The balance between hydrogen bonds, halogen bonds, and chalcogen bonds in the crystal structures of a series of 1,3,4-chalcogenadiazoles

Article abstract of DOI:10.3390/molecules26144125

In order to explore how specific atom-to-atom replacements change the electrostatic potentials on 1,3,4-chalcogenadiazole derivatives, and to deliberately alter the balance between inter-molecular interactions, four target molecules were synthesized and characterized. DFT calculations indicated that the atom-to-atom substitution of Br with I, and S with Se enhanced the σ-hole potentials, thus increasing the structure directing ability of halogen bonds and chalcogen bonds as compared to intermolecular hydrogen bonding. The delicate balance between these intermolecular forces was further underlined by the formation of two polymorphs of 5-(4-iodophenyl)-1,3,4-thiadiazol-2-amine; Form I displayed all three interactions while Form II only showed hydrogen and chalcogen bonding. The results emphasize that the deliberate alterations of the electrostatic potential on polarizable atoms can cause specific and deliberate changes to the main synthons and subsequent assemblies in the structures of this family of compounds.

Full text of DOI:10.3390/molecules26144125

molecules
Article
The Balance between Hydrogen Bonds, Halogen Bonds,
and Chalcogen Bonds in the Crystal Structures of a Series
of 1,3,4-Chalcogenadiazoles
Viraj De Silva, Boris B. Averkiev, Abhijeet S. Sinha and Christer B. Aakeröy *
Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA; slvdesilva@ksu.edu (V.D.S.);
averkiev@ksu.edu (B.B.A.); sinha@ksu.edu (A.S.S.)
* Correspondence: aakeroy@ksu.edu; Tel.: +1-785-532-6096
Abstract: In order to explore how specific atom-to-atom replacements change the electrostatic
potentials on 1,3,4-chalcogenadiazole derivatives, and to deliberately alter the balance between inter-
molecular interactions, four target molecules were synthesized and characterized. DFT calculations
indicated that the atom-to-atom substitution of Br with I, and S with Se enhanced the σ-hole potentials,
thus increasing the structure directing ability of halogen bonds and chalcogen bonds as compared to
intermolecular hydrogen bonding. The delicate balance between these intermolecular forces was
further underlined by the formation of two polymorphs of 5-(4-iodophenyl)-1,3,4-thiadiazol-2-amine;
Form I displayed all three interactions while Form II only showed hydrogen and chalcogen bonding.
The results emphasize that the deliberate alterations of the electrostatic potential on polarizable atoms
can cause specific and deliberate changes to the main synthons and subsequent assemblies in the
structures of this family of compounds.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: De Silva, V.; Averkiev, B.B.;
Sinha, A.S.; Aakeröy, C.B. The
Keywords: chalcogen bond; halogen bond; hydrogen bond; intermolecular interactions; polymor-
phism; σ-hole
Balance between Hydrogen Bonds,
Halogen Bonds, and Chalcogen
Bonds in the Crystal Structures of a
Series of 1,3,4-Chalcogenadiazoles.
Molecules 2021, 26, 4125. https://
doi.org/10.3390/molecules26144125
1. Introduction
One of the main goals of crystal engineering is to employ intermolecular interactions
in the assembly of crystalline materials with desired physiochemical properties [1–3]. To
realize this objective, and to effectively manipulate these synthetic vectors, we need to
further improve our understanding of the nature of these interactions.
Academic Editor: Borys Osmialowski
Received: 22 May 2021
Accepted: 5 July 2021
Published: 7 July 2021
The most influential and well-understood intermolecular force is, undoubtedly, the
hydrogen bond [
been extensively mapped out [
has found many practical applications in pharmaceutical co-crystallizations [8,9
4
], and, consequently, the active use of this supramolecular tool has
]. Hydrogen bonding as a structure directing force
], new
5–7
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
agricultural formulations [10], as well as in the design of new energetic materials [11].
However, over the past few decades, the recognition and understanding of potentially
competing intermolecular interactions, such as halogen and chalcogen bonding, have
opened alternative ways for bottom-up design of new crystalline materials [12–14].
Hydrogen bonding is a noncovalent interaction involving the positive electrostatic
potential on the hydrogen atom and a negative electrostatic potential of the acceptor atom
(Scheme 1). Electrostatic models can predict the directionality of the hydrogen bond rea-
sonably well; however, consideration of other components, such as charge transfer and
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
dispersion, is needed to properly understand the directionality [15,16]. Like hydrogen
bonds, halogen bonds share some of the same characteristics, whereby a positive electro-
static potential on a halogen atom and the negative electrostatic potential on an acceptor
atom can produce a ‘halogen bond’. In fact, this interaction is even more directional than
the hydrogen bond; however, it is worth keeping in mind that halogen bonds are not purely
electrostatic. Using high-level theoretical models, such as symmetry-adapted perturbation
Molecules 2021, 26, 4125. https://doi.org/10.3390/molecules26144125
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 4125
2 of 13
theory (SAPT), it is possible to obtain the breakdown of the intermolecular forces into indi-
vidual components of electrostatic, polarization, repulsion, and dispersion for a complete
understanding of the forces at play, which shows electrostatics alone cannot completely
describe and predict the structure directing ability of non-covalent interactions [17,18].
SAPT calculations and other periodic DFT calculations can be computationally taxing,
hence one of the simplest ways to estimate the directionality of such systems with accept-
able accuracy is through the use of molecular electrostatic potential maps (MEPs). This
approach provides a simple method for mapping out the distribution of electron densities
in molecular systems (in vacuo), whereby electron-efficient and -deficient areas can be
identified [19
,
20]. The most prominent
σ
-holes (electron-deficient areas) of a molecule can
-hole on halogen atoms provides
be identified by the positive electrostatic potential. The
σ
the main electrostatic driver for halogen bonding interactions [21,22].
Scheme 1. A simple view of the electrostatic component of hydrogen, halogen, and chalcogen bonds.
Chalcogen bonds, a relatively recent ‘discovery’, also share the same aspects of the
halogen bond, including the high directionality. However, chalcogen atoms can form
two highly directional chalcogen bonding interactions as a result of the presence of two
σ
-holes directly opposed to R-Ch bonds (Scheme 1) [23–26]. Importantly, by changing
the electrostatic potentials on these donor atoms, these noncovalent interactions can be
fine-tuned to be strong structure directing tools that can be utilized in crystal engineering
for creating competition between hydrogen, halogen, and chalcogen bonding [27,28].
Many drug molecules contain multiple functional groups comprising hydrogen, halo-
gen, and chalcogen atoms, and the presence of these can lead to increasing complexity as
to how molecules interact not only in drug formulations, such as co-crystals, but also at
an active site of specific receptors [8,29]. Each approved drug costs billions of dollars in
research and development and many potentially useful candidates fail due to low solubility
or poor stability, and such problems may be addressed with a more complete understand-
ing of how the balance between intermolecular forces leads to a specific structure with
unique bulk properties. Furthermore, 1,3,4-chalcogenadiazole moieties are known to show
anti-inflammatory and anticancer properties [30,31], and broadly speaking, chalcogen
atoms and their structural influence can also positively impact synthetic transformations
and catalysis. Given the fact that chalcogenadiazole moieties contain a variety of domains
that can act as chalcogen-bond donor/acceptor sites, they present a unique source for
the formation of a multitude of intermolecular interactions. The balance and competi-
tion between these non-covalent interactions will significantly impact solid-state structure
and subsequently the properties of the resulting bulk solid. In addition, the presence of
chalcogen bonds can, in principle, compete with or disrupt an intended supramolecular
synthetic strategy. These increased complexities can give rise to unexpected or unpre-
dictable structural influences, hence a systematic study of the possible structure directing
interactions of these moieties are required. Herein, we present a systematic structural
study on how the increased complexity of multiple competing intermolecular forces in a
single molecule is manifested in the solid-state. We focus on the 1,3,4-chalcogenadiazole
moiety (Figure 1) with different substituents in the second and fifth position as this allows
us to alter the chalcogen-bond donor from S to Se and the halogen-bond donor from Br
to I, allowing us to explore the balance between these interactions. Such atom-to-atom

Molecules 2021, 26, 4125
3 of 13
substitutions can potentially result in significant changes to the properties, such as, for
example, increased binding affinity of halogenated ligands I > Br [32], as well as increased
catalytic activity of selenocysteine-containing proteins over cysteine [33,34], which could
be associated with the shorter halogen or chalcogen bond formation in biological systems.
In TTF-TCNQ semiconductor systems, replacement of S with Se results in M-I transitions
at lower temperatures due to stronger coupling between the donor and acceptor [35].
With an improved insight into how chalcogen atoms form intermolecular interactions, we
may be able to (i) deepen our understanding of the origins of photophysical behavior of
charge-transfer complexes and (ii) develop more effective bottom-up syntheses for new
classes of semi-conductors and other high-value molecular materials.
Figure 1. 1,3,4-Chalcogenadiazole derivative with multiple donor and acceptor sites.
Based on relevant structures in the CSD [36–39], as well as on preliminary hydrogen-
bond propensity calculations (Table S1, Scheme S1) [40], it was deemed likely that a dimer
formation through a pair of identical hydrogen bonding (hydrogen-bond dimer) would
be most prominent in this system. However, the tunability of the different interactions
that can be produced within single component systems (Figure 2) can, in principle, lead
to a range of different synthons and structural arrangements. In this study, we wanted
to map out the structural landscape of a series of 1,3,4-chalcogenadiazoles and address
the following specific questions: (i) To what extent do atom-to-atom replacements change
electrostatic potentials? (ii) Which structure directing synthons are formed and how do
they control assembly? and (iii) Can the balance between hydrogen bonds, halogen bonds,
and chalcogen bonds be deliberately modulated?
Figure 2. Postulated interactions in the solid-state landscape of 1,3,4-chalcogenadiazoles.

Molecules 2021, 26, 4125
4 of 13
2. Results
The four target molecules are shown in Figure 3. Molecular electrostatic potential
(MEP) maps (in vacuo) of these molecules reveal how the magnitude of the MEPs change
in response to atom-to-atom replacements. A summary of the results is given in Table 1.
Based on these calculations, the positive electrostatic potentials on the more polarizable
atoms were observed to be larger, as expected. Electrostatic potentials on the same atom
type on different analogs did not change considerably when atom-to-atom replacements
were done.
Figure 3. Molecular electrostatic potential maps (MEPs) of the (a) T1-S-Br (b) T1-Se-Br (c) T1-S-I (d) T1-Se-I.
Table 1. MEP (kJ/mol) data for chalcogen and halogen atoms of the different target analogs.
Donor Atom
T1-S-Br
T1-Se-Br
T1-S-I
T1-Se-I
Chalcogen
Halogen
96.6
74.6
118.8
73.1
95.7
103.0
117.5
103.0
The crystal structure previously reported of T1-S-Br, CCDC refcode XUVTAK [41],
showed the hydrogen-bonded dimer formation with N3-H1···N1 and a single hydrogen
bond between N3-H2···N2 (Figure 2, far left schematic). The bromine atom did not partici-
pate in any notable halogen bonds; however, the sulfur atom engaged in a chalcogen bond
with the π-electron cloud, S1···C5, at 3.497 Å and 161.20◦ (Figure 4).
Figure 4. Structure directing interactions in the crystal structure of T1-S-Br [41].

Molecules 2021, 26, 4125
5 of 13
The crystal structure of T1-Se-Br contains two unique molecules in the asymmetric
unit with each of them showing different interactions with respect to the surrounding
molecules. The halogen atom in one of them formed a near-linear halogen bond (Figure 5)
Br···π electron cloud, Br27···C4 at 3.517(6) Å and 170.0(2)◦, while the other formed an
irregular Br7···Br27 contact in an almost perpendicular fashion, 99◦ (Figure S1). The
,
selenium atoms formed a bifurcated chalcogen bond, Se···π electron cloud and Se···
N
(Figure 5, Figure S1).
Figure 5. Primary intermolecular interactions in the crystal structure of T1-Se-Br.
T1-S-I crystallized in two different polymorphs. Form I was obtained from acetoni-
trile, and Form II from methanol. The polymorphs had different numbers of symmetry-
independent molecules (Z’) and completely different intermolecular connectivity. Form I
resulted in Z’ = 4, where all of them displayed closely related intermolecular connectivity
but with different bond geometries (Figure S2). Two molecules in the asymmetric unit
formed Type II halogen bonds that formed with the electrophilic area on one halogen atom
with an electron-rich area on the other halogen. In this halogen bonding, the halogen
atom simultaneously acted as both the donor and acceptor and the other two unique
molecules did not show any halogen bonds. The sulfur atoms engaged in chalcogen bonds
between S···N in which the nitrogen atom acted as a chalcogen-bond acceptor as well as a
hydrogen-bond acceptor, indicating that the hydrogen bond was most likely the prominent
interaction. In addition, two hydrogen bonds per molecule were formed between NH···
N
(Figure 6), leading to a 2-D chain-like assembly (Figure S3).

Molecules 2021, 26, 4125
6 of 13
Figure 6. (a) Asymmetric unit and (
structure of T1-S-I, Form I.
b) main intermolecular interactions in one of the four unique molecules in the crystal
The crystal structure of Form II (Figure 7) contains a hydrogen bond dimer between
N6-H6B···N4 and a single hydrogen bond between N6H6A···N5 of the heterocycle moiety.
No halogen bonds were present in the Form II (Figure 7). Finally, a chalcogen bond
comprised of S···π ring, S2···C9, at 3.568(7) Å and 162.1(2)◦ was observed.
Figure 7. Primary intermolecular contacts in the crystal structure of T1-S-I, Form II.
In the crystal structure of T1-Se-I, a hydrogen-bond dimer, N13-H13A···N11 (Figure 8)
,
is present along with a single N13-H13B···N12 hydrogen bond, which is similar to T1-S-Br
and Form II of T1-S-I. Consistent with the interaction observed for Se in T1-Se-Br, the sele-
nium atom of T1-Se-I also showed bifurcated chalcogen bonding, Se9···C3(
π), at 3.487(4)Å
and 165.75(14)◦, and Se9···N12, at 3.613(3) Å and 154.88(13)◦. In addition, the structure
contains one Type II halogen bond, I7···I7, at 4.0468(4) Å and 162.8(1)◦.
All relevant hydrogen, halogen and chalcogen bond geometries of T1-S-Br, T1-Se-Br,
T1-S-I and T1-Se-I are given in Table 2.

Molecules 2021, 26, 4125
7 of 13
Figure 8. Structure directing interactions in the crystal structure of T1-Se-I.
Table 2. Hydrogen, halogen, and chalcogen bond parameters of the five crystal structures.
DH/X/Ch—A
DH/X/Ch—A(deg)
D/X/Ch—A Å
N3-H1···N1
N3-H2···N1
S1···C5
2.957
2.996
3.497
163.42
167.10
161.20
1-S-Br
N33-H33b···N11
N13-H13b···N31
N33-H33a···N32
N13-H13a···N12
Se29···N32
2.943(8)
2.942(8)
2.981(7)
2.976(7)
3.646(5)
3.416(6)
3.603(6)
3.406(6)
3.517(6)
165.3(2)
166.1(2)
157.05(19)
157.82(19)
154.39(19)
162.6(2)
155.39(19)
163.3(2)
170.0(2)
T1-Se-Br
Se29···C25
Se9···N12
Se9-C3
Br27···C4
N1B-H1BA···N3D
N1A-H1AA···N3C
N1C-H1CA···N3A
N1D-H1DA···N3B
N1C-H1CB···N2B
N1A-H1AB···N2D
N1D-H1DB···N2A
N1B-H1BB···N2C
S1C···N2B
3.013(13)
3.016(13)
3.028(13)
3.008(13)
3.031(12)
2.992(12)
3.033(13)
3.027(12)
3.507(9)
3.517(10)
3.525(10)
3.559(10)
3.892(1)
176.8(7)
179.2(7)
179.2(7)
178.9(8)
157.4(6)
155.5(6)
158.7(13)
159.5(6)
163.6(4)
164.6(4)
162.4(4)
163.1(4)
174.7(3)
176.3(3)
T1-S-I Form I
S1D···N1A
S1A···N2D
S1B···N2C
I1C···I1A
I1A···I1B
3.813(1)
N6-H6B···N4
N6-H6A···N5
S2···C9
2.979(8)
3.019(7)
3.568(7)
178(8)
172(6)
162.1(2)
T1-S-I Form II

Molecules 2021, 26, 4125
8 of 13
Table 2. Cont.
DH/X/Ch—A
DH/X/Ch—A(deg)
D/X/Ch—A Å
N13-H13A···N11
N13-H13B···N12
Se9···N12
Se9···C3
2.940(5)
2.957(4)
3.613(3)
3.487(4)
4.0468(4)
4.0468(4)
165.6(3)
157.7(3)
154.88(13)
165.75(14)
162.8(1)
T1-Se-I
I7···I7
I7···I7
93.14(11)
3. Discussion
The calculated MEPs showed that when the smaller atoms (Br, S) were replaced
by a more polarizable alternative (I, Se), the electrostatic potentials undergo significant
transformations (Table 1, Figure 3). Changing bromine to iodine resulted in a 40% increase
in the positive σ-hole potential, while a selenium replacement of sulfur produced a 23%
enhancement. Even though intermolecular halogen bonds and chalcogen bonds are the
result of contributions from electrostatic, polarization, repulsion, and dispersion, it is
helpful to note that a relatively simplistic focus on the electrostatic component alone still
offers valuable guidance for predicting which synthons are going to be more likely to appear
in an extended structure. The increases in the electrostatic potential produce atoms that
are more likely to form more prominent halogen and chalcogen bonds, respectively, which
directly impacts their ability to more frequently deliver structure directing interactions in
the solid state.
Geometry optimizations (in vacuo) of all target molecules showed the two rings,
phenyl and 1,3,4-chalcogenadiazole, in each molecule to be close to coplanar geometry with
a range of torsion angles of
structures only allows one of the two
−
0.55 to +0.55◦ (Figure S4). The planarity of these optimized
σ
-holes to be accessed by the acceptors. In the
solid-state, however, these were not planar and had torsion angles ranging from 30–40◦
(Figure S4). In the sulfur analogs of 1,3,4-chalcogendiazole published in the CSD (Figure 9,
based on 152 relevant crystal structures), the majority had torsion angles less than 40◦and
most of them formed single chalcogen bond formation. The structures of the selenium
analogues in this study contained bifurcated chalcogen bond comprising both σ-holes. As
a result of the substitution of sulfur with selenium, an additional chalcogen bond becomes
structurally active and the supramolecular assembly proceeds along a different path.
Figure 9. Distribution of torsion angles based on 152 CSD-reported 1,3,4-thiadiazol structures.

Molecules 2021, 26, 4125
9 of 13
Atom-to-atom replacement of halogen atoms resulted in a more significant enhance-
ment of the electrostatic potentials compared to those noted in the case of the chalcogen
replacement. Despite this difference, only 3/5 structures contained noteworthy halogen
bonds, whereas chalcogen bonds were present in all five crystal structures examined herein.
Only one of the two bromine-based compounds formed halogen bonds, whereas the io-
dine compounds showed Type II halogen bond formation in 2/5 structures, Scheme 2.
All iodine-containing structures not undergoing halogen bonding show that despite the
predictability of the MEPs, it was not always perfect; however, in general, the increased
structural influence can be attributed to larger σ-hole potentials of the more polarizable
iodine atom. The lack of halogen bonds in previously reported fluorine [38] and chlo-
rine [39] analogs further validates the expectation that a more polarizable halogen atom is
more likely to influence the solid-state assembly in ways to go beyond simple (and less
directional) packing forces.
Scheme 2. Summary of notable intermolecular interactions in the crystal structures examined herein. sHB: Single Hydrogen
Bond. sChB: Single Chalcogen Bond. bChB: Bifurcated Chalcogen Bond.
A comparison of the frequency of occurrence of hydrogen, halogen, and chalcogen
bonds in the crystal structures of these 1,3,4-chalcogendiazole shows that the former was
the most prominent; hydrogen bonding exists in all of them and 4/5 exist as hydrogen
bond dimers and 5/5 as single hydrogen bond formation. The significance of the hydrogen
bonding and the delicate balance between the hydrogen, halogen, and chalcogen bonding
was clearly displayed in the two polymorphic structures. The melting points of Form
◦
I and Form II only differed by 1–2 C, implying that their lattice energies (and relative
stabilities) are closely matched. Since Form I contains halogen and hydrogen bonds
(chalcogen bonding was overshadowed by the hydrogen bonding), and Form II contains
chalcogen and hydrogen bonds, we can surmise that the impacts on the stability and
physical properties of the two σ-hole interactions are very similar.
4. Materials and Methods
4.1. Reagent and General Methods
All reagents were used as received without any further purification. MEPs were
calculated using density functional theory on molecules optimized in the gas phase using
Spartan’ 08 program with B3LYP/6-311++G** level of theory. All the NMRs were recorded
on a Bruker 400 MHz spectrophotometer. Single crystal X-ray diffraction data were obtained
using a Bruker MicroStar and a Rigaku XtaLAB Synergy-S with CuKα and MoKα sources.
The melting points were collected using a TA instrument DSC Q20 differential scanning
calorimeter.
4.2. Crystallization Experiments
Single crystals of the pure products of T1-Se-Br and T1-Se-I were obtained using the
slow evaporation method with methanol as the solvent. The pure product of T1-S-I was

Molecules 2021, 26, 4125
10 of 13
recrystallized using the slow evaporation method from acetonitrile and methanol to obtain
Form I and Form II, respectively.
4.3. Synthesis of Selenosemicarbazide
Thiosemicarbazide (3.64 g, 0.04 mol) was dissolved in dry ethanol and to this, iodomethane
(5.67 g, 0.04 mol) was added and the mixture was refluxed at 80 ◦C for 3 h. Upon cooling
the mixture in an ice bath, the product, hydrazinyl(methylthio)methanamine, precipitated
and this was air dried overnight and used for◦the following step.
To a mixture of Se and NaBH4 cooled to 0 C with ice, dry ethanol was added under N2
atmosphere. Once all the Se dissolved, hydrazinyl(methylthio)methanamine dissolved in
dry ethanol was added slowly. This was stirred overnight, and the resulting precipitate was
filtered in the fume hood, and the product was purified through column chromatography
1
as a grey/violet solid [31]. Yield 60%. Decomp: 174–176. H NMR (400 MHz, DMSO-d6)
δ
9.07 (s, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 4.52 (s, 2H), 13C NMR (101 MHz, DMSO)
δ 175.80.
77Se NMR (400 MHz, DMSO-d6) δ 146.16.
4.4. Synthesis of 5-(4-Bromophenyl)-1,3,4-thiadiazol-2-amine, T1-S-Br
First, 4-bromobenzoic acid (2.01 g; 0.01 mol), thiosemicarbazide (0.91g, 0.01 mol),
and POCl3 (5.0 mL) were mixed in a round-bottomed flask. This was refluxed at 75 ◦C
for 3 h. After cooling to room temperature, water (50.0 mL) was added slowly to the
mixture and the reaction mixture was further refluxed for 4 h. The progress of the reaction
was monitored using TLC and after the completion, the mixture was cooled to room
temperature and was basified to pH 8 using 30% NH4OH. The resulting precipitate was
filtered, and the product was purified using column chromatography. The product was a
light-yellow solid with a yield of 85%. MP: 212–214 ◦C. 1H NMR (400 MHz, DMSO-d6)
δ
7.68 (q, J = 8.7 Hz, 4H), 7.50 (s, 2H). 13C NMR (101 MHz, DMSO)
δ 169.32, 155.66, 132.55,
130.66, 128.60, 123.08.
4.5. Synthesis of 5-(4-Bromophenyl)-1,3,4-selenadiazol-2-amine, T1-Se-Br
First, 4-bromobenzoic acid (2.01g, 0.01 mol), selenosemicarbazide (1.38g, 0.01 mol),
and POCl3 (5.0 mL) were mixed in a round-bottomed flask. This was refluxed at 75 ◦C
for 3 h. After cooling to room temperature, water (50.0 mL) was added slowly to the
mixture and the reaction mixture was further refluxed for 4 h. The progress of the reaction
was monitored using TLC and after the completion, the mixture was cooled to room
temperature and was basified to pH 8 using 30% NH4OH. The resulting precipitate was
filtered, and the product was purified using column chromatography. The product was a
◦
light pink color solid with a yield of 65%. MP: 222–224 C. 1H NMR(400 MHz, DMSO-d6)
δ
7.64 (m, J = 8.5 Hz, 4H). 13C NMR (101 MHz, DMSO)
122.91. 77Se NMR (400 MHz, DMSO-d6) δ 562.04.
δ 173.10, 160.83, 133.54, 132.42, 129.30,
4.6. Synthesis of 5-(4-Iodophenyl)-1,3,4-thiadiazol-2-amine, T1-S-I
First, 4-iodobenzoic acid (2.48g, 0.01 mol), thiosemicarbazide (0.91g, 0.01 mol), and
◦
POCl3 (5.0 mL) were mixed in a round-bottomed flask. This was refluxed at 75 C for
3 h. After cooling to room temperature, water (50.0 mL) was added slowly to the mixture
and the reaction mixture was further refluxed for 4 h. The progress of the reaction was
monitored using TLC and after the completion, the mixture was cooled to room temperature
and was basified to pH 8 using 30% NH4OH. The resulting precipitate was filtered, and the
product was purified using column chromatography. The product was a white solid with a
◦
◦
yield of 70%. MP: Form I 239–241 C, From II 240–242 C. 1H NMR (400 MHz, DMSO-d6)
7.83 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz 2H), 7.49 (s, 2H). 13C NMR (101 MHz, DMSO)
169.45, 156.11, 138.57, 131.16, 128.75, 96.62.
δ
δ

Molecules 2021, 26, 4125
11 of 13
4.7. Synthesis of 5-(4-Iodophenyl)-1,3,4-selenadiazol-2-amine, T1-Se-I
First, 4-iodobenzoic acid (2.48g, 0.01 mol), selenosemicarbazide (1.38g, 0.01 mol),
and POCl3 (5.0 mL) were mixed in a round-bottomed flask. This was refluxed at 75 ◦C
for 3 h. After cooling to room temperature, water (50.0 mL) was added slowly to the
mixture and the reaction mixture was further refluxed for 4 h. The progress of the reaction
was monitored using TLC and after the completion, the mixture was cooled to room
temperature and was basified to pH 8 using 30% NH4OH. The resulting precipitate was
filtered, and the product was purified using column chromatography. The product was a
◦
greyish solid with a yield of 55%. MP: 219–221 C. 1H NMR (400 MHz, DMSO-d6)
δ 7.80 (d,
J = 8.4 Hz, 2H), 7.61 (s, 2H), 7.51 (d, J = 8.4 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 173.00,
161.07, 138.27, 133.86, 129.30, 96.24. 77Se NMR (400 MHz, DMSO-d6) δ 560.97.
5. Conclusions
In summary, it is clear that atom-to-atom substitution can lead to significant changes
in crystal structures especially when the less polarizable sulfur is replaced by a more polar-
izable selenium atom (a better chalcogen donor), leading to a more structurally influential
σ
-hole. Despite the fact that chalcogen bonds comprise a variety of components, MEPs offer
a simple way of mapping out electrostatic potentials in the 1,3,4-chalcogenadiazole sys-
tems. This information can provide reliable guidelines for predicting which intermolecular
interactions are going to be prominent in the solid state. By altering these electrostatic po-
tentials through covalent means, the influence of σ-hole interactions (such as halogen and
chalcogen bonds) can be controlled. Ultimately, this is of considerable practical importance
when designing crystal engineering strategies that involve a combination of reversible
non-covalent interactions.
Supplementary Materials: The following are available online. Table S1: Hydrogen bond propensity
(HBP) calculations using Mercury, Scheme S1: Schematic of 1,3,4-Chalcogenadiazole and the num-
bering used in HBP calculations, Figure S1: T1-Se-Br Secondary interactions of the second unique
molecule of the asymmetric unit, Figure S2: T1-S-I Form I Halogen bonding interactions formed by
each unique molecule in the asymmetric unit showing different bond geometries, Figure S3: T1-S-I
Form I Hydrogen bonder 2-D chain, Figure S4: T1-S-Br a) torsion angle of the optimized structure
in vacuum b) torsion angle of the molecule in the crystal structure, refcode XUVTAK, Table S2:
1
Crystallographic data. H, 13C and 77Se NMR spectrums.
Author Contributions: Conceptualization, investigation and writing V.D.S. and C.B.A.; X-Ray inves-
tigation, A.S.S., B.B.A. and C.B.A. All authors have read and agreed to the published version of the
manuscript.
Funding: Viraj De Silva acknowledges support from the Kansas State University and the NSF-
MRI grant CHE-2018414, which was used to purchase the single-crystal X-ray diffractometer and
associated software employed in this study.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Crystallographic data (CCDC 2083577, 2083645, 2083656, 2083657) can
be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (accessed on 14 May 2021), or
by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Acknowledgments: We acknowledge Victor W. Day for collecting XRD data for on T1-S-I (Form II).
Victor W. Day acknowledge NSF-MRI grant CHE-0923449, which was used to purchase the X-ray
diffractometer and software used in this study.
Conflicts of Interest: Authors declare no conflicts of interest.
Sample Availability: Samples of the compounds are not available from the authors.

Molecules 2021, 26, 4125
12 of 13
References
1.
2.
3.
4.
Desiraju, G.R. Crystal engineering: A holistic view. Angew. Chem. Int. Ed. 2007, 46, 8342–8356. [CrossRef]
Aakeröy, C.B.; Champness, N.R.; Janiak, C. Recent advances in crystal engineering. CrystEngComm 2010, 12, 22–43. [CrossRef]
Aakeroy, C.B. Crystal Engineering: Strategies and Architectures. Acta Cryst. 1997, B53, 569–586. [CrossRef]
Sarkar, N.; Sinha, A.S.; Aakeroÿ, C.B. Systematic investigation of hydrogen-bond propensities for informing co-crystal design and
assembly. CrystEngComm 2019, 21, 6048–6055. [CrossRef]
5.
6.
Wang, L.-C.; Zheng, Q.-Y. Hydrogen Bonding in Supramolecular Crystal Engineering; Springer: Berlin, Heidelberg, 2015; pp. 69–113.
Aakeröy, C.B.; Leinen, D.S. Hydrogen-Bond Assisted Assembly of Organic and Organic-Inorganic Solids. In Crystal Engineering:
From Molecules and Crystals to Materials; Springer: Dordrecht, The Netherlands, 1999; pp. 89–106.
Corpinot, M.K.; Bucˇar, D.K. A Practical Guide to the Design of Molecular Crystals. Cryst. Growth Des. 2019, 19, 1426–1453.
[CrossRef]
Kumar, A.; Kumar, S.; Nanda, A. A review about regulatory status and recent patents of pharmaceutical co-crystals. Adv. Pharm.
Bull. 2018, 8, 355–363. [CrossRef] [PubMed]
Aakeröy, C.B.; Grommet, A.B.; Desper, J. Co-Crystal Screening of Diclofenac. Pharmaceutics 2011, 3, 601–614. [CrossRef] [PubMed]
7.
8.
9.
10. Sandhu, B.; Sinha, A.S.; Desper, J.; Aakeröy, C.B. Modulating the physical properties of solid forms of urea using co-crystallization
technology. Chem. Commun. 2018, 54, 4657–4660. [CrossRef]
11. Gamekkanda, J.C.; Sinha, A.S.; Aakeröy, C.B. Cocrystals and Salts of Tetrazole-Based Energetic Materials. Cryst. Growth Des. 2020
20, 2432–2439. [CrossRef]
,
12. Rahman, F.U.; Tzeli, D.; Petsalakis, I.D.; Theodorakopoulos, G.; Ballester, P.; Rebek, J.; Yu, Y. Chalcogen Bonding and Hydrophobic
Effects Force Molecules into Small Spaces. J. Am. Chem. Soc. 2020, 142, 5876–5883. [CrossRef]
13. Mahmudov, K.T.; Kopylovich, M.N.; Guedes Da Silva, M.F.C.; Pombeiro, A.J.L. Chalcogen bonding in synthesis, catalysis and
design of materials. Dalt. Trans. 2017, 46, 10121–10138. [CrossRef] [PubMed]
14. Fourmigué, M.; Dhaka, A. Chalcogen bonding in crystalline diselenides and selenocyanates: From molecules of pharmaceutical
interest to conducting materials. Coord. Chem. Rev. 2020, 403, 213084. [CrossRef]
15. Platts, J.A.; Howard, S.T.; Bracke, B.R.F. Directionality of hydrogen bonds to sulfur and oxygen. J. Am. Chem. Soc. 1996, 118,
2726–2733. [CrossRef]
16. Kollman, P.A. A Theory of Hydrogen Bond Directionality. J. Am. Chem. Soc. 1972, 94, 1837–1842. [CrossRef]
17. Parrish, R.M.; Sherrill, C.D. Spatial assignment of symmetry adapted perturbation theory interaction energy components: The
atomic SAPT partition. J. Chem. Phys. 2014, 141, 44115. [CrossRef] [PubMed]
18. Misquitta, A.J.; Podeszwa, R.; Jeziorski, B.; Szalewicz, K. Intermolecular potentials based on symmetry-adapted perturbation
theory with dispersion energies from time-dependent density-functional calculations. J. Chem. Phys. 2005, 123, 214103. [CrossRef]
19. Murray, J.S.; Politzer, P. The electrostatic potential: An overview. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2011, 1, 153–163.
[CrossRef]
20. Murray, J.S.; Politzer, P. Molecular electrostatic potentials and noncovalent interactions. Wiley Interdiscip. Rev. Comput. Mol. Sci.
2017, 7, e1326. [CrossRef]
21. Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi, A.; Resnati, G.; Terraneo, G. The halogen bond. Chem. Rev. 2016, 116,
2478–2601. [CrossRef] [PubMed]
22. Desiraju, G.R.; Shing Ho, P.; Kloo, L.; Legon, A.C.; Marquardt, R.; Metrangolo, P.; Politzer, P.; Resnati, G.; Rissanen, K. Definition
of the halogen bond (IUPAC Recommendations 2013). Pure Appl. Chem 2013, 85, 1711–1713. [CrossRef]
23. Vogel, L.; Wonner, P.; Huber, S.M. Chalcogen Bonding: An Overview. Angew. Chem. Int. Ed. 2019, 58, 1880–1891. [CrossRef]
24. Scilabra, P.; Terraneo, G.; Resnati, G. The Chalcogen Bond in Crystalline Solids: A World Parallel to Halogen Bond. Acc. Chem.
Res. 2019, 52, 1313–1324. [CrossRef] [PubMed]
25. Wang, W.; Ji, B.; Zhang, Y. Chalcogen bond: A sister noncovalent bond to halogen bond. J. Phys. Chem. A 2009, 113, 8132–8135.
[CrossRef] [PubMed]
26. Aakeroy, C.B.; Bryce, D.L.; Desiraju, G.R.; Frontera, A.; Legon, A.C.; Nicotra, F.; Rissanen, K.; Scheiner, S.; Terraneo, G.;
Metrangolo, P.; et al. Definition of the chalcogen bond (IUPAC Recommendations 2019). Pure Appl. Chem. 2019, 91, 1889–1892.
[CrossRef]
27. Robertson, C.C.; Wright, J.S.; Carrington, E.J.; Perutz, R.N.; Hunter, C.A.; Brammer, L. Hydrogen bonding: Vs. halogen bonding:
The solvent decides. Chem. Sci. 2017, 8, 5392–5398. [CrossRef] [PubMed]
28. Ahmed, M.N.; Madni, M.; Anjum, S.; Andleeb, S.; Hameed, S.; Khan, A.M.; Ashfaq, M.; Tahir, M.N.; Gil, D.M.; Frontera, A. Crystal
engineering with pyrazolyl-thiazole derivatives: Structure-directing role of π-stacking and σ-hole interactions. CrystEngComm
2021, 23, 3276. [CrossRef]
29. Scholfield, M.R.; Vander Zanden, C.M.; Carter, M.; Ho, P.S. Halogen bonding (X-bonding): A biological perspective. Protein Sci.
2013, 22, 139–152. [CrossRef] [PubMed]
30. Hu, Y.; Li, C.Y.; Wang, X.M.; Yang, Y.H.; Zhu, H.L. 1,3,4-Thiadiazole: Synthesis, reactions, and applications in medicinal,
agricultural, and materials chemistry. Chem. Rev. 2014, 114, 5572–5610. [CrossRef] [PubMed]
31. Chen, Z.; Li, D.; Xu, N.; Fang, J.; Yu, Y.; Hou, W.; Ruan, H.; Zhu, P.; Ma, R.; Lu, S.; et al. Novel 1,3,4-Selenadiazole-Containing
Kidney-Type Glutaminase Inhibitors Showed Improved Cellular Uptake and Antitumor Activity. J. Med. Chem. 2019, 62, 589–603.
[CrossRef] [PubMed]

Molecules 2021, 26, 4125
13 of 13
32. Zaldini Hernandes, M.; Melo Cavalcanti, S.T.; Rodrigo Moreira, D.M.; Filgueira de Azevedo Junior, W.; Cristina Lima Leite, A.
Halogen Atoms in the Modern Medicinal Chemistry: Hints for the Drug Design. Curr. Drug Targets 2010, 11, 303–314. [CrossRef]
33. Kim, H.Y.; Gladyshev, V.N. Different catalytic mechanisms in mammalian selenocysteine- and cysteine-containing methionine-R-
sulfoxide reductases. PLoS Biol. 2005, 3, 1–10. [CrossRef] [PubMed]
34. Jacob, C.; Giles, G.I.; Giles, N.M.; Sies, H. Sulfur and Selenium: The Role of Oxidation State in Protein Structure and Function.
Angew. Chem. Int. Ed. 2003, 42, 4742–4758. [CrossRef] [PubMed]
35. Etemad, S. Systematic study of the transitions in tetrathiafulvalene- tetracyanoquinodimethane (TTF-TCNQ) and its selenium
analogs. Phys. Rev. B 1976, 13, 2254–2261. [CrossRef]
36. Wan, R.; Wang, Y.; Han, F.; Wang, P. 5-(4-Phenoxy-phen-yl)-1,3,4-thia-diazol-2-amine. Acta Crystallogr. Sect. E Struct. Reports
Online 2009, 65, o1044. [CrossRef] [PubMed]
37. Zhang, J.Q.; He, Q.; Jiang, Q.; Mu, H.; Wan, R. 5-(4-Bromo-2-nitrophenyl)-1,3,4-thiadiazol-2-amine. Acta Crystallogr. Sect. E Struct.
Reports Online 2011, 67, o2255. [CrossRef] [PubMed]
38. Wan, R.; Han, F.; Wu, F.; Zhang, J.J.; Wang, J.T. 5-(4-Fluorophenyl)-1,3,4-thiadiazol-2-ylamine. Acta Crystallogr. Sect. E Struct.
Reports Online 2006, 62, 5547–5548. [CrossRef]
39. Kerru, N.; Gummidi, L.; Bhaskaruni, S.V.H.S.; Maddila, S.N.; Singh, P.; Jonnalagadda, S.B. A comparison between observed and
DFT calculations on structure of 5-(4-chlorophenyl)-2-amino-1,3,4-thiadiazole. Sci. Rep. 2019, 9, 1–17. [CrossRef] [PubMed]
40. Wood, P.A.; Feeder, N.; Furlow, M.; Galek, P.T.A.; Groom, C.R.; Pidcock, E. Knowledge-based approaches to co-crystal design.
CrystEngComm 2014, 16, 5839–5848. [CrossRef]
41. Lynch, D.E. CSD Communication. 2009. Available online: https://www.ccdc.cam.ac.uk/structures/search?sid=ConQuest&
coden=001078&year=2009&pid=ccdc:717882&aulast=Lynch (accessed on 7 May 2021).