Exploiting the Role of Molecular Electrostatic Potential, Deformation Density, Topology, and Energetics in the Characterization of S?N and Cl?N Supramolecular Motifs in Crystalline Triazolothiadiazoles

Article abstract of DOI:10.1021/acs.cgd.5b01499

A detailed analysis of the molecular and crystal packing of a series of pharmaceutically active triazolothiadiazole derivatives is reported. The most notable feature from the analysis of the supramolecular motifs is the presence of inversion dimers due to the formation of strong S?N chalcogen bonds. This has been unequivocally established via inputs from energy calculations from PIXEL, the topological analysis using the approach of QTAIM from AIMALL, an analysis of the molecular electrostatic potentials plotted on Hirshfeld surfaces, and the analysis of the 3D-deformation densities obtained using Crystal Explorer. The total interaction energy for this contact is in the range of 28-33 kJ/mol in the molecules under investigation, and the electrostatic (Coulombic + polarization) contribution toward the total stabilization energy is more than 70%, indicating that such interactions are principally electrostatic in origin. The results from the analysis of the molecular ESP depict that this interaction exists between a strongly electropositive σ-hole on the sulfur atom and an electronegative region on the nitrogen. 3D-deformation density (DD) maps reveal the presence of a charge depletion (CD) region on the sulfur atom which is directed toward the charge concentration (CC) region on the nitrogen atom facilitating formation of such contacts in the crystal. These are further invesigated by QTAIM based calculations which establish the closed-shell nature of these contacts. The crystal packing is further stabilized by the presence of significantly important π?π stacking interactions, wherein the interaction energies, calculated by the PIXEL method, reveal that some of these interactions in crystals have significant contributions from electrostatic components, with a lesser contribution from dispersion forces that normally dominate such interactions. The existence of a contribution of ～48% from electrostatics between stacked rings owing to their unique electrostatic complementarity is a rare supramolecular feature observed in crystal packing in these solids. In addition, the existence of C-H?O, C-H?N, C-H?F, and Cl?N interactions is also characterized by a significant electrostatic component in their formation in crystals of these compounds.

Full text of DOI:10.1021/acs.cgd.5b01499

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Article
Exploiting the role of molecular electrostatic potential, deformation
density, topology and energetics in the characterization of S···N
and Cl···N supramolecular motifs in crystalline triazolothiadiazoles
Imtiaz Khan, Piyush Panini, Salah Ud-Din Khan, Usman Ali Rana,
Hina Andleeb, Deepak Chopra, Shahid Hameed, and Jim Simpson
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b01499 • Publication Date (Web): 12 Jan 2016
Downloaded from http://pubs.acs.org on January 16, 2016
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Exploiting the role of molecular electrostatic potential,
deformation density, topology and energetics in the
characterization of S···N and Cl···N supramolecular
motifs in crystalline triazolothiadiazoles
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Imtiaz Khana, Piyush Paninib, Salah UdꢀDin Khanc, Usman Ali Ranac, Hina Andleeba, Deepak
Choprab,*, Shahid Hameeda,*, Jim Simpsond,*
aDepartment of Chemistry, QuaidꢀiꢀAzam University, Islamabadꢀ45320, Pakistan
bCrystallography and Crystal Chemistry Laboratory, Department of Chemistry, IISER, Bhopal
462066, India
cDeanship of Scientific Research, College of Engineering, King Saud University, PO Box 800,
Riyadh 11421, Saudi Arabia
dDepartment of Chemistry, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand
*Corresponding authors. Eꢀmail: dchopra@iiserb.ac.in (D.Chopra); Tel.: +91ꢀ07556692370;
Fax: +91ꢀ07556692392; Eꢀmail: shameed@qau.edu.pk (S. Hameed); Tel.: +92 51 9064 2133;
Fax: +92 51 2241; Eꢀmail: jsimpson@alkali.otago.ac.nz (J. Simpson) Tel: +64 3 479 7914;
Fax: +64 3 479 7906;
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Abstract
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A detailed analysis of the molecular and crystal packing of a series of pharmaceutically active
triazolothiadiazole derivatives is reported. The most notable feature from the analysis of the
supramolecular motifs is the presence of inversion dimers due to the formation of strong S···N
chalcogen bonds. This has been unequivocally established via inputs from energy calculations
from PIXEL, the topological analysis using the approach of QTAIM from AIMALL, an analysis
of the molecular electrostatic potentials plotted on Hirshfeld surfaces and the analysis of the 3Dꢀ
deformation densitities obtained using Crystal Explorer. The total interaction energy for this
contact is in the range of 28ꢀ33 kJ/mol in the molecules under investigation and the electrostatic
(Coulombic + polarization) contribution towards the total stabilization energy is more than 70%
indicating that such interactions are principally electrostatic in origin.The results from the
analysis of the molecular ESP depicts that this interaction exists between a strongly
electropositive σꢀhole on the sulfur atom with an electronegative region on the nitrogen. 3Dꢀ
deformation density (DD) maps reveals the presence of a charge depletion (CD) region on the
sulfur atom which is directed towards the charge concentration (CC) region on the nitrogen atom
facilitating formation of such contacts in the crystal. These are further invesigated by QTAIM
based calculations which establish the closedꢀshell nature of these contacts. The crystal packing
is further stabilized by the presence of significantly important π...π stacking interactions, wherein
the interaction energies, calculated by the PIXEL method, reveal that some of these interactions
in crystals have significant contributions from electrostatic components, with a lesser
contribution from dispersion forces that normally dominate such interactions. The existence of a
contribution of ~48% from electrostatics between stacked rings owing to their unique
electrostatic complementarity is a rare supramolecular feature observed in crystal packing in
these solids. In addition, the existence of CꢀH···O, CꢀH···N, CꢀH···F, Cl···N interactions are
also characterized by a significant electrostatic component in their formation in crystals of these
compounds.
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1. Introduction
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Intermolecular interactions play a very essential role in many branches of science including
molecular recognition and aggregation, crystal engineering, polymorphism. They also have great
importance in biochemistry and structural biology1-4. It is a very important tool to understand
such interactions when designing a material with specific desirable properties5-6. Hence, the
study of different intermolecular interactions has always been a fascinating area of research in
science. In general, the primary focus of the study of intermolecular interactions has been on the
conventional hydrogen bond (e.g., NH···O and OH···O) and its utilization in the design of
required supramolecular structures6. Increasingly, however, the importance of the weak
hydrogen bond, CꢀH···X (X= N, O, halogens, π electrons) has also been realized in different
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areas7-11 and the nature and characteristics of such interactions is now very well understood12-13
.
In recent years, attention has shifted towards the study of other classes of intermolecular
interaction such as π···π contacts14, lp···π interactions15-17, halogen bonds18-19, chalcogen
bonds20-25 etc. π···π interactions were found to be important in biological molecules like DNA,
proteins and other important functional materials of organic origin14. A recently recognized class
of interactions are those between the charge depleted (CD) region, known as a σꢀhole26-29, on an
atom (mainly involving atoms of groups IV−VII in the periodic table) with the charge
concentrated (CC) region of an atom or part of a molecule, such as a πꢀring. Amongst these, the
most commonly investigated interaction is the “halogen bond”, which involves an interaction of
the CD region on a halogen atom, opposite to a sigma bond, with the other, nonꢀhydrogen atoms
in the molecule. According to the recent IUPAC definition30, “A halogen bond occurs when there
is evidence of a net attractive interaction between an electrophilic region associated with a
halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular
entity”. One of the characteristic features associated with this interaction, similar to that of the
hydrogen bond, is that these are highly “directional” and the strength depends very much on the
magnitude of the CD region on the halogen atom.
Moreover, carbon bonds31, pincogen bonds32-33 (Group V elements) and chalcogen bonds20-25
(Group VI elements) are similar interactions that also involve the presence of a σꢀhole. These are
currently a prime research focus so that such contacts can be used effectively to construct
supramolecular assemblies. Furthermore, their importance has been widely recognized in
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different areas, including chemical biology, drug design, and functional organic materials
research18-33
.
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Recognizing the importance of the aboveꢀmentioned interactions, in the present study, a series of
five pharmaceutically active triazolothiadiazole derivatives have been synthesized and their
crystal structures have been investigated by single crystal XꢀRay diffraction. The packing of
molecules in the crystal involve important supramolecular interactions and the nature and
properties of these have been quantitatively investigated with contributions from different
computational approaches. For the current study, the heterocycles and aromatic systems that
make up the molecules were choosen because they occur in numerous structurally diverse
bioactive natural products, synthetic drugs and pharmaceuticals. Such drug candidates drug
candidates find widespread applications in medicinal chemistry, and have gained eminence due
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to their substantial therapeutic potential for the effective treatment of various disorders34-35
.
Amongst them, conjugated heterocycles derived from the 1,2,4ꢀtriazole scaffold are particularly
special heterocyclic ring systems featured in a large number of compounds with diverse and
important biological activities. These hybrid structures have been observed in a wide variety of
therapeutically important compounds demonstrating a broad spectrum of biological functions
including use as antitumor, antiviral, antihelmintic, antifungal, antibacterial, antitubercular, antiꢀ
inflammatory or analgesic agents and as CNSꢀstimulants, PDE4 inhibitors or hypoglycemic
agents36-45. In addition, triazolothiadiazoles have also been identified as selective inhibitors of the
cꢀMet proteins46 and are used as molluscicidal agents47, growth promoters48, or as cholinesterase,
monoamine oxidase, alkaline phosphatase and urease inhibitors49.
2. Experimental
2.1. General
All commercially available reagents were used as received. Thin layer chromatography (TLC)
was performed on Merck DFꢀAlufoilien 60F254 0.2 mm precoated plates. Product spots were
visualized under UV light at 254 and 365 nm. Melting points were recorded on a Stuart melting
point apparatus (SMP3) and are uncorrected. Infraꢀred (IR) spectra were recorded on FTS 3000
MX, BioꢀRad Merlin (Excalibur model) spectrophotometer. 1H NMR spectra were recorded on a
Bruker Avance (300 MHz) spectrometer. Chemical shifts (δ) are quoted in parts per million
(ppm) downfield of tetramethylsilane, using residual protonated solvent as internal standard
(DMSOꢀd6 at 2.50 ppm). Protonꢀdecoupled 13C NMR spectra were recorded on a Bruker Avance
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(75 MHz) spectrometer using deuterated solvent as internal standard (DMSOꢀd6 at 39.52 ppm).
The elemental analysis was performed on Leco CHNSꢀ932 Elemental Analyzer, Leco
Corporation (USA).
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2.2. Preparation of triazolothiadiazoles
2.2.1. General procedure for the synthesis of 4-amino-1,2,4-triazole-3-thiols (3a-c)
The appropriate carbohydrazide (1a-c) (1.0 mmol) was stirred with a solution of potassium
hydroxide (1.5 mmol) dissolved in methanol (10 mL) at 0ꢀ5 °C. Carbon disulfide (1.5 mmol)
was added slowly to this solution and the reaction mixture was left overnight at room
temperature. The solid potassium dithiocarbazinate product (2a-c) was filtered, washed with
chilled methanol and dried. It was used directly for next step without further purification.
To a solution of the corresponding potassium dithiocarbazinate (2a-c) in water (8 mL), hydrazine
hydrate (2.0 mmol) was added and the reaction mixture was refluxed for 4ꢀ5 h. During progress
of the reaction, the mixture turned green with the evolution of hydrogen sulphide and finally
became homogeneous. It was then diluted with little cold water and acidified with conc.
hydrochloric acid. The white precipitated solid was filtered, washed with cold water and
recrystallized from aqueous ethanol to afford the compounds (3a-c). The physical and
spectroscopic data obtained were found to be consistent with those observed in literature48, 50-51
.
2.2.2. General procedure for the synthesis of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles (4a-e)
A mixture of the corresponding 4ꢀaminoꢀ1,2,4ꢀtriazoleꢀ3ꢀthiol (3a-c) (1.0 mmol) and the
substituted aromatic/heteroꢀaromatic acids (1.1 mmol) in POCl3 (5 mL) was refluxed for 6 h. The
reaction mixture was slowly poured into crushed ice with stirring and neutralized with sodium
bicarbonate. The precipitated mass was filtered, washed with cold water, dried, and recrystallized
(ethanol) to afford the 1,2,4ꢀtriazolo[3,4ꢀb][1,3,4]thiadiazoles (4a-e) 48, 50-51. The synthesis of
compound 4d has been reported by us previously52, and the spectroscopic data obtained for 4a
were found to be consistent with those observed in literature48.
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2.2.1.1. 6-(2-Chloro-4,5-difluorophenyl)-3-(pyridin-3-yl)-[1,2,4]triazolo[3,4-
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b][1,3,4]thiadiazole (4b)
Offꢀwhite solid (79%): m.p 147ꢀ148 C; Rf: 0.65 (10% MeOH/CHCl3); IR (ATR, cm‒1): 3015
o
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(ArꢀH), 1593 (C=N), 1572, 1499 (C=C) 1168 (CꢀF), 1023 (CꢀCl); H NMR (300 MHz, DMSOꢀ
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d6): δ 9.39 (s, 1H, ArꢀH), 8.74 (d, 1H, J = 6.9 Hz, ArꢀH), 8.56ꢀ8.52 (m, 1H, ArꢀH), 8.41ꢀ8.35 (m,
1H, ArꢀH), 8.15ꢀ8.14 (m, 1H, ArꢀH), 8.14ꢀ8.08 (m, 1H, ArꢀH); 13C NMR (75 MHz, DMSOꢀd6): δ
170.89, 163.55, 159.74, 156.82, 151.26, 148.43, 147.54, 144.09, 137.39, 135.67, 132.63, 131.24,
126.89, 121.27, 120.99, 119.99. Analysis Calcd for C14H6ClF2N5S: C, 48.08; H, 1.73; N, 20.02;
S, 9.17. Found: C, 47.96; H, 1.65; N, 19.92; S, 9.24.
2.2.1.2. 6-(4-Fluorobenzyl)-3-(pyridin-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4c)
o
Brown solid (75%): m.p 187ꢀ188 C; Rf: 0.62 (10% MeOH/CHCl3); IR (ATR, cm‒1): 3048 (Arꢀ
H), 1602 (C=N), 1569, 1506 (C=C) 1218 (CꢀF); 1H NMR (300 MHz, DMSOꢀd6): δ 8.80 (bs, 2H,
ArꢀH), 8.14 (d, 2H, J = 5.7 Hz, ArꢀH), 7.54ꢀ7.49 (m, 2H, ArꢀH), 7.27ꢀ7.20 (m, 2H, ArꢀH), 4.55
(s, 2H, CH2); 13C NMR (75 MHz, DMSOꢀd6): δ 171.86, 163.74, 160.51, 156.42, 151.16, 143.72,
132.87, 131.99, 131.94, 131.87, 131.76, 119.83, 116.36, 116.07, 36.74. Analysis Calcd. for
C15H10FN5S: C, 57.87; H, 3.24; N, 22.49; S, 11.30. Found: C, 57.68; H, 3.32; N, 22.31; S, 11.43.
2.2.1.3. 3-(Pyridin-4-yl)-6-(p-tolyloxymethyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazolezole (4e)
o
Brown solid (78%): m.p 194ꢀ195 C; Rf: 0.61 (10% MeOH/CHCl3); IR (ATR, cm‒1): 3041 (Arꢀ
H), 1605 (C=N), 1546, 1528 (C=C); 1H NMR (300 MHz, DMSOꢀd6): δ 8.82 (d, 2H, J = 6.0 Hz,
ArꢀH), 8.15ꢀ8.13 (m, 2H, ArꢀH), 7.15 (d, 2H, J = 8.4 Hz, ArꢀH), 7.03 (d, 2H, J = 8.7 Hz, ArꢀH),
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5.61 (s, 2H, OCH2), 2.25 (s, 3H, CH3); C NMR (75 MHz, DMSOꢀd6): δ 169.79, 156.02,
155.42, 151.21, 143.88, 132.77, 131.53, 130.55, 119.83, 115.46, 65.43, 20.55. Analysis Calcd for
C16H13N5OS: C, 59.43; H, 4.05; N, 21.66; S, 9.92. Found: C, 59.56; H, 3.96; N, 21.58; S, 9.74.
2.3. Single crystal Growth
The compounds 4a-e were dissolved in hot solution of ethanol. On slow evaporation of the
solvent at room temperature (20‒25 °C), good quality crystals suitable for Xꢀray diffraction were
obtained.
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2.4. Single crystal data collection and structure solution
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The Xꢀray measurements for all compounds were carried out on a Bruker APEXII Kappa CCD
single crystal diffractometer equipped with a graphite monochromator. MoKα radiation (λ =
0.71073 Å) was used for the collection, which was controlled by APEX253 with data collected at
90(2)K. Data were corrected for Lorentz and polarization effects using SAINT53 and multiꢀscan
absorption corrections were applied using SADABS53. The structures were solved by direct
methods using SHELXSꢀ9754 and refined using fullꢀmatrix leastꢀsquares procedures with
SHELXLꢀ201455 and Titan200056. All nonꢀhydrogen atoms were refined anisotropically and all
hydrogen atoms bound to carbon were placed in the calculated positions, and their thermal
parameters were refined isotropically with Ueq = 1.2—1.5 Ueq(C). The molecular plots and
packing diagrams were drawn using Mercury57 and additional metrical data were calculated
using PLATON58.
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2.4.1. Modelling of disorder
The paraꢀmethylphenoxy group and the pyridyl group in 4e was observed to be disordered over
two orientations, with occupancy ratios 0.428(9):0.572(9) and 0.434(8): 0.566(8) respectively.
The disorder associated with this molecule was carefully modeled using the PART command in
SHELXL201455. The thermal parameters were constrained to be equal using the EADP
command. The pyridine and benzene rings of both the major (labelled as “B”) and the minor
components were constrained to be a regular hexagon using the FLAT command with C−C bond
lengths and CꢀCꢀC bond angles restrained using DFIX.
2.5. Theoretical calculations
2.5.1. Calculation of the Lattice energies and the Interaction Energies (I.E.)
Lattice energies of all the compounds were calculated by the PIXEL method in the CLP
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computer program package [version 12.5.2014] . For this purpose all hydrogen atoms were
moved to their corresponding neutron distances and accurate electron density around the
molecule was calculated at MP2/6ꢀ31G** using Gaussian 0960. The total lattice energy was
partitioned into their Coulombic, polarization, dispersion and repulsion contributions (Table 2).
PIXEL energy calculations also provide molecule interaction energies (I.E.) related by the
symmetry element in the crystal. The selected molecular pairs along with their interaction
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energies (again with the total interaction energy partitioned into their Coulombic, polarization,
dispersion and repulsion contributions) are presented in Table 3. The intermolecular interactions
involved in linking molecular pairs also appear in Table 3. It was found that the results obtained
by these PIXEL energy calculations are comparable to those calculated using high level MP2 and
DFTꢀD quantum mechanical calculations61.
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2.5.2. Hirshfeld surface, 2D-Fingerprint plot and 3D deformation density
Hirshfeld surfaces mapped with different properties and 2Dꢀfingerprint plots were generated
using CrystalExplorer 3.062. These have proven to be a useful visualization tool for the analysis
of intermolecular interactions in the crystal packing63. The Hirshfeld surface is defined in a
crystal as the region around a molecule where the ratio of the electron distribution of a sum of
spherical atoms for the molecule (the promolecule) to the corresponding sum over the crystal
(the procrystal) equals to 0.5. The shape and nature of the surface is directly influenced by the
environment around the molecule in the crystal. The 2Dꢀfingerprint plot provides quantitative
information about the decomposition of the Hirshfeld surfaces into contributions from the
different intermolecular interactions present in the crystal structure. In this study, the electrostatic
potential (ESP) were mapped on the Hirshfeld surface64 over the range ꢀ0.06 au (red), through 0
(white), to 0.06 au (blue). For this purpose, ab initio wavefunctions were obtained at HF/6ꢀ
311G** using the Gaussian software. Molecular geometries were taken directly from the
relevant crystal structure with Hꢀatoms at their neutron distances. Further, 3D deformation
density for the molecule at the crystal geometry has also been plotted over the electron density
isoꢀsurface (the value is 0.008 e/au3) using CrystalExplorer 3.0. For this purpose, ab initio
wavefunctions were also obtained at HF/6ꢀ311G**.
2.5.3. Calculation of Topological Parameters
Theoretical calculations based on the quantum theory of atoms in molecules (QTAIM)65-66 were
performed using the software AIMALL67 on selected molecular motifs, extracted from the
crystal structure. For this purpose, ab initio calculations for the selected dimers, were performed
at the MP2/6ꢀ31G** level of theory using Gaussian 09. Hꢀatoms were moved to their neutron
distances before the calculation. Selected topological parameters including electron densities (ρb)
and Laplacian operators (∇2ρc) at the bond critical points (BCPs) were obtained (Table 4). The
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local stabilization energy for the different intermolecular interactions was also estimated (Table
4) through an Espinosa−Molins−Lecomte (EML) relationship68 as follows:
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14
15
16
17
Table 1: Crystallographic and Refinement Data
4a
4b
4c
4d
4e
Empirical
C11H6N4O2S
C14H6ClF2N5S
C15H10FN5S
C14H9FN4OS
C16H13N5OS
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
formula
CCDC No.
Formula weight 258.3
1431641
1431642
349.75
1431643
311.34
990263
300.31
1431645
323.37
Temperature
Wavelength
Crystal system
Space group
90(2) K
90(2) K
0.71073 Å
Tetragonal
I4/m
90(2) K
0.71073 Å
Triclinic
Pꢀ1
90(2) K
90(2) K
0.71073 Å
Monoclinic
P21/n
0.71073 Å
Orthorhombic
Pbcn
0.71073 Å
Monoclinic
P21/c
Unit cell
dimensions
a = 10.7264(7) Å, b a = 20.944(3) Å, a = 4.8756(4) Å, a = 13.699(3) Å, a = 11.3550(8) Å,
= 4.9865(3) Å,
c = 19.6574(13) Å, c = 6.5748(9) Å,
β = 92.788(4)°
b = 20.944(3) Å, b = 10.3551(9) Å, b = 9.328(2) Å,
c=13.4098(12) Å, c = 20.497(4) Å,
α = β = γ = 90°
b = 8.6409(7) Å,
c = 15.7538(13) Å,
β = 105.418(4)°
α = 90.293(4)°
β = 98.760(4)°
γ = 90.571(4)°
α = β = γ = 90°
Volume
Z
1050.17(12) Å3
4
1.633 g cm–3
2884.0(9) Å3
8
1.611 g cm–3
669.08(10) Å3
2619.3(10) Å3
8
1.523 g cm–3
1490.1(2) Å3
4
1.441 g cm–3
2
Density
1.545 g cm–3
(calculated)
Absorption
coefficient
F(000)
0.307 mm–1
0.437 mm–1
1408
0.257 mm–1
320
0.263 mmꢀ1
0.229 mmꢀ1
672
528
1232
Crystal size
0.50 × 0.21 × 0.05
mm3
0.470 × 0.450 ×
0.190 mm3
2.482 to 26.307° 2.482 to 24.948°
Theta range for 3.804 to 33.336°
data collection
Index ranges
2.751 to 27.153° 1.967 to 34.104
ꢀ16<=h<=15;
ꢀ7<=k<=7;
ꢀ29<=l<=27
18398
ꢀ15 =< h =< 16;
0 =< k =< 25;
0 =< l =< 8
1439
ꢀ7 =< h =< 7;
ꢀ15 =< k =< 16;
ꢀ21 =< l =< 19
15447
ꢀ17<=h<=14;
ꢀ11<=k<=11;
ꢀ25<=l<=25
28565
ꢀ13<=h<=13;
ꢀ10<=k<=10;
ꢀ16<=l<=18
16051
Reflections
collected
Independent
reflections
3792
0.0608]
[Rint
=
1439 [Rint
0.0378]
=
4652 [Rint
0.0349]
=
2639 [R(int) = 2591 [R(int)
0.0685] 0.0531]
=
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Refinement
method
Data / restraints 3792/ 0 / 162
/ parameters
Fullꢀmatrix leastꢀ Fullꢀmatrix leastꢀ Fullꢀmatrix leastꢀ Fullꢀmatrix leastꢀ Fullꢀmatrix leastꢀ
squares on F2
squares on F2
1439/ 0/ 139
squares on F2
4652/ 0/ 199
squares on F2
2639 / 0 / 190
squares on F2
2591/ 0/ 266
Goodnessꢀofꢀfit 1.019
1.164
1.066
1.022
1.082
on F2
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Final R indices R1 = 0.0437, wR2 R1 = 0.0722, wR2 R1 = 0.0382, wR2 R1 = 0.0352, wR2 R1 = 0.0418,
[I>2sigma(I)] = 0.1168 = 0.1848 = 0.0960 = 0.0900 wR2 = 0.1049
indices (all R1 = 0.0695, wR2 R1 = 0.0809, wR2 R1 = 0.0480, wR2 R1 = 0.0464, wR2 R1 = 0.0576,
R
data)
Largest
peak and hole
= 0.1313
diff. 0.522 and ꢀ0.376 0.632 and
eÅꢀ3 ꢀ0.722 eÅꢀ3
= 0.1891
= 0.1021
= 0.0969
wR2 = 0.1146
0.220 and
0.504 and
0.225 and
ꢀ0.255 eÅꢀ3
ꢀ0.309 eÅꢀ3
ꢀ0.267 eÅꢀ3
Table 2: Lattice energy (kJ/mol) partitioned into Coulombic, polarization, dispersion and
repulsion contributions by the PIXEL method.
Code
ECoul
ꢀ90.8
EPol
ꢀ37.2
EDisp
ERep
162.3
ETot
ꢀ130.3
1.
2.
3.
4.
5.
ꢀ164.6
ꢀ188.7
ꢀ199.9
ꢀ163.3
ꢀ214.7
4a
4b
4c
4d
4e
ꢀ79.7
ꢀ94.7
ꢀ71.2
ꢀ102.5
ꢀ33.4
ꢀ41.6
ꢀ26.9
ꢀ46.3
154.0
183.5
116.8
215.2
ꢀ147.8
ꢀ152.6
ꢀ144.6
ꢀ148.4
Table 3: Interaction energies (I.E. in kJ/mol) obtained from PIXEL method for the different
molecular pairs and the possible interactions involved. Neutron values are given for all DꢀH···A
interactions.
Centroid-
Centroid
Distance
(Å)
Selected Involved
Interactions
Motifs
Symmetry code
Geometry (Å/ °)
ECoul EPol EDisp ERep ETot
4a (P21/n, Z = 4)
7.493
6.041
7.545
ꢀ72.8 ꢀ30.6 ꢀ30.8 102.7 ꢀ31.5
2.805(2)
3.473(2)
I
-x+1, -y+1, -z+1
-x+1, -y, -z+1
S1···N2
Molecular Stacking
Cg2···Cg2
ꢀ15.1 ꢀ8.1 ꢀ28.7 21.3 ꢀ30.6
ꢀ8.3 ꢀ5.1 ꢀ32.0 22.4 ꢀ22.9
II
3.386(2)/ 2.56/ 133
3.252(2)/ 2.37/ 138
III
IV
-x, -y-1, -z+1
C6-H6···O2
11.141 ꢀ20.8 ꢀ6.7 ꢀ10.2 15.4 ꢀ22.3
x-1/2, -y+1/2, z-1/2
C10-H10···N1
Molecular stacking
Cg1···Cg4
Molecular stacking
Cg1···Cg2
5.182
4.987
ꢀ7.6 ꢀ3.1 ꢀ37.6 26.1 ꢀ22.2
3.760(2)
3.399(2)
V
-x, -y, -z+1
x, y-1, z
0.2
ꢀ8.0 ꢀ5.9 ꢀ25.4 22.7 ꢀ16.5
ꢀ7.0 ꢀ2.4 ꢀ7.1 4.8 ꢀ11.6
ꢀ5.8 ꢀ47.0 32.8 ꢀ19.7
VI
8.675
3.525(2)/ 2.70/ 133
3.559(2)/ 2.49/ 171
VII
-x+1/2, y+1/2, -z+1/2
x-1/2, -y-1/2, z-1/2
C9-H9···Cg4
11.372
VIII
C11-H11···O1
4b (I4/m, Z = 8; Z' = 0.5)
ꢀ16.3 ꢀ7.6 ꢀ53.0 41.7 ꢀ35.2
ꢀ27.6 ꢀ11.8 ꢀ23.5 35.0 ꢀ27.8
Molecular stacking
C1···C11 (Cg2···Cg4)
6.813
9.948
3.316(2)
I
y+1/2, -x+1/2, z+1/2
y, -x+1, z
3.240(2)/ 2.18/ 167
II
C11 -H11···N5
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3.457(2)/ 2.62/ 134
2.908(2)/ 143(1)/ 111(1)
C14 -H14···F1
C12-F1···F2-C13
Molecular stacking
C5···C5 (Cg1···Cg1)
Cl1···N2
7.889
8.439
ꢀ0.4 ꢀ1.8 ꢀ26.1
ꢀ21.5 ꢀ11.5 ꢀ29.7 43.1 ꢀ19.5
ꢀ8.1 ꢀ3.6 ꢀ10.0 9.2 ꢀ12.5
5.0
ꢀ23.4
3.700(2)
III
IV
V
-x+3/2, -y+1/2, z+1/2
-x+1, -y, z
3.070(2)
3.431(2)
3.600(2)/ 2.53/ 172
3.589(2)/ 2.68/ 141
S1···S1
C6 -H6···N2
C6 -H6···N1
13.107
y+1, -x+1, z
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4c (P-1, Z = 2)
3.603(2)/ 2.62/ 150
C15-H15···N1
Molecular stacking
C3···N2 (Cg2···Cg2)
C7-H7···N4
C9-H9B···N5
C9-H9A···C11
C1···C7 (Cg2···Cg1)
Molecular stacking
C2···C7 (Cg3···Cg1)
5.664
ꢀ33.5 ꢀ13.7 ꢀ52.1 44.0 ꢀ55.2
I
-x+2, -y+1, -z+1
3.260(2)
3.556(2)/ 2.50/ 165
3.580(2)/ 2.65/ 144
3.849(2)/ 2.77/ 172
3.315(2)
7.212
4.876
ꢀ35.4 ꢀ14.5 ꢀ51.7 51.6 ꢀ50.0
ꢀ7.6 ꢀ11.5 ꢀ69.6 52.8 ꢀ35.9
II
-x+3, -y, -z+1
x+-1, y, z
III
6.377
8.324
ꢀ10.9 ꢀ3.6 ꢀ30.0 10.8 ꢀ33.7
ꢀ74.3 ꢀ30.6 ꢀ32.0 108.8 ꢀ28.2
IV
V
-x+2, -y, -z+1
-x+1, -y+1, -z+1
x, y, z-+1
3.782(2)
2.807(2)
S1···N2
3.168(2)/ 2.42/ 125
3.288(2)/ 2.65/ 117
C5 -H5···F1
C6 –H6···F1
13.410
ꢀ5.3 ꢀ1.4 ꢀ10.6
7.1
ꢀ10.3
VI
4d (Pbcn, Z = 8)
5.914
5.988
ꢀ26.6 ꢀ11.5 ꢀ65.0 56.7 ꢀ46.4
3.410(2)/ 2.47/ 145
I
-x+1, -y, -z+1
C8-H8B···O1
3.738(2)/ 2.81/ 144
3.758(2)/ 2.68/ 174
3.666(2)/ 2.86/ 131
3.386(2)/ 2.52/ 136
3.385(2)/ 2.59/ 130
C5-H5···C7
C8-H8A···C5
C10-H10···C1
C8-H8B···O1
C14-H14···N1
ꢀ8.9 ꢀ7.2 ꢀ50.5 33.2 ꢀ33.4
II
-x+1/2, y-1/2, z
9.328
ꢀ16.1 ꢀ5.3 ꢀ17.6 13.1 ꢀ25.9
III
x, y+1, z
12.367 ꢀ17.7 ꢀ6.8 ꢀ14.2 12.9 ꢀ25.9
3.526(2)/ 2.66/ 137
3.382(3)/ 2.40/ 150
3.223(2)/ 2.57/ 118
IV
V
-x+1, -y-1, -z+1
x-1/2, y+1/2, -z+3/2
x, -y, z-1/2
C7-H7···N1
C11-H11···N2
C7-H7···F1
9.940
ꢀ12.3 ꢀ5.4 ꢀ11.5 13.8 ꢀ15.4
ꢀ3.6 ꢀ1.1 ꢀ10.3 5.9 ꢀ9.1
10.382
VI
4e (P21/c, Z = 4)
3.425(2)/ 2.44/ 150
3.526(2)/ 2.76/ 127
C9-H9A···N1
C5B-H5B···S1
Molecular stacking
C4B···C10B
C1···C11B
Molecular stacking
Cg1···Cg3
8.021
ꢀ25.4 ꢀ11.0 ꢀ61.1 54.7 ꢀ42.8
I
x, -y+1/2, z-1/2
3.319(2)
3.393(2)
7.055
8.715
ꢀ27.1 ꢀ13.9 ꢀ82.5 85.1 ꢀ38.4
ꢀ56.4 ꢀ22.0 ꢀ25.9 71.3 ꢀ33.0
3.431(2)
II
-x+1, -y+1, -z+1
-x+1, -y, -z+1
2.913(2)
III
IV
S1···N2
3.555(8)/ 2.48/ 172
3.451(5)/ 2.75/ 122
C11B-H11B···N5B
C9-H9B···N5B
10.622 ꢀ16.8 ꢀ7.4 ꢀ20.9 21.7 ꢀ23.4
x, -y+3/2, z+1/2
10.005
13.684
ꢀ8.3 ꢀ5.3 ꢀ31.9 25.5 ꢀ20.1
ꢀ8.1 ꢀ3.2 ꢀ9.0 7.4 ꢀ12.9
3.585(2)/ 2.71/ 138
3.551(7)/ 2.56/ 152
V
-x, y-1/2, -z+3/2
C15B-H15B···C12B
C6B-H6B···N1
VI
-x+1, y+1/2, -z+1/2
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Table 4: Topological parameters for the selected interactions in different molecular motifs of 4a,
4b and 4c.
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9
Compound
code_ motif
Interaction
Bond path
Electron density
Laplacian
EML35
Interaction
[ρBCP (e/Å3)]
[∇2ρBCP (e/Å5)] energy (kJ/mol)
[Rij (Å)]
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S1ꢁꢁꢁN2
N2ꢁꢁꢁN2
2.809
3.016
0.137
0.067
1.469
0.791
18.4
9.1
4a_I
H11ꢁꢁꢁN5
F1ꢁꢁꢁF2
2.197
2.917
2.655
0.134
0.039
0.032
1.476
0.731
0.484
15.6
7.3
4b_II
H14ꢁꢁꢁF1
4.5
S1ꢁꢁꢁCl1 (intra)
Cl1ꢁꢁꢁN2
2.982
3.083
3.442
0.131
0.074
0.057
1.652
0.921
0.735
18.5
9.5
4b_IV
4c_V
S1ꢁꢁꢁS1
6.0
S1ꢁꢁꢁN2
N2ꢁꢁꢁN2
2.816
2.921
0.136
0.081
1.474
0.973
18.5
11.0
3. Results and Discussion
3.1. Chemistry
The reaction sequences employed for the synthesis of title compounds are illustrated in Scheme
1. The carbohydrazides (1a-c), on reaction with carbon disulfide in methanolic potassium
hydroxide afforded the corresponding dithiocarbazinates (2a-c) in good yields and were directly
used for the next step without further purification. The corresponding 4ꢀaminoꢀ1,2,4ꢀtriazoleꢀ3ꢀ
thiols (3a-c) were then synthesized by refluxing salts (2a-c) with hydrazine hydrate (80%).
Scheme 1. Synthetic protocol for the preparation of triazolothiadiazoles (4a-e).
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Condensation of the appropriate triazole (3a-c) with various aromatic/heteroꢀaromatic carboxylic
acids in phosphorous oxychloride under reflux provided access to a diverse array of 1,2,4ꢀ
triazolo[3,4ꢀb][1,3,4]thiadiazoles (4a-e) in good yields48,50-51. The appearance of new stretching
bands in the IR spectra and disappearance of characteristic peaks for the –SH and –NH2 groups
clearly indicated the smooth cyclization. Signals observed at 4.55 and 5.61 ppm as singlets for
the methylene group confirmed the formation of triazolothiadiazoles (4c, e). 13C NMR spectra of
the condensed heterocycles showed the presence of carbon signals at appropriate chemical shift
values. The purity of the newly synthesized hybrid compounds was also determined by elemental
analysis.
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(b)
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(c)
(d)
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(e)
Figure 1: ORTEP plots of (a) 4a (b) 4b (c) 4c (d) 4d and (e) 4e showing the atom numbering, with
ellipsoids drawn with 50% probability level. “Cgn” represents the centroid of the nth ring, shown by
magenta spheres. For clarity only the major components of the disordered pyridyl and tolyl rings in 4e are
shown.
3.2. Molecular structures
The structures of the five reported molecules, Fig. 1, are sufficiently similar to be discussed
together. Although the structure of 4d has been reported previously52 it is included in this
discussion for comparative purposes. Each molecule comprises a central triazolothiadiazole unit
with substitiuents on the C1 carbon atom of the triazole ring and the C2 carbon of the thiadiazole
unit. 2ꢀfuranyl substituents are found on C1 and C2 for 4a and on C1 for 4d. In contrast C1
carries a 3ꢀpyridyl substituent in 4b and 4ꢀpyridyl rings in 4c and 4e. Interestingly, all previously
studied triazolothiadiazole compounds in the Cambridge Crystallographic Database69 are
characterized by the presence of substituents on the C atoms of both the triazoloꢀ and thiadiazole
rings as is found here. Compounds 4a and 4b with aromatic substituents at C1 and C2 are planar,
4b strictly so, suggesting a reasonable degree of conjugation over the entire molecule. The
benzyl substituents at C2 for 4c, 4d and 4e destroy the molecular planarity although for 4c and
4d the C1 pyridyl substituents remain close to the plane of the triazolothiadiazole ring system.
Despite the disorder in the pyridyl ring for 4e both components also lie reasonably close to the
triazolothiadiazole plane.
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Bond distances and angles within the triazolothiadiazole unit compare reasonably well with those
of 40 other triazolo[3,4ꢀb][1,3,4]thiadiazole derivatives whose structures were found in the
Cambridge Crystallographic database69. 11 additional structures are found in which
triazolothiadiazole derivatives act as ligands to transition metal complexes, binding to the metal
exclusively via the N2 atoms of the triazole rings70-71. A significant elongation of the S1—C2
distance in comparison to S1—C3 bond in the molecules reported here appears from comparison
with related compounds to be a characteristic feature of triazolo[3,4ꢀb][1,3,4]thiadiazoles. Only
three instances of compounds with furan substituents have been reported previously, two with
the furan on the triazole50-52 and the other on the thiadiazole ring72.
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3.3. Crystal packing analysis: Inputs from PIXEL energy calculations
Lattice energy calculations, using the PIXEL method, for all compounds shows that the
dispersion energy is the major component (56ꢀ62 %, Table 2), a wellꢀknown finding in the case
of organic molecules. However, it was also observed that compounds 4a, 4c and 4e exhibit a
significant electrostatic (coulombic + polarization, 128, 136.3 and 148.8 kJ/mol) and repulsion
contributions (162.3 kJ/mol, 183.5 kJ/mol and 215.2 kJ/mol) for 4a, 4c and 4e respectively). This
was not found to be the case for 4b and 4d (Table 2). The presence of different kinds of
intermolecular interactions that are involved in the crystal packing of these molecules may
explain this observation. This will be extensively analyzed in the following section via inputs
from both experimental and theoretical procedures.
3.3.1. Analysis of the molecular packing in 4a
The compound 4a crystallizes in the centrosymmetric monoclinic space group P21/n with Z = 4.
Two interactions, inversion dimer formation resulting from short S1…N2 contacts [labelled I,
Figure 2(a)] and an offset πꢁꢁꢁπ stacking interactions involving adjacent triazole rings [labelled II,
Figure 2(a)] show the greatest stabilization, with I.E. = ꢀ31.5 kJ/mol for I and I.E. = ꢀ30.6
kJ/mol for II. The short inversion related S1···N2 contacts have dSꢁꢁꢁN = 2.805(2) Å, which is
0.55Å shorter than the sum of the van der Waals radii73 of sulfur (1.80 Å) and nitrogen (1.55 Å).
Partition of the total stabilization energy into different energetic contributions shows a very high
contribution from the repulsion component (102.7 kJ/mol) in comparison to those found for 4b
and 4d, Table 2). An increase in the repulsion component for the shorter contacts, leading to the
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formation of molecular pairs in a crystal with reduced stability, has been observed previously74.
Furthermore, the electrostatic (Coulombic + polarization) contribution is 77% of the total
stabilization energy for motif I in 4a suggesting that the SꢁꢁꢁN contact in motif I is principally
electrostatic in origin. The stabilization energy of this dimer is comparable to the previously
reported interaction energy of a selenadiazole dimer75.
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In order to gain more insights into the nature of this short S…N contact for 4a, it was also
analyzed by considering the Hirshfeld surfaces and 2Dꢀfingerprint plots. The electrostatic
potential mapped on the Hirshfeld surface of 4a displays the presence of a positive ESP on the Sꢀ
atom (σꢀhole) of magnitude +0.085au. This electropositive region on the Sꢀatom interacts with
an electronegative region over the Nꢀatom (ꢀ0.093au) resulting in the formation of the short
dimeric SꢁꢁꢁN contact in the crystal packing. Its contribution to the Hirshfeld surface of 4a is
7.3% [Fig. 2(b)]. This observation confirms the electrostatic origin of such SꢁꢁꢁN interactions and
may be classified as a “chalcogen bond”20-25. A pair of spikes for the SꢁꢁꢁN contacts was observed
on the decomposed 2Dꢀfingerprint plot.
3Dꢀdeformation density (DD) maps were also plotted using Crystal Explorer. The wave function
was calculated at the HF/ 6ꢀ311G(d,p) level using Gaussian. This reveals the presence of a
charge depletion (CD) region at the S1 which is directed towards the charge concentration (CC)
region over N2, facilitating formation of the S1ꢁꢁꢁN2 contacts in the crystal [Fig. 2(c)].
Theoretical calculations based on the quantum theory of atoms in molecules (QTAIM) using
AIMALL confirms the presence of a bond critical point (BCP) for the SꢁꢁꢁN interaction (Rij =
2.809 Å) [Fig 2(d)]. Values for the topological parameters at the BCP are ρ
b = 0.137 e/Å3 for the
electron density, and ∇2ρb = +1.469 e/Å5 for the Laplacian, (Table 4). The presence of a BCP for
an N2ꢁꢁꢁN2 contact was also observed in the molecular pair with a longer bond path length (Rij =
3.016 Å). The short dimeric S1ꢁꢁꢁN2 contacts clearly impose this relatively close approach of the
N2 atoms. As a consequence of this, the CC regions on the two N2 atoms approach close to one
another, as seen in the 3Dꢀdeformation density (DD) map [Fig. 2(c)]. This may explain the high
repulsion energy contribution towards this molecular motif I, Fig 2a. However, in the crystal
packing of 4a the interactions between the CD and CC regions in the S1…N2 contact provides
the overall stabilization in this motif.
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A second stabilizing contact with similar stabilization energy (motif II, ꢀ30.6 kJ/mol, d =
3.4737(9) Å) results from an offset πꢁꢁꢁπ interactions, involving adjacent triazole rings [centroid
‘Cg2’, Fig. 2(b)] with a contribution from the dispersion energy of 55%. Interestingly, this value
is significantly less than the dispersion energies found for other πꢁꢁꢁπ contacts formed by these
molecules [motifs V, Cg1ꢁꢁꢁCg4, d = 3.7601(10) Å and VI, Cg1ꢁꢁꢁCg2, d = 3.3988(9) Å, Table
3)] where the contributions from the dispersion energies are 78% and 89% for motifs V and VI
respectively.
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Molecular packing in 4a involves the formation of a chain of molecules approximately along the
crystallographic aꢀ axis through the S1ꢁꢁꢁN2 inversion dimers, I, together with C6—H6ꢁꢁꢁO2
hydrogen bonds (motif III, I.E. = ꢀ22.9 kJ/mol) [Fig. 2(a)]. The C—HꢁꢁꢁO hydrogen bonds
generate R2 (20) rings76. Both sides of these chains are bordered by another set of molecules that
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lie almost at right angles to the chain. These are linked to molecules in the chain by C10—
H10ꢁꢁꢁN1 (motif IV, I.E. = ꢀ22.3 kJ/mol), C9—H9ꢁꢁꢁCg4 (motif VII, I.E. = ꢀ16.5 kJ/mol) and
C11—H11ꢁꢁꢁO1 (motif VIII, I.E. = ꢀ11.6 kJ/mol) hydrogen bonds These bordering molecules are
also stacked as a result of the II, V and VI πꢁꢁꢁπ stacking interactions, as mentioned previously
[Fig. 2(a)].
The electrostatic potential has been mapped over the Hirshfeld surface of 4a [Fig. 2(f)]. A clear
separation of the electropositive and electronegative regions was observed over the flat surfaces
of the planar 4a molecule. An electronegative region is found on both the faces of the molecule
in the vicinity of the O1 furan ring centroid, Cg1 and for half of the triazole ring, Cg2. The other
half of the triazole ring, the thiadiazole and the O2 furan rings lay in an area of positive potential.
These observations support the observation of πꢁꢁꢁπ stacking interactions with motifs II, V and
VI. It is interesting to note that the two furan rings each have opposite potentials on both faces
of the molecule which clearly facilitates the πꢁꢁꢁπ (Cg1ꢁꢁꢁCg4) contact between them.
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Figure 2(a): Packing of molecules in 4a stabilised by dimeric SꢁꢁꢁN chalcogen bonds, πꢁꢁꢁπ interactions
and weak CꢀHꢁꢁꢁO and CꢀHꢁꢁꢁN hydrogen bonds. Roman numerals (in red) in this and subsequent
diagrams indicate the molecular motifs detailed in Table 3.
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Figure 2(b): The Hirshfeld surface for 4a mapped with electrostatic potential (ESP) over the range ꢀ0.06
au (red) through 0.0 (white) to 0.06 au (blue) for 4a. The corresponding decomposed 2D fingerprint plot
for the SꢁꢁꢁN contact is also presented.
Figure 2(c): 3Dꢀdeformation density map for 4a showing the presence of CD regions (in red) and CC
regions (in blue), mapped using Crystal Explorer 3.0. The isosurfaces are drawn at 0.008 eau−3. (d) A
molecular plot of a selected dimer, showing the presence of bond critical points (brown spheres) for the
various intermolecular contacts (Table 4)
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Figure 2(e): Packing of molecules in 4a, displaying the different molecular layers, formed by SꢁꢁꢁN
chalcogen bonds and weak CꢀHꢁꢁꢁO hydrogen bonds both of which form inversion dimers. The layers are
interconnected by πꢁꢁꢁπ stacking interactions.
Figure 2(f): Front and back view of the electrostatic potential (ESP) mapped over the Hirshfeld surface
for 4a in the range ꢀ0.06 au (red) through 0.0 (white) to 0.06 au (blue).
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3.3.2. Analysis of the molecular packing in 4b
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The compound 4b crystallizes in the centrosymmetric tetragonal I4/m space group with Z = 8.
The entire molecule was observed to lie on a mirror plane parallel with the crystallographic ab
plane, with one half of the molecule (Z' = 0.5) in the asymmetric unit.
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Unlike 4a, with two furan substituents on the triazolothiadiazole ring system, 4b has a pyridine
ring bound to C1 of the triazole ring and a difluorochlorobenzene substituent on C2 of the
thiadiazole ring. With all atoms lying in the mirror plane the molecule is strictly planar which
facilitates πꢀstacking interactions in the crystal packing. Indeed the most stabilized dimeric
molecular pair (motif I, IE = ꢀ35.2 kJ/mol, d = 3.316Å) was observed to consist of πꢁꢁꢁπ
interactions, involving the triazole ring [labeled with ‘Cg2’, Fig. 3(a)] with the
difluorochlorobenzene ring (Cg4), the contribution from dispersion energy being 52%.
Electrostatic potentials mapped over the Hirshfeld surface of 4b reveal a flat smooth surface with
similar characteristics to those previously observed for 4a. Cg1 and half of the Cg2 ring have
electronegative surfaces on both faces while the remainder of the surface, covering Cg3 and Cg4,
is electropositive [Fig. 3(b)]. Hence the triazole and difluorochlorobenzene rings exhibit
opposite electrostatic complementarity leading to significantly strong πꢁꢁꢁπ stacking in the crystal
packing. This is commensurate with motif I being the most stabilized contact in 4b [Figs. 3(a) &
3(b)]. This is the only interaction observed for this molecular pair which has a 32% electrostatic
contribution towards the total interaction energy (Table 3). This is a “very rare supramolecular
feature” as πꢁꢁꢁπ interactions are primarily considered to be dispersive in origin77.
An additional heavily offset πꢁꢁꢁπ stacking interaction III (IE = ꢀ23.4 kJ/mol) results from an
interaction between adjacent pyridine rings that lie in the electronegative regions of the Hirshfeld
surface. Despite the substantial offset, C5 atoms on adjacent rings are separated by 3.700(2) Å.
In sharp contrast to I where electrostatic effects play a significant role, this motif is found to have
a 92% contribution from the dispersion energy, Table 3.
In addition to these πꢁꢁꢁπ stacking interactions, an eclectic mix of intermolecular C—H…N and
C—HꢁꢁꢁF hydrogen bonds, Cl1ꢁꢁꢁN2 [3.071(6) Å], type II F1ꢁꢁꢁF2, halogen bonds and short
S1ꢁꢁꢁS1 contacts, 3.432(3) Å, link each molecule to four others and generate infinite, strictly
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planar sheets in the ab plane [Fig. 3(c)]. The second most stable molecular pairing motif II, (IE
= ꢀ7.8 kJ/mol) results from a short, directional C11—H11ꢁꢁꢁN5 hydrogen bond, bolstered by a
C14—H14···F1 hydrogen bond, involving the highly acidic atom H14, and an FꢁꢁꢁF halogen
bond, 2.908(8) Å, that approximates to type II geometry78-79. The strength of the C—HꢁꢁꢁN
contact can be attributed to the acidity of the H11 atom that lies between two F atoms and a Cl
atom and the wellꢀrecognized basicity of the pyridine N atom. The PIXEL calculations show that
the total contribution from electrostatic effects is extremely high and found to be 63% for motif
II (Table 3). The 3D deformation density map for the motif II [Fig. 3(d)] clearly shows that
H11 points towards the CC region around the pyridine nitrogen atom, N5. Moreover, for the
FꢁꢁꢁF halogen bond, the map shows clearly that the CD region of F1 points towards the CC region
on F280. Topological calculations based on QTAIM theory on a dimer generated by motif II
confirms the presence of a (3, ꢀ1) BCP for the C—HꢁꢁꢁN, FꢁꢁꢁF and C—HꢁꢁꢁF interactions [Figs.
3(e), Table 4].
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The electronic nature of the motif II was further analyzed from the ESP mapped over the
Hirshfeld surface for 4b. In the C11—H11ꢁꢁꢁN5 contact, the highly electropositive region (0.112
au) around H11 interacts with highly electronegative (ꢀ0.100 au) region around the N5 [Figs.
3(f)]. This also confirms the strongly electropositive character of H11 and correspondingly
strong electronegative nature of N5 as discussed previously. The pair of sharp spikes observed
on 2Dꢀfingerprint plot for this contact, is characteristic of a strong interaction. These
observations also reflect the substantial electrostatic component found for this motif in the
PIXEL calculations.
An obvious feature of the sheets of 4b molecules formed in the ab plane are the inversion dimers
generated by pairs of Cl1ꢁꢁꢁN2 halogen bonds together with an SꢁꢁꢁS chalcogen bond (motif IV,
IE = ꢀ19.5 kJ/mol). There are some similarities between this motif and the inversion related
SꢁꢁꢁN contacts adopted in motif I by 4a, consisting of dimeric SꢁꢁꢁN contacts. A significant
difference between the two motifs is that for 4b the molecules are translated away from one
another to accommodate the longer N1ꢁꢁꢁCl1 and S1ꢁꢁꢁS1 distances. An immediate effect of this
translation is that sensible SꢁꢁꢁN contacts are precluded. The presence of two fluorine substituents
on the benzene ring makes the Clꢀatom more electronꢀdeficient and polarizes the electron density
with a larger CD region on the Clꢀatom opposite to the CꢀCl bond [Fig. 3(d)]. This facilitates
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attraction by the CC region about N2 forming the two ClꢁꢁꢁN halogen bonds81. The deformation
map also shows some polarization of the electron density around the Sꢀatom such that it is not
directed towards the N2 atom. Instead, the intermolecular SꢁꢁꢁS chalcogen bond forms with
equivalent C3—S1ꢁꢁꢁS1 angles, and is reminiscent of the wellꢀknown situation82 with type I
halogen bonds. However, the CD region about the S atom does face the CC region on the
adjacent Cl1 atom facilitating the formation of an intramolecular SꢁꢁꢁCl chalcogen bond83 [Fig.
3(d)].
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QTAIM calculations on a dimer generated by motif IV again shows the presence of (3, ꢀ1)
BCP’s [Fig. 3(e)] and provides additional evidence about the formation of these contacts in the
crystal packing of 4b (Table 4). Furthermore, the Hirshfeld surface shows electropositive region
(σꢀhole, +0.056 au) on the Cl1 ideally positioned to interact with the highly electronegative
region over N2 (ꢀ0.094 au) resulting in the formation of the halogen bond [Fig. 3(g)]. The ESP
over S1 is moderately positive but the value is much less in comparison to the value found for 4a
leading to the formation of the SꢁꢁꢁN chalcogen bond. A pair of spikes was observed in the
decomposed 2D fingerprint plots for the ClꢁꢁꢁN interaction with the SꢁꢁꢁS contact generating a
single spike. No characteristic signature was observed for the SꢁꢁꢁN contact as expected [Fig.
3(g)].
The final items in the extensive catalogue of contacts stabilizing the packing of 4b are a pair of
weak bifurcated C6—H6ꢁꢁꢁN1 and C6—H6ꢁꢁꢁN2 hydrogen bonds [motif V, IE = ꢀ12.5 kJ/mol]
Figure 3(c). The latter is short, highly directional and close to linearity (2.53Å, 172°) while the
other is a weaker contact (2.68 Å, 141°), Table 3.
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Figure 3(a): Formation of layers of 4b molecules along the c axis through πꢁꢁꢁπ interactions.
Figure 3 (b): Front and back view of the electrostatic potential (ESP) mapped over the Hirshfeld surface
for 4b over the range ꢀ0.06 au (red) through 0.0 (white) to 0.06 au (blue).
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Figure 3(c): Packing view perpendicular to the ab plane for 4b showing the formation of a molecular
sheet due to ClꢁꢁꢁN, SꢁꢁꢁS and FꢁꢁꢁF contacts together with weak CꢀHꢁꢁꢁN and CꢀHꢁꢁꢁF hydrogen bonds.
Figure 3(d): A 3Dꢀdeformation density map showing the presence of CD regions (in red) and CC regions
(in blue) on the 4b, mapped by Crystal Explorer 3.0. Brown arrows indicate the intramolecular S…Cl
interaction. The isosurfaces are drawn at 0.008 eau−3.
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Figure 3(e): Molecule plots for motifs II and IV in 4b, showing the presence of bond critical points
(brown spheres) for different inter and intraꢀmolecular atomꢀatom contacts (Table 4)
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Figure 3(f): Decomposed ESP map, plotted on the Hirshfeld surface of 4b, showing the contribution of
H11···N5 contacts together with the corresponding 2D fingerprint plot.
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Figure 3(g): Molecular ESP mapped on the Hirshfeld surface of 4b, displaying the Cl···N and S···S
contacts along with their corresponding 2D fingerprint plots.
3.3.3. Analysis of molecular packing in 4c
The compound 4c crystallizes in the centrosymmetric triclinic space group Pꢀ1 with Z=2.
Unlike 4b, 4c is not a planar molecule due to the replacement of the difluorochlorobenzene
substituent with a paraꢀfluorobenzyl group on C2 of the thiadiazole ring. However the
triazolothiadiazole ring system and the pyridyl ring, with centroids Cg1, Cg2 and Cg3, remain
reasonably coplanar and were found to be involved in πꢁꢁꢁπ molecular stacking interactions in the
crystal packing [Fig. 4(a)]. Such contacts provide the most stabilized motifs I (IE = ꢀ55.2
kJ/mol; involving a Cg2 to Cg2 contact), III (IE = ꢀ35.9 kJ/mol; Cg1 to Cg2) and IV (IE = ꢀ33.7
kJ/mol; Cg3 to Cg1) (Table 3).
The electrostatic potentials mapped over the Hirshfeld surfaces of both faces of the planar
segments of 4c are shown in Fig 4(b). It is noteworthy that the ESP over the Cg1, Cg2 and Cg3
rings has similar characteristics to those observed in the corresponding Hirshfeld surfaces of 4b,
Figs. 3(b). The πꢀrings, involved in the molecular stacking, shows interactions between regions
of opposite electrostatic complimentarity. Hence, the most stabilized motif I involves the
interaction between the electropositive segment of the Cg2 ring with the complimentary
electronegative part of the same ring on the oppposite surface. This results in a 48% contribution
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from electrostatics towards the total stabilization energy (Table 3). The other two motifs III and
IV were found to display 22% and 33% electrostatic contributions respectively towards their
total stabilization energies. In motif III, a weak C1ꢀH9AꢁꢁꢁCg4 hydrogen bond, Table 3 adds
additional support to the Cg2ꢁꢁꢁCg1 πꢁꢁꢁπ stacking interaction.
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Chains of molecules parallel to the (110) plane through two sets of inversion dimers are
represented by motifs II and V [Figs. 4(c)]. The former results from inversion related C7—
H7…N4 contacts that form R2 (14) rings76. These are further stabilised by C9—H9BꢁꢁꢁN5
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hydrogen bonds forming R2 (7) rings. The hydrogen atom H9B is strongly acidic on account of
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this being connected to two strongly electron withdrawing fluorobenzene ring and the
triazolothiadiazole ring. V results from S1ꢁꢁꢁN2 inversion dimers very similar to those found in
the packing of 4a. These chains are interconnected by very weak bifurcated C5—H5ꢁꢁꢁF1 and
C6—H6ꢁꢁꢁF1 hydrogen bonds (motif VI, IE = ꢀ10.3 kJ/mol) with the formation of a molecular
layer approximately parallel to (110). The C7—H7ꢁꢁꢁN4 inversion dimers and C9—H9BꢁꢁꢁN5
hydrogen bonds, motif II (IE = ꢀ50.0 kJ/mol), represent the second most stabilized packing
motifs for 4c. The contribution to this motif from electrostatics is again significant to the extent
of 49% (Table 3). The Hirshfeld plots focussing on these contacts show a strongly
electronegative area around N5 (ꢀ0.085 au) as would be expected for a pyridine nitrogen atom.
This will interact strongly with the moderately electropositive area (+0.064 au) around the acidic
sp3 hydrogen, H9B as a neighbour of the thiadiazole ring [Fig. 4(d)]. The second C(sp2)—HꢁꢁꢁN
hydrogen bond is revealed as a weaker interaction. This involves the acidic hydrogen, the sp2 H7,
in a moderately electopositive region (0.047au) as it is adjacent to the pyridine N5 atom. This
inteacts with the weakly electropositive region about N4 (ꢀ0.025au) [Fig. 4(d)]. These HꢁꢁꢁN
contacts display a pair of spikes on the decomposed 2Dꢀfingerprint plot, and contribute 15.1%
over the total Hirshfeld surface of 4c.
The moderately strong motif V (IE = ꢀ28.2 kJ/mol) involves the formation of dimers through
short SꢁꢁꢁN chalcogen bonds with a 77% contribution from electrostatics towards the total
stabilization. As is observed in the case of 4a, the motif was also observed to have a high
contribution from the repulsion energy undoubtedly due to the close approach of the N2 atoms
imposed by the stronger SꢁꢁꢁN chalcogen bond. ESP mapped over the Hirshfeld surface shows the
presence of highly electropositive region (the ‘σꢀhole’ 0.101 au) on the S1 atom opposite to the
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Crystal Growth & Design
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CꢀS bond interacting with the highly electronegative region (ꢀ0.103 au) around the N2 atom [Fig.
4(e)]. This confirms the electrostatic origin of such chalcogen interactions. Further, topological
calculations using AIMALL confirms the presence of (3, ꢀ1) BCPs for the SꢁꢁꢁN interactions and
a corresponding N2···N2 BCP underscoring the repulsive contribution to the overall energy of
the system [Fig. 4(f), Table 4]. The 3D deformation density map clearly shows that the SꢁꢁꢁN
chalcogen bond results from a significant interaction between the CD region on the Sꢀatom with
the CC region on the Nꢀatom and also displays the possibility of repulsive N2ꢁꢁꢁN2 contacts [Fig.
4(g)].
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Figure 4(a): Formation of layers via πꢁꢁꢁπ stacking along with a weak CꢀHꢁꢁꢁπ hydrogen bond in 4c.
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