Quantitative assessment of the nature of noncovalent interactions in: N -substituted-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-amines: Insights from crystallographic and QTAIM analysis

Article abstract of DOI:10.1039/d0ra00733a

Three adamantane-1,3,4-thiadiazole hybrid derivatives namely; N-ethyl-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-amine I, N-(4-fluorophenyl)-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-amine II and (4-bromophenyl)-5-(adamantan-1-yl)-N-1,3,4-thiadiazole-2-amine III

Full text of DOI:10.1039/d0ra00733a

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Quantitative assessment of the nature of
noncovalent interactions in N-substituted-5-
(adamantan-1-yl)-1,3,4-thiadiazole-2-amines:
insights from crystallographic and QTAIM analysis†
Cite this: RSC Adv., 2020, 10, 9840
Ali A. El-Emam,a Elangovan Saveeth Kumar,b Krishnakumar Janani,b Lamya H. Al-
d
e
c
Wahaibi,c Olivier Blacque,
M. Judith Percino
Mohamed I. El-Awady,
Nora H. Al-Shaalan,
f
b
*
and Subbiah Thamotharan
Three adamantane-1,3,4-thiadiazole hybrid derivatives namely; N-ethyl-5-(adamantan-1-yl)-1,3,4-
thiadiazole-2-amine I, N-(4-fluorophenyl)-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-amine II and (4-
bromophenyl)-5-(adamantan-1-yl)-N-1,3,4-thiadiazole-2-amine III, have been synthesized and crystal
structures have been determined at low temperature. The structures revealed that the orientation of the
amino group is different in non-halogenated structures. Intra- and intermolecular interactions were
characterized on the basis of the quantum theory of atoms-in-molecules (QTAIM) approach.
Intermolecular interaction energies for different molecular pairs have been obtained using the PIXEL
method. Hirshfeld surface analysis and 2D-fingerprint plots revealed that the relative contributions of
different non-covalent interactions are comparable in compounds with halogen (Br and F) substitutions.
Crystal structures of II and III show isostructural behaviour with 1D supramolecular constructs. In all
three structures, the N–H/N hydrogen bond was found to be stronger among other noncovalent
interactions. The H–H bonding showed a closed shell in nature and played significant roles in the
stabilization of these crystal structures.
Received 23rd January 2020
Accepted 2nd March 2020
DOI: 10.1039/d0ra00733a
rsc.li/rsc-advances
marketed drugs or new drug candidates under clinical investi-
gation. The major pharmacological activities of 1,3,4-
Introduction
thiadiazole-based drugs include carbonic anhydrase inhibitory
activity,2 antibacterial,3 antifungal,4 anticancer,5 antiviral,6 try-
panosomicidal,7 and anti-leishmanial activities.8 On the other
hand, adamantane-based derivatives are currently used as effi-
cient therapies for the treatment of various pathological disor-
ders.9 In almost all cases, the incorporation of an adamantyl
moiety into several molecules results in compounds with rela-
tively high lipophilicity, which in turn modulate the bioavail-
ability of these molecules.10
In continuation of our interest in the structural and phar-
macological properties of adamantane-based derivatives,11 we
present herein the crystal structures of three N-substituted-5-
(adamantan-1-yl)-1,3,4-thiadiazole-2-amine derivatives. To
delineate the effect of substituents and to have a qualitative
picture of intermolecular interactions present in these
compounds, we performed Hirshfeld surface and 2D-
ngerprint plots.12 The lattice energies of these crystals and
intermolecular interactions strengths of different molecular
pairs observed in these structures were further quantied by the
PIXEL method.13 Furthermore, the topological parameters for
noncovalent interactions at their bond critical points (BCPs)
were computed based on Bader's quantum theory of atoms in
1,3,4-Thiadiazole derivatives have long been known for their
diverse applications in the medical, agricultural and material
science elds.1 In the medical eld, the 1,3,4-thiadiazole
nucleus represents the essential pharmacophore of several
aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University,
Mansoura 35516, Egypt
bBiomolecular Crystallography Laboratory, Department of Bioinformatics, School of
Chemical and Biotechnology, SASTRA Deemed University, Thanjavur-613401, India.
E-mail: thamu@scbt.sastra.edu
cDepartment of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman
University, Riyadh 11671, Saudi Arabia
dDepartment of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich,
Switzerland
eDepartment of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura
University, Mansoura 35516, Egypt
f
´
´
´
´
Unidad de Polımeros y Electronica Organica, Instituto de Ciencias, Benemerita
´
Universidad Autonoma de Puebla, Val3-Ecocampus Valsequillo, Independencia O2
Sur 50, San Pedro Zacachimalpa, Puebla-C.P. 72960, Mexico
† Electronic supplementary information (ESI) available: Potential energy surface
scan, topological parameters for intra- and intermolecular interactions,
molecular graphs for intra- and intermolecular interactions. CCDC 1977639,
1977643 and 1977750. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/d0ra00733a
9840 | RSC Adv., 2020, 10, 9840–9853
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molecules (QTAIM) framework.14 The noncovalent bonding a goniometer head and immediately transferred to the diffrac-
nature and character (HB and van der Waals interactions) were tometer. Single crystal X-ray diffraction data were collected on
assessed by rst four criteria of Koch–Popelier.15
a Rigaku OD XtaLAB Synergy, Dualex Pilatus 200 K diffrac-
These four criteria are (i) topology (BCP), (ii) electron density tometer using a single wavelength X-ray source (Cu Ka radia-
r(r) at the BCP (iii) Laplacian of the electron density V2r(r) and tion: l ¼ 1.54184 A) (Rigaku Oxford Diffraction, 2015) from
ꢀ
(iv) mutual penetration of the H and the acceptor atom. The a micro-focus sealed X-ray tube and an Oxford liquid-nitrogen
fourth criterion of KP (hereaer KP-4) compares the bonding (rD Cryostream cooler. Pre-experiment, data collection, data
and rA) and non-bonding radii of donor (r0D) and acceptor atoms reduction and analytical absorption correction21 were per-
(r0A). The bonding radii are taken as length from the BCP to the formed with the program suite CrysAlisPro (CrysAlisPro
nuclei, whereas non-bonding radii of hydrogen and the acceptor (Version 1.171.40.16c), Rigaku Oxford Diffraction, 2018) using
atoms are taken as the gas phase van der Waals radii.16 The Olex2, a complete structure solution, renement and analysis
strong and weak intermolecular interactions in different mole- program.22 The structures were solved with the SHELXT small
cules have been quantitatively analyzed using the rst four molecule structure solution program.23 All non-hydrogen atoms
criteria of KP successfully.17 The strength of various noncovalent were rened with the SHELXL 2018/3 program package by full-
interactions at their BCPs in these three structures was quantied matrix least-squares minimization on F2.24 The position of
using an empirical scheme [De ¼ ꢀ0.5 ꢁ V(r)] proposed by EML18 amine H atom was located from a difference Fourier map and
and the total electronic energy density H(r) [H(r) ¼ V(r) + G(r); freely rened. In compound I, the methyl H were constrained to
ꢀ
where V(r) and G(r) represent potential energy density and kinetic an ideal geometry with C–H ¼ 0.98 A and Uiso(H) ¼ 1.5Ueq(C),
energy density] proposed by Cremer & Kraka.19 In the bromo but were allowed to rotate freely about the C–C bond. The
derivative, we observed a homo-halogen (Br/Br) contact and remaining H atoms were placed in calculated geometrical
ꢀ
found to be important for stabilization. We report herein positions with C–H ¼ 0.93–1.00 A and Uiso(H) ¼ 1.2Ueq(C).
a detailed CSD (Cambridge Structural Database) analysis of Br/
Br interaction to know its geometrical preferences.
Hirshfeld surface analysis
The Hirshfeld surface analysis has been performed with
CrystalExplorer-17.5 program using the X-ray geometries aer
normalizing the H involving distances with N–H ¼ 1.009 and
Experimental
Synthesis and crystallization
25
ꢀ
C–H ¼ 1.083 A. The interatomic contacts were visualized on
The title N-substituted-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-
amines I, II and III were synthesized starting with
adamantane-1-carbohydrazide A via treatment with the appro-
priate isothiocyanate to yield the corresponding 1-[(1-
adamantan-1-yl)carbonyl]-4-substituted thiosemicarbazides B,
which were cyclized to their 1,3,4-thiadiazole analogues I–III
using sulphuric acid at room temperature for 24 hours (Scheme
1).20 Pure single crystals for X-ray analysis were obtained by slow
evaporation of CHCl3 : EtOH (1 : 1) solution at room tempera-
ture. A detailed synthesis procedure and 1H NMR spectral data
for compounds I–III are given in ESI.†
the Hirshfeld surface using three different colour (red-white-
blue) scales. The red-white-blue colour schemes were used to
identify the interatomic contact distances are shorter than vdW
separation (red), equal to vdW separation (white) and longer
than vdW separation (blue) from the Hirshfeld surface that was
mapped over the function of dnorm. 2D-ngerprint plots were
obtained from the Hirshfeld surface analysis in order to
compute the relative contributions of different intermolecular
interactions exist in the crystal structures.
PIXEL energy calculation
Intermolecular interaction energies for different dimers in the
crystal structures of I–III and lattice energies for these
compounds were calculated using the PIXELC module of CLP
program.13 The intermolecular interaction energy (Etot) is the
sum of the coulombic (Ecoul), polarization (Epol), dispersion
(Edisp) and repulsion (Erep) energy terms. The X-ray geometries
were used aer the normalizing the H involving bond lengths as
mentioned above. For the PIXEL calculation, the electron
density of the molecules of I–III has been calculated at MP2/6-
31G** level of theory using Gaussian program.26
Single crystal X-ray structure determination
The selected suitable single crystals of compounds I–III were
mounted using polybutene oil on a exible loop xed on
DFT computation and QTAIM analysis
All the quantum chemical calculations were performed with the
program Gaussian 09 program.26 In order to gain more insights
into nature of intermolecular interactions found within
different molecular dimers identied from PIXEL energy anal-
ysis, the topological analysis was performed with the AIMALL
package.27 For this, the wave functions were generated from the
Scheme 1 The synthetic pathway for the target compounds I–III.
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single point energy calculation (at crystal structure geometry
with the normalized H involving distances to their typical
neutron values) at the M06-2X-D3/cc-pVTZ level of theory.28,29
Further, to understand the preference of N–H group orienta-
tion, we performed rigid potential energy surface scan for the
torsion angle S1–C3–N1–C2 in compound I using Jaguar
program30 with B3LYP functional,31 and 6-31G(d) basis set. The
molecular electrostatic potentials were also computed with
WFA-SAS program32 to identify the electrostatic complementary
regions within the molecule.
Fig. 1 Thermal ellipsoidal plot of compound I. The ellipsoids are
drawn at the 50% probability level.
Results and discussion
molecule (Fig. 1). Four fused cyclohexane rings constitute the
adamantane moiety and each of these six-membered rings is in
chair conformation as evident from the Cremer and Pople
puckering parameters.33 The orientation of the N–H group is in
syn conformation with respect to the orientation of the S atom.
Similar orientation has been observed in a closely related
structure of methylamine derivative.34
In order to understand the preference of syn conformation of
amine group in the solid state, we performed a rigid potential
energy surface scan (PES). The results suggest that the syn
conformation (S1–C3–N1–C2 ¼ 5ꢂ) is found to be minimum
energy conformer and the energy difference between syn and
In the present study, we explored the role of various non-
covalent interactions in three adamantane derivatives using
different theoretical approaches. Two of the structures (II and
III) contain halogen atoms (F and Br). Crystal data, data
collection details and renement statistics for all three
compounds are presented in Table 1.
Crystal structure of I
Compound I crystallizes in the monoclinic system with the
space group of P21/c and its asymmetric unit comprises of one
Table 1 Crystal data and refinement parameters for compounds I–III
I
II
III
Crystal data
Chemical formula
Mr
C
14H21N3S
C18H20FN3S
329.43
C18H20BrN3S
390.34
263.40
Crystal system, space group
Temperature (K)
a, b, c (A)
Monoclinic, P21/c
160 (2)
9.8339 (2), 15.8974 (2),
9.4749 (2)
Triclinic, P1
160 (2)
6.7254 (7), 10.9787 (5),
11.9955 (10)
116.607 (6), 94.587 (8),
90.941 (6)
Triclinic, P1
160 (2)
6.7648 (2), 11.4551 (2),
11.4985 (2)
110.417 (2), 95.240 (2),
93.613 (2)
ꢀ
a, b, g (ꢂ)
90, 114.464 (2), 90
ꢀ3
V (A )
1348.26 (5)
4
788.01 (12)
2
827.26 (3)
2
Z
Radiation type
Cu Ka
2.01
Cu Ka
1.93
Cu Ka
4.57
m (mmꢀ1
)
Crystal size
0.16 ꢁ 0.14 ꢁ 0.05
0.14 ꢁ 0.05 ꢁ 0.02
0.28 ꢁ 0.11 ꢁ 0.08
Data collection
Diffractometer
XtalLab Synergy,
Dualex, Pilatus 200 K
Analytical
XtalLab Synergy,
Dualex, Pilatus 200 K
Analytical
XtalLab Synergy,
Dualex, Pilatus 200 K
Analytical
Absorption correction
Tmin, Tmax
0.795, 0.902
0.851, 0.972
0.461, 0.767
No. of measured, independent
and observed [I > 2s(I)] reections
15 881, 2920, 2798
12 473, 3183, 2735
14 178, 3385, 3269
Rint
0.022
0.637
0.063
0.625
0.021
0.625
ꢀꢀ1
(sin q/l)max (A
)
Renement
R[F2 > 2s(F2)], wR(F2), S
No. of reections
0.032, 0.084, 1.06
2920
0.065, 0.203, 1.06
3183
0.023, 0.061, 1.05
3385
No. of parameters
H-atom treatment
168
212
212
H-atom treated by a
mixture of independent
and constrained renement
0.30, ꢀ0.31
H-atom treated by a mixture of
independent and
constrained renement
0.40, ꢀ0.34
H-atom treated by a mixture
of independent and
constrained renement
0.27, ꢀ0.51
ꢀꢀ3
Drmax, Drmin (e A
)
CCDC no.
1977639
1977750
1977643
9842 | RSC Adv., 2020, 10, 9840–9853
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H–Csp3 type (involving H atoms of adamantane and terminal
methyl groups) H–H bonding interactions. The dispersion
energy contributes 66–78% towards the stabilization of this and
the subsequent dimers (M3–5) observed in I.
Molecules of I which are related by center of inversion that
generate a molecular dimer M3 (Etot: ꢀ5.4 kcal molꢀ1). This
dimer is stabilized by an intermolecular C–H/N (involving
H14B and N3) interaction and two short H/H contacts (2.14
ꢀ
and 2.33 A) involving H atoms of adjacent adamantane moie-
ties. Dimers M4 (Etot
:
ꢀ4.1 kcal molꢀ1
) and M5 (Etot:
ꢀ3.2 kcal molꢀ1) are generated via short intermolecular Csp3–
H/H–Csp3 type H–H bonding interactions. Adjacent ada-
mantane moieties are interacting in M4, while adamantane and
ethyl groups are interacting in M5. It is noted that the adjacent
dimers of M2 are interconnected by motif M3 and this
arrangement generate a sequence of motifs M2–M3–M2. The
adjacent M2–M3–M2 sequences are further interlinked by motif
M4 as shown in Fig. 4.
Fig. 2 Wireframe showing the crystal structure of I projected onto
different planes (a) ac plane and (b) ab plane. All the H atoms have been
omitted for clarity.
anti-conformations (180ꢂ) is being as small as 0.68 kcal molꢀ1
The PES diagram for compound I is given in ESI (Fig. S1†).
.
The adamantane core and the 1,3,4-thiadiazole ring are
positioned nearly co-planar (6.98ꢂ) as evident from the dihedral
angle formed between the mean planes of the respective units.
The ethylamine moiety makes a dihedral angle of 21.51ꢂ with
respect to the mean plane of the 1,3,4-thiadiazole ring. The
topological analysis for the molecule of I (X-ray geometry) reveals
that there is no intramolecular non-covalent interaction formed.
As illustrated in Fig. 2, the crystal structure of I can be
described as layers in which adamantane moieties from adjacent
layers are positioned closer to each other. This closer arrange-
ment is stabilized by weak and short intermolecular Csp3–H/H–
Csp3 type of interactions. As mentioned in the experimental
section, the PIXEL energy analysis was carried out to identify the
energetically signicant molecular dimer in the crystalline state.
In I, there are ve molecular pairs (M1–5) identied from the
PIXEL energy analysis and intermolecular interaction energies
(Etot) for these dimers along with their partitioned energies are
presented (Table 2 and Fig. 3). It should be emphasized that the
energetically least dimers (M4–5) are purely stabilized by short
intermolecular Csp3–H/H–Csp3 contacts. Similar adamantane–
adamantane interactions (motif M4) mediated by Csp3–H/H–
Csp3 bonding has been reported earlier.11 This interaction is
named as H–H bonding and non-electrostatic nature of this
closed-shell interaction have been discussed in detail.35
Crystal structure of the uoro derivative II
The uoro derivative II crystallizes in the triclinic system with
ꢁ
the centrosymmetric P1 space group and one molecule in the
asymmetric unit (Fig. 5). The fused cyclohexane rings of the
adamantane core exhibit chair conformation as observed in I.
The orientation of the N–H group is in anti-conformation with
respect to the orientation of S atom. This feature is completely
different in the crystal structure of I and its closely related
structure.34 The uoro phenyl ring makes a dihedral angle of
36.59ꢂ with the plane of the ve-membered ring.
Topological analysis has been performed for X-ray geometry
of II to identify possible intramolecular noncovalent interac-
tions. The topological parameters and molecular graphs are
presented in ESI (Table S1 and Fig. S3†). An intramolecular
C–H/S (involving H3 and S1) interaction is existed in the
molecule of II. The dissociation energy (De) for this interaction
was calculated to be 2.87 kcal molꢀ1 with the Rij value of 2.599 A.
ꢀ
The crystal packing of II is completely different as compared
to the crystal structure of I. The crystal packing can be described
as hydrogen-bonded dimer mediated by N–H/N interaction
and dimeric units packed as columnar manner along the crys-
tallographic b axis (Fig. 6). In each column, the adjacent
N–H/N mediated dimeric pairs are interlinked by intermo-
lecular C–H/F interaction and p-stacking interaction between
adjacent uorophenyl rings. Further, the adamantane moiety of
II in one column interacts with the adamantane moieties of the
adjacent column via short intermolecular Csp3–H/H–Csp3
type H–H bonding interactions.
Three intermolecular interactions (N1–H1/N2, C1–H1B/
N3 and C2–H2A/S1) stabilize the molecular dimer M1 (Etot
:
ꢀ11.5 kcal molꢀ1 with 70% contribution of electrostatic energy
towards stabilization). The hydrogen bonding geometry favours
ꢀ
for the N1–H1/N3 interaction (H1/N3 ¼ 2.40 A and :N1–
H1/N3 ¼ 143ꢂ). We note that the H2A/S1 interaction is
ꢀ
established by slightly longer (by 0.12 A) than the sum of the
In compound II, eight energetically signicant molecular
pairs (motifs M6–M13; see Table 2 and Fig. 7) were revealed by
the PIXEL energy analysis. The intermolecular interaction
energies for these molecular pairs are ranging from ꢀ21.7 to
ꢀ1.8 kcal molꢀ1. These molecular dimers are stabilized by
different types of non-covalent interactions such as a strong N–
H/N, several weak C–H/C(p), C–H/N, C–H/F, p-stacking
interaction and short Csp3–H/H–Csp3 type H–H bonding
interactions.
vdW radii of H and S atoms. The NCI plot and topological
analysis reveals that the N1–H1/N3 interaction is not existing
and only directional intermolecular N1–H1/N2 hydrogen
bonding along with C1–H1B/N3 and C2–H2A/S1 interactions
are formed (Fig. S2, ESI†). The second strongest molecular pair
(M2; Etot: ꢀ10.5 kcal molꢀ1) forms through three intermolecular
C–H/N (involving H11B and N1), C–H/Cg1(p) (involving H6A
and centroid of the ve-membered ring) and a short Csp3–H/
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Table 2 Intermolecular interaction energies (in kcal molꢀ1) obtained by the PIXEL method for various molecular pairs observed in the crystal
structures of I–III
Geometrya
Motif
CD
Symmetry
Important interactions
(H/A, :D–H/A)
Ecoul
Epol
Epol
Erep
12.5
14.1
7.5
Etot
Compound I
M1
M2
M3
7.915
x, ꢀy + 3/2, z ꢀ 1/2
ꢀx + 1, ꢀy + 1, ꢀz + 1
ꢀx + 2, ꢀy + 1, ꢀz + 2
N1–H1/N2
C1–H1B/N3
C2–H2A/S1
C11–H11B/N1
H11A/H1A
C6–H6A/Cg1
C14–H14B/N3
H14B/H13A
H10B/H13A
H10A/H8A
H9/H2A
1.98, 176
2.68, 136
3.11, 131
2.63, 141
2.22, 119
2.77, 152
2.72, 140
2.14, 149
2.33, 142
2.20, 152
2.37, 165
ꢀ11.4
ꢀ5.0
ꢀ2.4
ꢀ5.4
ꢀ5.4
ꢀ11.5
ꢀ10.5
ꢀ5.4
4.755
6.831
ꢀ2.9
ꢀ2.0
ꢀ2.9
ꢀ2.0
M4
M5
6.638
9.139
ꢀx + 2, ꢀy + 1, ꢀz + 1
ꢀ2.0
ꢀ0.7
ꢀ1.3
ꢀ0.4
ꢀ1.3
ꢀ0.4
7.0
1.7
ꢀ4.1
ꢀ3.2
ꢀx + 2, y ꢀ 1/2, ꢀz + 3/2
Compound II
M6
M7
7.831
4.947
ꢀx + 2, ꢀy + 1, ꢀz + 1
ꢀx + 1, ꢀy + 1, ꢀz + 1
N1–H1/N2
Cg1/Cg1
1.91, 175
3.712 (4)
2.70, 172
2.74, 157
2.72, 137
2.86, 142
2.37, 120
2.39, 168
2.38, 123
3.848 (4)
2.34, 123
2.38, 123
2.21, 145
ꢀ26.5
ꢀ3.6
ꢀ12.1
ꢀ2.6
ꢀ9.4
26.4
10.0
ꢀ21.7
ꢀ11.8
ꢀ15.7
C17–H17B/C4
C17–H17B/C3
C10–H10A/N2
C11–H11/C8
H11/H14B
C10–H10B/F1
H14A/H14A
Cg2/Cg2
M8
6.725
x ꢀ 1, y, z
ꢀ1.7
ꢀ1.3
ꢀ10.3
6.4
ꢀ6.9
M9
8.488
7.520
10.551
11.492
ꢀx + 1, ꢀy, ꢀz + 1
ꢀ2.3
ꢀ1.2
ꢀ0.9
ꢀ1.7
ꢀ0.8
ꢀ0.7
ꢀ0.4
ꢀ0.8
ꢀ6.0
ꢀ6.8
ꢀ5.7
ꢀ5.9
3.8
4.2
3.4
5.4
ꢀ5.3
ꢀ4.6
ꢀ3.6
ꢀ2.9
M10
M11
M12
ꢀx + 1, ꢀy + 1, ꢀz + 2
ꢀx + 2, ꢀy, ꢀz + 1
ꢀx + 1, ꢀy + 2, ꢀz + 2
H16/H17A
H16/H18B
H18A/H6
M13
14.388
x ꢀ 1, y + 1, z + 1
ꢀ0.5
ꢀ0.4
ꢀ2.8
2.0
ꢀ1.8
Compound III
M14
M15
M16
7.626
ꢀx, ꢀy + 2, ꢀz + 1
ꢀx + 1, ꢀy + 2, ꢀz + 1
ꢀx, ꢀy + 1, ꢀz + 1
N1–H1/N2
C5–H5/N3
Cg1/Cg1
1.93, 169
2.59, 149
3.687 (1)
ꢀ28.0
ꢀ2.3
ꢀ2.8
ꢀ13.3
ꢀ2.5
ꢀ1.9
ꢀ10.6
ꢀ19.0
ꢀ10.6
28.5
14.2
7.6
ꢀ23.4
ꢀ9.6
ꢀ7.7
5.201
8.088
H6/H14B
2.27, 118
1.93, 145
3.06, 159
3.02, 125
2.38, 135
2.33, 106
2.18, 111
3.11, 138
2.92, 150
2.36, 147
2.90, 145
3.706 (1), 148.1 (1)
H10A/H10A
C15–H15A/S1
C5–H5/Br1
H2/H15B
H2/H11
H3/H11
C13–H13/Br1
C6–H6/Br1
H18A/H16
C17–H17B/Br1
C1–Br1/Br1
M17
M18
6.765
6.639
x ꢀ 1, y, z
ꢀ2.1
ꢀ2.7
ꢀ1.0
ꢀ2.0
ꢀ7.2
3.2
9.6
ꢀ7.1
ꢀ6.9
ꢀx + 1, ꢀy + 1, ꢀz + 1
ꢀ11.8
M19
M20
M21
M22
M23
11.498
13.867
16.453
13.863
16.338
x, y, z ꢀ 1
ꢀ1.1
ꢀ2.1
ꢀ0.8
ꢀ0.5
ꢀ0.6
ꢀ0.4
ꢀ0.8
ꢀ0.4
ꢀ0.4
ꢀ0.2
ꢀ4.7
ꢀ3.9
ꢀ4.3
ꢀ2.7
ꢀ1.5
2.5
3.3
2.7
1.9
1.5
ꢀ3.6
ꢀ3.4
ꢀ2.9
ꢀ1.8
ꢀ0.8
ꢀx + 1, ꢀy + 2, ꢀz
ꢀx, ꢀy + 1, ꢀz + 2
x ꢀ 1, y, z + 1
ꢀx + 2, ꢀy + 2, ꢀz
a
Neutron values are given for all D–H/A interactions. CD: centroid-to-centroid distance of the molecular pair. Cg1 and Cg2 are the centroids of the
thiadiazole and phenyl rings, respectively.
The strongest dimer (M6; Etot: ꢀ21.7 kcal molꢀ1) in this supported by a bifurcated intermolecular C–H/C(p) interac-
structure is formed by an intermolecular N–H/N interaction tions (involving H13B and C3/C4).
involving amine H atom and one of the N atoms of the thia-
Dimer M8 (Etot: ꢀ6.9 kcal molꢀ1) is featured with three
diazole ring with R22(8) synthon.36 This dimer is predominantly intermolecular interactions such as C–H/N (involving H10A
electrostatic in nature with 80% contribution towards the and N2), C–H/C(p) (involving H11 and C8) and a short Csp3–
stabilization. The other dimers (M7–M13) found in this struc- H/H–Csp3 (involving H11 and H14B) type H–H bonding
ture are dispersive in nature with the contribution of 66–81% interactions.
A
highly directional intermolecular C–H/F
molecular dimer M9 (Etot
towards stabilization. Dimer M7 (Etot: ꢀ11.8 kcal molꢀ1) forms interaction generates
a
:
by centrosymmetrically related molecules and stabilized by p- ꢀ5.3 kcal molꢀ1). We note that the dispersion energy is nearly
stacking interaction between adjacent ve-membered rings and
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Fig. 6 Ball and stick diagram showing the crystal structure of II viewed
down the a axis and all the H atoms have been omitted for clarity.
Fig. 3 Different dimeric motifs observed in crystal structure of I.
stacked against each other with the centroid-to-centroid
distance of 3.848 A in M11 (Etot: ꢀ3.6 kcal molꢀ1). This stack-
ꢀ
ing interaction is emanated from two adjacent dimers of M1.
Dimer M12 (Etot: ꢀ2.9 kcal molꢀ1) stabilizes by short and
three centered Csp3–H/H–Csp3 (involving H16 and H17A/
H18B) H–H bonding interactions in which two adjacent ada-
mantane moieties are participated. Further, the neighbouring
dimers formed by M9 interlinked by motif M12 as shown in
Fig. 7. The least dimer M13 (Etot: ꢀ1.8 kcal molꢀ1) in II also
stabilizes with H–H bonding interaction (involving H18A and
H6) with Csp3–H/H–Csp2 type. It is of interest to note that the
motifs M6, M9, M12 and M13 generate a molecular sheet as
shown in Fig. 8.
Fig. 4 Supramolecular association mediated by Csp3–H/H–Csp3
type H–H bonding interactions (motifs M3 and M4) in I. Small spheres
represent the centroid of the five-membered ring.
Crystal structure of the bromo derivative III
The bromo derivative III crystallizes in the triclinic system with
ꢁ
the centrosymmetric P1 space group and one molecule in the
asymmetric unit (Fig. 9). The conformation of the fused cyclo-
hexane rings and the orientation of the N–H group are very
similar to that of the structure of II. The bromophenyl ring is
Fig. 5 Thermal ellipsoidal plot of compound II. The ellipsoids are
drawn at the 50% probability level.
contributing 2 fold excess that of electrostatic energy towards
the stabilization of this dimer.
In M10 dimer (Etot: ꢀ4.6 kcal molꢀ1), adjacent adamantane
moieties interconnected through Csp3–H/H–Csp3 H–H
bonding interaction. This motif helps to link the adjacent
dimers formed by motif M7. The combination of motifs M7 and
M10 generate a molecular ribbon which runs along the crys-
tallographic c axis (Fig. S4, ESI†). The uorophenyl rings are
Fig. 7 Molecular pairs formed by different intermolecular interactions
in II.
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Fig. 8 Supramolecular sheet constructed by motifs M6, M9, M12 and
M13 in II.
Fig. 10 Crystal packing of III viewed down the a axis. All the H atoms
have been omitted for clarity.
less twisted as compared to uorophenyl ring in II with respect
to the mean plane of the ve-membered ring. The dihedral
angle between bromophenyl and ve-membered ring is being
11.13ꢂ.
The QTAIM analysis reveals that the conformation of mole-
cule III is stabilized by an intramolecular C–H/S interaction.
nature with the electrostatic energy contribution of 80%. The
other dimers in this structure except dimer M20 are dispersive
in nature with the dispersion contribution ranging from 65–
80% towards the stabilization of these dimers. In the case of
dimer M20 stabilization, the contribution of electrostatic and
dispersion energies are 43 and 57%, respectively. We note that
the way adjacent M14 dimers are interconnected is different as
compared to the structure of II. The adjacent M14 dimers are
associated via Csp2–H/H–Csp3 type of H–H bonding interac-
tions (motif M18; Fig. S6, ESI†). In motif M18, the H atoms of
phenyl and adamantane moieties are involved in the H–H
bonding interactions with the separation of H/H atoms are
ꢀ
Moreover, the bond path distance (2.439 A) is quite shorter for
an intramolecular C–H/S interaction as compared to II. The
dissociation energy (De) for this interaction was computed to be
3.63 kcal molꢀ1. The molecular graph and topological param-
eters are presented in ESI (Table S2 and Fig. S5†).
The crystal structure of the bromo derivative is stabilized by
intermolecular N–H/N, C–H/N, C–H/Br, C–H/S, p-stack-
ing, short Csp2–H/H–Csp3 and Csp3–H/H–Csp3 types of H–H
bonding and a Br/Br contact. The crystal packing of III is
somewhat similar to that of II. The basic motif can be described
as a hydrogen-bonded dimer formed by N–H/N and C–H/N
interactions and this motif arranged as columnar fashion along
the crystallographic b axis (Fig. 10).
ꢀ
ranging from 2.18 to 2.36 A.
Molecules related by center of inversion form a molecular
stacking (motif M15, Etot: ꢀ9.6 kcal molꢀ1) in which ve-
There are ten molecular dimers (M14–M23; see Fig. 11 and
12) brought out from the crystal structure with the PIXEL energy
analysis. The intermolecular interaction energies (Etot) for these
dimers range from ꢀ23.4 to ꢀ0.8 kcal molꢀ1. The strongest
dimer is formed by intermolecular N–H/N (involving H1 and
N2) and C–H/N (involving H5 and N3) interactions (motif M14,
Etot: ꢀ23.4 kcal molꢀ1). This strong dimer is electrostatic in
Fig. 9 Thermal ellipsoidal plot of compound III. The ellipsoids are Fig. 11 Molecular pairs formed by different intermolecular interac-
drawn at the 50% probability level.
tions in III.
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Fig. 12 (a) Molecular pairs formed by different intermolecular interactions and (b) molecular sheet formed by intermolecular C–H/Br and
Csp2–Br/Br–Csp2 interactions in III.
membered ring stacking against bromophenyl ring. The derivative. The intermolecular interaction energies for these
molecular p-stacking arrangement is further supported by dimers are as strong as ꢀ7.1 kcal molꢀ1 and as weak as
intermolecular H–H bonding with a short distance of 2.27 A. ꢀ1.8 kcal molꢀ1. The phenyl protons are acting as donors for
ꢀ
The adjacent M15 dimers are interlinked via intermolecular two of the C–H/Br interactions and the protons of the ada-
H–H bonding interactions in which the neighbouring ada- mantane moiety acts as donors for the other two interactions.
mantane moieties are involved (motif M21).
We note that the H/Br contact in motif M19 is slightly longer
In motif M16 (Etot: ꢀ7.7 kcal molꢀ1), adamantane moiety of (by 0.06 A) than the sum of vdW radii of interacting atoms and
ꢀ
one molecule interacts with the adamantane moiety of the the corresponding contacts in other motifs are formed less
centrosymmetrically related molecule via Csp3–H/H–Csp3 than the sum of vdW. The least dimeric motif (M23, Etot
:
type of H–H bonding interaction with a very short contact ꢀ0.8 kcal molꢀ1) forms by intermolecular Csp2–Br/Br–Csp2
ꢀ
distance of 1.93 A. This dimer is further supported by a weak contact and this interaction is classied as type I (trans-
intermolecular C–H/S interaction (involving H15A and S1). It geometry) contact.37 As shown in Fig. 12(b), supramolecular
should be noted that the H/S distance is slightly longer than sheet forms by Csp2–Br/Br–Csp2 and two C–H/Br
ꢀ
(by 0.07 A) the sum of the van der Waals radii of the interacting interactions.
atoms.
To grasp the geometrical choices of homo-halogen contact
Four intermolecular C–H/Br interactions (motifs M17, (Br/Br), we carried out a CSD search (CSD version 5.40,
M19, M20 and M22) observed in the crystal structure of bromo November 2018) with conditions along with the inter-contact
Fig. 13 Molecular electrostatic potential surfaces of the structures (a) I, (b) II and (c) III mapped over the electronic density at 0.001 au contour.
Colour ranges (in kcal molꢀ1): red: greater than 15; yellow: between 15 and 0; green: between 0 and ꢀ15 and blue: greater than ꢀ15. Important
Vs,max and Vs,min values are given along with small hemispheres.
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Fig. 14 Hirshfeld surfaces highlight the close inter-contacts observed in structures (a) I, (b) II and (c) III.
between Br atoms is less than the sum of van der Waals radii 45 kcal molꢀ1 and this feature indicating that the amine proton
38
ꢀ
(3.7 A). This search yielded 947 hits with 1147 contacts and has best donating tendencies as compared to other protons in
the minimum and average Br/Br distance are found to be the molecule. Similarly, the most negative potentials are
ꢀ
3.241 and 3.575 A, respectively. Further analysis suggests that observed for N atoms of the thiadiazole ring. The Vs,min values
39% of the contacts show type I [C–Br/Br (q1); Br/Br–C (q2) for these atoms are slightly higher in I as compared to II and III.
and q1 ¼ q2] geometry and these contacts are located on the We also note that the accepting tendency for S atom is in the
diagonal. It should be noted that 51% of the contacts display order of I > II > III.
quasi type I geometry (|q1 ꢀ q2| < 20ꢂ). The remaining contacts
The uoro and bromo derivatives show interesting features as
(10%) belong to type II geometry (q1 y 90; q2 y 180 or q1 y can be seen from the Fig. 13. In the uoro derivative, there is a s-
180; q2 y 90). The scatterplots of Br/Br distance and two hole along C1–F1 bond in which the outermost region of its
angles (q1 and q2) are given in ESI (Fig. S7†). This is surface,42 with the Vs,max value of ꢀ15.1 kcal molꢀ1 and the
undoubtedly revealed that the Br/Br contact has more unshared electrons on the F atom form negative potentials around
tendency to adopt type I geometry as observed in III.
its central portion with the Vs,min value of ꢀ16.6 kcal molꢀ1. A
It is noted that the unit cell dimensions are comparable for strong Vs,max value on the outermost region of C–F bond facilitates
structures II and III. To delineate the isostructurality between II a directional non-covalent bonding. In contrast, the outermost
and III, we calculated the isostructurality index (P) for these portion of the C–Br surface has a positive potential with Vs,max
structures as described by Fabian and Kalman39 and the P value value of 11.2 kcal molꢀ1. The central part of this bond constitutes
is found to be zero. This value suggests that they are isostructural. negative potentials with the Vs,min value of ꢀ11.0 kcal molꢀ1. The
To gain more information on the degree of packing similarity, we negative potential corresponds to the lone-pair electrons of Br
utilized XPac program.40 The XPac analysis reveals that these two atom. The MESP and PIXEL energy analysis collectively suggest
structures display 1D supramolecular construct (row of mole-
´
´
´
´
cules match) as shown in ESI (Fig. S8†). The dissimilarity index
(x) was calculated to be 11.2 and this parameter quanties the
deviation between these structures from perfect geometrical
similarity. The stretch parameter (D) gives information on the
change in the intermolecular distance between two structures.
ꢀ
This value is calculated to be 0.42 A for these structures.
Molecular electrostatic potential surface map
The molecular electrostatic potential surface map (MESP) has
been extensively used to analyze noncovalent interactions and
to identify electrophilic/nucleophilic sites on the molecule.41
The electrostatic potential mapped over the electronic density
isosurface of the molecule at 0.001 au. The most positive (Vs,max
)
and negative potentials (Vs,min) are highlighted with small
hemispheres along with values (Fig. 13). In all three structures,
the amine H shows the most positive potentials in the range 42–
Fig. 15 2D-fingerprint plots for structures (a) I (b) II and (c) III. The
percentage relative contributions of different intermolecular contacts
are given.
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ꢀꢀ3
Table 3 Topological parameters for intermolecular interactions in selected molecular pairs of I [r(r): electron density (e A ), V2r(r): Laplacian of
ꢀꢀ5
ꢀ
electron density (e A ); V(r): potential energy density, G(r): kinetic energy density; H(r): total energy density; Rij: bond path (A), De ¼ ꢀ0.5 ꢁ V(r)
in kcal molꢀ1 and the values of V(r), G(r) and H(r) are expressed in kJ molꢀ1 bohrꢀ3
]
Interaction
Rij
DrD ꢀ DrA
DrD + DrA
r(r)
V2r(r)
V(r)
G(r)
H(r)
De
M1
N1–H1/N2
C1–H1B/N3
C2–H2A/S1
2.010
2.712
3.142
0.243
0.157
0.108
0.769
0.065
ꢀ0.116
0.173
0.049
0.034
1.949
0.555
0.364
ꢀ55.1
ꢀ9.4
ꢀ5.6
54.1
12.3
7.8
ꢀ1.0
2.9
2.2
6.6
1.1
0.7
M2
C11–H11B/N1
H11A/H1A
2.643
2.291
0.172
0.154
0.124
0.034
0.060
0.052
0.695
0.590
ꢀ12.6
ꢀ10.6
15.8
ꢀ13.3
3.2
2.7
1.5
1.3
M3
C14–H14B/N3
H14B/H13A
H10B/H13A
2.741
2.171
2.368
0.046
0.053
0.038
0.512
0.568
0.393
ꢀ8.7
ꢀ10.8
ꢀ7.2
11.3
13.2
8.9
2.6
2.3
1.8
1.0
1.3
0.9
M4
H10A/H8A
2.229
2.410
0.048
0.032
0.500
0.359
ꢀ9.4
ꢀ6.3
11.5
8.0
2.1
1.8
1.1
0.7
M5
H9/H2A
that the Br atom is preferred to interact with both electrophilic wide red spots on the HS, whereas a small red spots appeared
(positive site) and nucleophilic (negative site) sites.
for intermolecular H13A/H14B contact (motif M3) in I. In II,
three intermolecular short contacts (H1/N2, H10B/F1 and
H7A/C3/C4) are visible on the HS. In III, the motif M13,
comprises two intermolecular contacts (involving H1 and N2
and H5 and N3) is visible on the HS. The former contact is
very short and shown as bright red areas, while the latter is
shown as a paint red spots. It should be noted that
Qualitative analysis of intermolecular interactions with
Hirshfeld surface (HS) and 2D ngerprint plots (2D-FP)
As can be seen from the HS diagram (Fig. 14), the intermo-
lecular H1/N2 contact (motif M1) is shown as intense and
ꢀꢀ3
Table 4 Topological parameters for intermolecular interactions in selected molecular pairs of II [r(r): electron density (e A ), V2r(r): Laplacian of
ꢀꢀ5
ꢀ
electron density (e A ); V(r): potential energy density, G(r): kinetic energy density; H(r): total energy density; Rij: bond path (A), De ¼ ꢀ0.5 ꢁ V(r)
in kcal molꢀ1 and the values of V(r), G(r) and H(r) are expressed in kJ molꢀ1 bohrꢀ3
]
Interaction
Rij
DrD ꢀ DrA
0.274
DrD + DrA
0.832
r(r)
V2r(r)
1.922
0.611
V(r)
G(r)
61.3
13.6
H(r)
ꢀ9.0
3.1
De
M6
N1–H1/N2
1.943
3.133
0.220
0.053
ꢀ70.3
ꢀ10.5
8.4
1.3
M7
C17–H17B/C4
0.125
0.151
M8
C10–H10A/N2
C11–H11/C8
H11/H14B
2.753
2.912
2.429
0.157
0.031
0.021
0.031
0.047
0.040
0.041
0.532
0.450
0.453
ꢀ9.1
ꢀ8.2
ꢀ8.2
11.8
10.2
10.3
2.7
2.0
2.1
1.1
1.0
1.0
M9
C10–H10B/F1
2.406
2.427
0.069
0.281
0.052
0.040
0.811
0.437
ꢀ13.8
ꢀ8.0
17.9
10.0
4.1
2.0
1.6
1.0
M10
H14A/H14A
M12
H16/H17A
H16/H18B
2.405
2.441
0.040
0.038
0.433
0.412
ꢀ8.0
ꢀ7.5
9.9
9.4
1.9
1.8
1.0
0.9
M13
H18A/H6
2.279
0.051
0.563
ꢀ10.2
12.8
2.6
1.2
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intermolecular Csp3–H10A/H10A–Csp3 (motif M15) type Another remarkable difference is noticed for H/X (X ¼ Br and
H–H bonding is also identied on the HS with red spots.
F) contacts and the shortest H/F and H/Br contacts are
ꢀ
The ngerprint plots are used to delineate the relative located near 2.4 and 2.9 A, respectively. The relative contri-
contribution of different intermolecular contacts (Fig. 15). In bution of H/Br is slightly higher (3.4%) as compared to the
all three structures, the H/H contacts constitute signicant contribution of H/F. According to the PIXEL energy analysis,
amount of interactions of the total HS area ranging from 52.2 the Br atom is involved as an acceptor in four different motifs,
to 70.5%. The shortest intermolecular H/N contacts are whereas the F atom is involved in only motif. Overall, the
ꢀ
located near 2.0 A with double spikes in all three structures. shortest distances of H/X contacts and their relative contri-
Further, there is a reduction in the relative contribution of H/ butions in the respective structure are in good agreement with
C/C/H contacts which represent intermolecular C–H/C(p) the PIXEL energy analysis. The intermolecular C/C contacts
interaction and a slight increase of H/S interaction in I as contribute only 2% to the total HS area in II and III, no such
compared to II and III. The feature of H/S interaction is in contact is observed in I. We observe that the Br/Br contact
good agreement with the MESP. Moreover, the reduction of contributes only about 0.9% to the total HS area.
H/C contacts is largely compensated by intermolecular H/H
interactions.
QTAIM analysis
The relative contributions of different intermolecular
The topological parameters are computed for different non-
covalent interactions at their point critical points (BCPs) in
selected dimeric pairs of I–III to evaluate their nature and
strength (Tables 3–5). The molecular graphs of selected
molecular dimers featuring various noncovalent interactions at
the bond critical points are given in ESI (Fig. S9–S11†). For the
evaluation of intermolecular interactions, the rst four criteria
[(i) bond critical point (ii) electron density r(r), (iii) the
contacts are comparable in the bromo and uoro derivatives.
However, a noticeable difference is observed for the distribu-
tion of these contacts on the ngerprint plots. For instance,
the H/H contacts are appeared as a sharp spike with the
ꢀ
shortest distance is located around 1.9 A in III, while the
corresponding contacts are showed blunt end towards the
ꢀ
shortest contacting region which is closer to 2.2 A in II.
ꢀꢀ3
Table 5 Topological parameters for intermolecular interactions in selected molecular pairs of III [r(r): electron density (e A ), V2r(r): Laplacian of
ꢀꢀ5
ꢀ
electron density (e A ); V(r): potential energy density, G(r): kinetic energy density; H(r): total energy density; Rij: bond path (A), De ¼ ꢀ0.5 ꢁ V(r)
in kcal molꢀ1 and the values of V(r), G(r) and H(r) are expressed in kJ molꢀ1 bohrꢀ3
]
Interaction
Rij
DrD ꢀ DrA
DrD + DrA
r(r)
V2r(r)
V(r)
G(r)
H(r)
De
M14
N1–H1/N2
C5–H5/N3
1.953
2.620
0.275
0.172
0.821
0.156
0.217
0.051
1.912
0.650
ꢀ68.6
ꢀ10.6
60.4
14.2
ꢀ8.3
8.2
1.3
3.6
M15
H6/H14B
2.383
0.048
0.543
ꢀ9.4
12.1
2.7
1.1
M16
H10A/H10A
C15–H15A/S1
1.963
3.078
0.082
0.039
0.920
0.391
ꢀ17.9
ꢀ6.6
21.5
8.6
3.6
2.0
2.1
0.8
0.149
0.119
ꢀ0.061
M17
C5–H5/Br1
3.064
0.023
0.049
0.520
ꢀ9.0
11.6
2.6
1.1
M18
H3/H11
H2/H11
H2/H15B
2.316
2.530
2.487
0.056
0.049
0.038
0.659
0.608
0.452
ꢀ12.2
ꢀ10.7
ꢀ7.7
15.1
13.6
10.0
2.9
2.9
2.3
1.5
1.3
0.9
M19
C13–H13/Br1
3.128
2.942
2.400
2.926
0.119
0.185
ꢀ0.059
0.039
0.053
0.037
0.050
0.430
0.552
0.395
0.555
ꢀ7.4
ꢀ9.9
ꢀ7.2
ꢀ9.9
9.6
12.5
9.0
2.1
2.6
1.8
2.6
0.9
1.2
0.9
1.2
M20
C6–H6/Br1
0.125
M21
H18A/H16
M22
C17–H17B/Br1
0.073
0.145
12.5
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Fig. 16 Total electronic density distribution H(r) showing the formation of strong intermolecular N–H/N hydrogen bonds in (a) I, (b) II and (c) III.
All the plots are drawn in the plane comprising the atoms involved in the hydrogen bond and small green spheres represent the bond critical
points.
Laplacian of electron density V2r(r) and mutual penetration of should be noted that the positive value of the Laplacian of
the H and the acceptor atom] of KP are used.43 It is worthy to
note that the H–H bonding is characterized using the rst 3
criteria of KP.
VðrÞ
electron density, H(r) < 0 and
. 1 reveal that intermolecular
GðrÞ
N1–H1/N2 interaction is found to be intermediate bonding
nature between shared and closed shell interaction as similar to
the motif I. We note that the intermolecular C–H/F and C–H/
C(p) interactions are found to be stronger aer N–H/N
hydrogen bond based on the H(r) values.
In I, one N–H/N and three C–H/N, one C–H/S, one
C–H/C and ve Csp3–H/H–Csp3 type H–H bonding interac-
tions were observed. The bond critical points (BCPs) are clearly
detected and conrmed the existence of these interactions
except C–H/C(p) interaction. The r(r) values for these inter-
In III, the Laplacian of the electron density values for
intermolecular N–H/N and C–H/N interactions comply with
the proposed values for hydrogen bonds. The KP-4 rule
suggests that N–H/N, C–H/N and three C–H/Br (out of
four) interactions are showing hydrogen bonding character.
The H–H bonding interactions in this structure are closed
shell in nature. The distribution of total electronic energy
density H(r) is shown in Fig. 16 for intermolecular N–H/N
hydrogen bond in all three structures. From this gure one can
see the transit region (between shared and closed shell nature)
for N–H/N hydrogen bond in II and III. In III, the stronger
interaction is found to be N–H/N followed by C–H/N, H–H
bonding and C–H/Br interactions in regard to the H(r) values.
The analysis of topological properties for these interactions
apparently supports the importance of weak nature of non-
classical H–H bonding interactions.
ꢀꢀ3
actions lie in the range 0.032–0.173 e A and these values
ꢀꢀ3
satisfy the KP limit [0.013 < r(r) e A < 0.236] for hydrogen
bonds. It is interesting to convey that only three intermolecular
interactions (N1–H1/N2, C11–H11B/N1 and Csp3–H11A/
H1A–Csp3 type H–H bonding) are in agreement with the sug-
2
ꢀꢀ5
gested values [0.580 < V r(r) e A < 3.355] of KP. The KP-4 rule
is found to be extremely important to differentiate the classical
hydrogen bonds from van der Waals interactions. As shown in
Table 3, all the classical intermolecular interactions showing
hydrogen bonding character except C–H/S interaction.
The dissociation energies for these interactions are in the
range of 0.7 to 6.6 kcal molꢀ1. Among these interactions, the
intermolecular N1–H1/N2 (motif M1) hydrogen bond has
a negative total electronic density H(r) value of ꢀ1.0 kJ molꢀ1
bꢀ3. The positive value of Laplacian and H(r) < 0 indicate that
the N–H/N interaction shows the intermediate bonding
character between shared and closed shell interaction.44 The
remaining interactions including H–H bonding are closed
shell in nature as they obey the positive value of Laplacian and
H(r) > 0. The results clearly demonstrate that the H–H
bonding interactions also play signicant roles in the crys-
talline state of I.
Conclusions
In the present investigation, three pharmaceutically promising
adamantane–thiadiazole hybrid derivatives have been synthe-
sized and their crystal structures at low temperature have been
determined. The orientation of the amino group was completely
different between halophenylamino and ethylamino deriva-
tives. This feature was not favoured for the formation of
a R22(8) synthon in I. Crystal structures of II and III showed
isostructural behaviour with 1D supramolecular construct.
Further, different theoretical tools were used to characterize the
noncovalent interactions present in these compounds. Hirsh-
feld surface analysis revealed that the halogenated compounds
showed similar relative contributions of different intermolec-
ular interactions, whereas ethylamino derivative showed varia-
tions in the relative contributions of H/H and H/C and H/S
contacts as compared to halogenated derivatives. Topological
analysis was performed for selected dimeric pairs of these
In II, the dissociation energies for intermolecular interac-
tions are in the range of 0.9–8.4 kcal molꢀ1 (Table 4). The De
value for Csp3–H/H–Csp3 and Csp3–H/H–Csp2 interactions
are found to be 0.9–1.2 kcal molꢀ1. The r(r) values for inter-
molecular interactions noted in II full the KP limit. However,
only three intermolecular interactions (N1–H1/N2, C17–
H17B/C4 and C10–H10B/F1) are obeyed the proposed KP
limit for the Laplacian of the electron density. The positive value
VðrÞ
of Laplacian, H(r) > 0 and
\1 for the H–H bonding suggest
GðrÞ
that they are closed shell in nature. The remaining interactions
are classied as hydrogen bond on the basis of KP-4 rule. It
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compounds. The rst four criteria of KP have been used to
characterize the nature and strength of noncovalent interac-
tions. The results indicate that there was a strong N–H/N
hydrogen bond formed between amino group and one of the N
8 G. Serban, Molecules, 2019, 24, 1557.
9 (a) J. Liu, D. Obando, V. Liao, T. Lifa and R. Codd, Eur. J. Med.
Chem., 2011, 46, 1949–1963; (b) L. Guy and A. Graciela, Curr.
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atoms of the thiadiazole ring. The strength of this interaction 10 L. Wanka, K. Iqbal and P. R. Schreiner, Chem. Rev., 2013,
was found to be relatively weaker in I as compared to II and III. 113, 3516–3604.
The molecular electrostatic potential surface map suggested 11 (a) L. H. Al-Wahaibi, S. Sujay, G. G. Muthu, A. A. El-Emam,
that the S atom showed weaker accepting tendencies in varying
degrees and participated in van der Waals interactions. The
intermolecular C–H/N, C–H/F and C–H/Br and C–H/C(p)
showed hydrogen bonding character and H–H bonding inter-
actions displayed weak and closed shell in nature.
N. S. Venkataramanan, F. A. M. Al-Omary, H. A. Ghabbour,
J. Percino and S. Thamotharan, J. Mol. Struct., 2018, 1159,
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Conflicts of interest
The authors declare that they have no competing interests.
13 (a) A. Gavezzotti, J. Phys. Chem. B, 2003, 107, 2344–2353; (b)
A. Gavezzotti, Mol. Phys., 2008, 106, 1473–1485; (c)
A. Gavezzotti, New J. Chem., 2011, 35, 1360–1368; (d)
A. Gavezzotti, J. Phys. Chem. B, 2002, 106, 4145–4154.
Acknowledgements
This work was funded by the Deanship of Scientic Research at 14 R. Bader, Atoms in Molecules: A Quantum Theory, Oxford
Princess Nourah bint Abdulrahman University through the University Press, USA, 1994.
Research Group Program (Grant No. RGP-1438-0010). ST thanks 15 U. Koch and P. L. A. Popelier, J. Phys. Chem. B, 1995, 99,
the DST-SERB (SB/YS/LS-19/2014) for nancial support. ST and 9747–9754.
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