figure 6.
The two large adjacent deep-red regions labeled 1 in the dnorm maps (front view) are
common to all four structures, and represent the H···S/S···H contacts attributed to a pair of
N−H···S hydrogen bonds that form the inversion dimers. These contacts can also be seen as a
pair of symmetrical sharp spikes at de + di ≅ 2.3 Å in the FP plots (labeled 1 in Figure 8). In