Interplay of Inter- and Intramolecular Interactions in Crystal Structures of 1,3,4-Thiadiazole Resorcinol Derivatives

Article abstract of DOI:10.1021/acs.cgd.8b00077

Five new 1,3,4-thiadiazole derivatives have been synthesized, and their crystal structures have been determined by single crystal X-ray diffraction. The influence of substituents on molecular geometry and the three-dimensional arrangement of molecules has

Full text of DOI:10.1021/acs.cgd.8b00077

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Article
Interplay of inter- and intramolecular interactions in crystal
structures of 1,3,4-thiadiazole resorcinol derivatives
Anna A. Hoser, Daniel Michal Kami#ski, Alicja Skrzypek, Arkadiusz
Matwijczuk, Andrzej Niewiadomy, Mariusz Gagos, and Krzysztof Wozniak
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00077 • Publication Date (Web): 05 Jun 2018
Downloaded from http://pubs.acs.org on June 5, 2018
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Interplay of interꢀ and intramolecular interactions in crystal
structures of 1,3,4ꢀthiadiazole resorcinol derivatives
Anna A. Hoser1#*, Daniel M. Kamiński2#, Alicja Skrzypek3, Arkadiusz Matwijczuk4,
Andrzej Niewiadomy2,5, Mariusz Gagoś6 and Krzysztof Woźniak1*
#Both authors have equal contribution
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1Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Żwirki i Wigury
101, 02ꢀ089 Warszawa, Poland
2Department of Chemistry, Maria CurieꢀSkłodowska University, pl. Marii CurieꢀSkłodowskiej 2, 20ꢀ031 Lublin,
Poland
3Department of Chemistry, University of Life Sciences in Lublin, Akademicka 15, 20ꢀ950 Lublin, Poland
4Department of Biophysics, University of Life Sciences in Lublin, Akademicka 13, 20ꢀ950 Lublin, Poland
5Institute of Industrial Organic Chemistry, Annopol 6, 03ꢀ236 Warszawa, Poland
6Department of Cell Biology, Institute of Biology and Biotechnology, Maria CurieꢀSkłodowska University,
20ꢀ033 Lublin, Poland
* Corresponding authors:
Anna A. Hoser (annahoser@chem.uw.edu.pl),
Krzysztof Woźniak (kwozniak@chem.uw.edu.pl)
Keywords: 1,3,4ꢀthiadiazole, structure, intermolecular interactions, resonance light
scattering, crystal growth mechanism, theoretical calculations
Abstract
Five new 1,3,4ꢀthiadiazole derivatives have been synthesized and their crystal
structures have been determined by single crystal Xꢀray diffraction. The influence of
substituent on molecular geometry and the 3D arrangement of molecules has been studied by
means of single crystal Xꢀray diffraction, fluorescence, UVꢀVis spectroscopy and
computational methods. The 1,3,4ꢀthiadiazole derivatives occur in two possible conformations
in their crystal lattices: with the orthoꢀhydroxyl group of the resorcyl ring pointing towards
the S or the N atoms from the 1,3,4ꢀthiadiazole ring. In the latter conformation, an intraꢀ
molecular hydrogen bond is created which is energetically favourable for the isolated
molecule as confirmed by theoretical calculations. However, for the molecules in the crystal
structures in the former conformation, some intermolecular interactions between the
neighbouring molecules are strong enough to overrule the intramolecular OH…N hydrogen
bond. In the case of one of the 1,3,4ꢀthiadiazole derivatives, a significant disorder was
observed and both conformations were present in one crystal lattice in the ratio 80% to 20%
for the two conformers, respectively. On the basis of resonance light scattering results, we
explain why crystals of 1,3,4ꢀthiadiazole derivatives can be grown form DMSO and are
difficult to be grown from methanol solution.
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Introduction
Thiadiazole is a fiveꢀmembered heterocyclic system containing two nitrogen and one
sulphur atoms. There are several isomers of thiadiazole including 1,2,3ꢀ thiadiazole, 1,2,4ꢀ
thiadiazole, 1,2,5ꢀthiadiazole, and 1,3,4ꢀ thiadiazole. Many thiadiazole derivatives exhibit
well documented antiꢀinflammatory, analgesic activity, and anticancer activity1. They also
demonstrate their potential applications in medicine.
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The 1,3,4ꢀthiadiazole derivatives (TBD) presented in this work (see Figure 1) have
antifungal and AChE/BuChE inhibitory activity2 as well as antitumor3, antiꢀinflammatory4
and antimicrobial5 properties. Additionally, the group of the 1,3,4ꢀthiadiazol compounds
chosen for this study exhibit the effects of keto/enol tautomerism induced by changes in
environment polarizability6,7 and some unique interactions in model lipid systems8. The
selected test compounds of group 1,3,4ꢀthiadiazols are also ligands, forming complexes with
metal ions of the d block9. The 1,3,4ꢀthiadiazols examined here mainly exhibit dual
fluorescence or two separate emissions10,11
.
While the synthesis, physicochemical properties and biological activities of
thiadiazoles were extensively studied, less attention has been paid to their crystal structures.
As thiadiazoles are known to have poor solubility, some efforts have been made to improve
their physicochemical properties by coꢀcrystallization12,13. Bis(pirydyl)thiadiazoles were
effectively used in MOF synthesis14 to create novel metal–organic architectures. Regarding
crystallographic studies of 1,3,4ꢀthiadiazoles: crystal structures of 2ꢀbenzamidoꢀ5ꢀ(4ꢀfluoroꢀ3ꢀ
phenoxyphenyl)ꢀ1,3,4ꢀthiadiazoles derivatives have been studied with systematic variation in the
functional group at the para position of the benzamido ring15. Crystallisation of the 2ꢀ(4ꢀ
fluorophenylamino)ꢀ5ꢀ(2,4ꢀdihydroxybenzeno)ꢀ1,3,4ꢀthiadiazole (FABT) from DMSO
provides two different polymorphic forms of FABT/DMSO solvates16, whereas
crystallization from water solutions of different alcohols, such as methanol, propanꢀ2ꢀol, and
butanol, with addition of HCl, provides different solvates of 2ꢀ(4ꢀfluorophenylamino)ꢀ5ꢀ(2,4ꢀ
dihydroxyꢀphenyl)ꢀ1,3,4ꢀthiadiazole chloride17.
Here, we will focus on (Xꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)benzeneꢀ1,3ꢀdiols. Depending on the
substituent, the (Xꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)benzeneꢀ1,3ꢀdiol molecule occurs in its crystal
structures in two different conformations: with the ortho hydroxyl group of the resorcyl ring
pointing towards the sulphur atom (“S”) or towards the nitrogen atom (“N”) both from the
thiadiazole ring. In the “N” conformation, the pseudo heteroaromatic ring is formed via
intramolecular hydrogen bond OꢀH…N. The presence of this pseudo heteroaromatic ring has
several consequences on the structure and properties of TBDs, e.g., the OꢀH…N
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intramolecular hydrogen bond formation shortens the distance between the resorcyl and
thiadiazole rings, thus affecting the FTIR spectra (i.e. new bands characteristic for the
aromatic rings appear). It also influences on the biological properties of TBDs and the
specific properties related to the rotation of resorcyl ring, and thus different electron density
distributions have an effect on the properties of biological systems such as lipid membranes18
and proteins.19,20
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From crystal engineering point of view, it is interesting to investigate why for some
systems one observes an intramolecular hydrogen bonding and the “N” conformation,
whereas for others the “S” conformation. There are three empirical general Etter’s rules21
which explain how hydrogen bonding networks are formed in crystal structures:
(1) All good proton donors and acceptors are used in hydrogen bonding.
(2) Sixꢀmemberedꢀring intramolecular hydrogen bonds are formed in preference to
intermolecular hydrogen bonds.
(3) The best proton donors and acceptors remaining after intramolecular hydrogenꢀbond
formation form intermolecular hydrogen bonds to one another.
According to rule (2), in TBDs analysed in this paper, the “N” conformation should be
preferred over the “S” one. Moreover, analysis of CSD resources reveals that probability of
formation of the sixꢀmembered ring in the case of systems in which the hydroxyl group linked
to aromatic ring form intramolecular hydrogen bonding with nitrogen atom equals 94.8%22.
Interestingly, in the case of the analysed systems, one observed not only the “N”, but
also “S” conformations. We investigated why and when one of these two forms (“S” or “N”)
is preferred in TBDs crystals. Some interesting attempts to investigate conformation of
hydroxyl groups in resorcinol ring were already accomplished23ꢀ25, although studied systems
were different than ours.
The following new derivatives of (1,3,4ꢀthiadiazolꢀ2ꢀyl)benzeneꢀ1,3ꢀdiols have been
studied: (I) 4ꢀ[5ꢀphenyl)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl]benzeneꢀ1,3ꢀdiol, (II) 4ꢀ[5ꢀ(4ꢀmethylphenyl)ꢀ
1,3,4ꢀthiadiazolꢀ2ꢀyl] benzeneꢀ1,3ꢀdiol, (III) 4ꢀ[5ꢀtertꢀbutylphenyl)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl]ꢀ
benzeneꢀ1,3ꢀdiol, (IV) 4ꢀ[5(1,3ꢀbenzodioxolꢀ5ꢀyl)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl]ꢀbenzeneꢀ1,3ꢀdiol,
(V) 4ꢀ[5ꢀ2ꢀfluorophenyl)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl]benzeneꢀ1,3ꢀdiol (see Figure 1). In this work,
we present the structures of these compounds and discuss the implications resulting from the
interplay between the intraꢀ and interꢀ molecular interactions of the molecules in their crystal
lattices. This interplay may explain the mechanism of the crystal growth for TBDs.
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(I)
(II)
(III)
(IV)
(V)
Figure 1. Atom labelling schemes and the ORTEP representations of Anisotropic
Displacement Parameters (ADPs) at the 50% probability level for the studied
compounds.
Since there have been a number of recent studies of the biological activity of thiadiazoles,
we intended this analysis to aid the understanding at molecular level the mechanisms of
biological activity of different TBDs.
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Experimental
Synthesis and crystallization. The 5ꢀsubstitutedꢀ(1,3,4ꢀthiadiazolꢀ2ꢀyl)benzeneꢀ1,3ꢀdiol
derivatives (I ꢀ V) were synthesized by the reaction of commercially available hydrazides
with sulphinylobis [(2,4ꢀdihydroxyphenyl)methanethion (STB) in methanol at reflux (2.5ꢀ3h)
as described elsewhere.2,26,27,28 Molecular formulae and the simplified reaction scheme are
presented in Scheme 1. STB was obtained from combination of 2,4ꢀ
dihydroxybenzenecarbodithioic acid and SOCl2 in diethyl ether29 to give the 1,3,4ꢀthiadiazole
ring. The reaction products were recrystallized from methanol several times until ~95% purity
was achieved. The sulphur was removed postꢀreaction by heating the mixture in hexane at its
boiling point. The compounds were crystallized from dimethyl sulfoxide (DMSO) (at room
temperature for 2ꢀ3 weeks). All solvents used were purchased from SigmaꢀAldrich.
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Xꢀray diffraction measurements. Single crystal Xꢀray diffraction data for I and IV were
collected on a singleꢀcrystal Agilent Technologies SuperNova Xꢀray diffractometer, whereas
II and III on Xꢀray κꢀaxis KM4CCD diffractometer at 100(2) K with MoKα radiation. Data
reduction was done using CrysAlis RED software30. The structures were solved with direct
methods and then successive leastꢀsquare refinements were carried out based on the fullꢀ
matrix leastꢀsquares on F2 using the SHELX program package31. Data collection for single
crystals of V (T=100K) was carried out on a Bruker AXS KAPPA APEX II ULTRA
diffractometer with the TXS rotating molybdenum anode and multilayer optic. Indexing,
integration and scaling were performed with the original Bruker Apex II software32. The
multiꢀscan absorption correction was applied using SADABS33. Structures of compounds I,
IV and V exhibit disordered. The most difficult to model is disorder in I. We tried two
different approaches. In the first of them, we used rigid body refinement and filled channels
with TBD molecules. Refinement was stable, but statistics after refinement were quite high (R
factor around 15%). Therefore, we used the SQUEEZE34 option and obtained a better model
(R factor 10% for all data) with empty channels. We decided to submit to CSD results with
the SQUEEZE option, however, we believe, that our refinement with the rigid body is good
enough just to show how channels are probably filled in by molecules (Figure 3 (d)). In the
case of structure IV, two independent disorders appear, one in the p-hydroxyl group (50:50)
and the second one in the DMSO molecule. Structure V is disordered in such a way, that two
conformations appear for the orthoꢀhydroxyl group of the resorcyl ring pointing towards the S
or the N atoms from the 1,3,4ꢀthiadiazole ring (80% toward S and 20% toward N). All further
details regarding disorder treatment can be found in the cif files.
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OH
H
N
R
S
N
STB
R
5
C
O
NH2
∆
HO
MeOH, 2,5 - 3 godz.
2
N
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R:
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O
IV
I
O
II
CH3
V
F
III
C(CH3)3
Scheme 1. Top – one step reaction used in synthesis of 1,3,4ꢀthiadiazoles. Below – formulae
of substituent present in the studied 1,3,4ꢀthiadiazoles.
Computational details. To understand better the nature of disorder in V, calculations of the
total crystal energy for both possible conformations of V were performed using the PIXEL35ꢀ38
and CRYSTAL0939 programs using the crystallographic structures and lattice parameters as an
input. For the PIXEL calculations, the crystal structures were used to calculate the molecular
electron density by standard quantum chemical methods using GAUSSIAN40 (GAUSSIAN98
version) at the MP2/6ꢀ31G** level of theory. Electron density model of the molecule was
then analysed using the PIXEL program package which allows for calculation of dimer and
cohesive energies. A cluster of molecules of radius 18 Å was used for lattice energy
evaluation. PIXEL provides crystal cohesive energy and also its partition into electrostatic,
polarisation, dispersion, and repulsion components.
The CRYSTALEXPLORER41 program (CRYSTALEXPLORER17 version) was also used to
evaluate interaction energies for selected dimers present in II and V. Similarly as in PIXEL,
the total energy of a given dimer is equal to the sum of electrostatic, polarisation, dispersion
and exchangeꢀrepulsion components. The molecular electron density was calculated at the
DFT(B3LYP)/6ꢀ31G** level of theory using the aboveꢀdescribed CRYSTALꢀoptimised
molecular geometries. The dimer interaction energies were further utilized to generate the soꢀ
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called energy frameworks. For more details of theoretical computations see the Supporting
Materials.
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Spectroscopic methods. Electronic absorption spectra were recorded at 23oC on a doubleꢀ
beam UVꢀVis spectrophotometer Cary 300 Bio (Varian, USA) equipped with a thermostated
cuvette holder with a 66 multicell Peltier block. Temperature was controlled with a
thermocouple probe (Cary Series II, Varian, USA), placed directly into the quartz cuvette.
The spectra were recorded from 200 to 600 nm.
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Fluorescence synchronous spectra were recorded with a Cary Eclipse spectrofluorometer
(Varian). Resonance light scattering measurements were performed as in Pasternack and
Collings42. The excitation and emission monochromators of the spectrofluorimeter were
scanned synchronously (0.0 nm interval between excitation and emission wavelength), the
slits were set to 1.5 nm.
Results and Discussion
We will first compare molecular geometry of TBD molecules from different structures, and
then describe crystal lattices focusing on intermolecular interactions and packing
arrangements.
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Molecular geometry. The presented structures are composed of the resorcyl ring bonded to
1,3,4ꢀthiadiazole ring at the position 2, in all structures. Different substituents are bonded to
1,3,4ꢀthiadiazole ring at position 5 (see Figure 1). The 5ꢀsubstitutedꢀ(1,3,4ꢀthiadiazolꢀ2ꢀ
yl)benzeneꢀ1,3ꢀdiol subunit in all cases is flat (see Figure 2 (a)). Bond lengths and angles in
the resorcyl ring are practically the same (within the level of errors) in all presented
structures. The orthoꢀhydroxyl group can be oriented either towards the sulphur atom, as in
IV, or towards the nitrogen from the 1,3,4ꢀthiadiazole ring (see structures I, II, III, and
previously studied 1,3,4ꢀthiadiazole13). The structure of V is disordered and both forms occur
in the crystal lattice, but the Va (the “S” conformation) is dominant (~80%). The
intramolecular hydrogen bond OH…N has influence on the geometrical parameters – e.g. in
the “N” conformation, the C8ꢀC9 bond length is shorter and the CꢀOH (ortho hydroxyl group)
bond length is longer than in the “S” conformation (see Figure 2 (b)). Also the C8ꢀC9 bond
length differs between the “N” and “S” conformations by 0.016 Å. The observed shorter C8ꢀ
C9 bond length of the N conformer is also confirmed by quantum chemical calculations for
the isolated molecules.
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The C12ꢀO1 bond lengths (structures II, III, IV and V) vary depending on the position
of the DMSO molecule due to formation of a strong hydrogen bonding between the para-
hydroxyl group and solvent molecule. The average CꢀS bond length is equal to 1.734Å, (with
standard uncertainty of 0.004 Å) while the variation range of this parameter is in the range
from 1.726(1) Å up to 1.738(2) Å, as it can be expected for the single bond of this type43.
For the N2ꢀN3 bond of the 1,3,4ꢀthiadiazole ring, the bond length values are in the range from
1.365(2) up to 1.376(2) Å (on average 1.371 Å, with esd 0.004 Å). These bonds are very
similar for all molecules and exhibit a single bond character. Similarly, the linking C4ꢀC7
bond is 1.468 Å (within the level of errors). The rest of the bond lengths and valence angles in
resorcyl and 1,3,4ꢀthiadiazole rings are very similar to the ones previously described16 .
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(a)
(b)
Figure 2. A comparison of the 1,3,4ꢀthiadiazole molecular geometry of all measured
structures (a). Comparison of selected bond lengths (b). All bond lengths in (b) are in
Å.
Intermolecular interactions and packing motives. Presented structures are stabilized by
hydrogen bonding and, as it could be expected for such aromatic systems, by π..π interactions.
Structure I is the only one from this series which crystallizes without any solvent moleculeꢀ
DMSO ꢀ in the unit cell. Moreover, it crystallizes in the Fdd2 space group. Molecules of TBD
in the N conformation form chains along the b axis via hydrogen bonding between the paraꢀ
hydroxyl group and the nitrogen atom from the thiadiazole ring (see Figure 3 (a)). Along the
c axis, the lattice is stabilized by π..π stacking (see Figure 3(b)). Finally, the a axis chains
form lattice channels, filled with disordered molecules of TBD (see Figure 3 (c) and (d)).
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(a)
(b)
(c)
(d)
Figure 3. Structure I – motives and packing (a) chain (b) stacking (c) channels (d) channel
filled with TBD molecules.
In all other structures, the interactions between 1,3,4ꢀthiadiazole molecule and DMSO are
crucial for the crystal lattice stability: the paraꢀhydroxyl group from the thiadiazole forms a
hydrogen bond with oxygen from DMSO (see Figure 4). In II and V, only one DMSO
molecule is interacting with one paraꢀOH group from TBD, whereas in the case of III, a
bifurcated hydrogen bond is created with one oxygen atom from DMSO accepting two
hydrogen atoms from two different TBD molecules. In the case of IV, the paraꢀOH group
from the resorcyl ring of TBD is disordered and exist in two different hydrogen bonding
patterns: the first one which involves two TBD molecules, and the second one in which
thiadiazole interacts with disordered DMSO molecules.
Faceꢀtoꢀface π…π stacking and CꢀH…O or CꢀH…π interactions are also important for
stabilization of the crystal lattice: In II, IV and V, the TBD molecules are situated in the same
plane and form layers held together by π…π stacking interactions, and are further stabilized
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by weak dispersive CꢀH…O or CꢀH…π interactions with DMSO. In III, the TBD molecule is
substituted by a large nonplanar tertꢀbuthyl group. Due to its steric hindrance, it is not
possible to form such layers in a similar manner as in II, IV and V (see Figure 5). Thus, in
the structure III, the TBD molecules are less planar and the π…π stacking interactions mostly
occur between the resorcinol rings. Additionally, the structure III is the only one from this
series in which the TBD molecules are perpendicular one to another due to the CꢀH…C
interactions between the tert-buthyl groups from the neighboring molecules and due to the
CꢀH…π interactions.
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Structure V exhibits similar packing motives as structure II. Layers of the thiadiazole
molecules are held together by interactions with DMSO in one direction and by stacking
interactions in the others. However, a closer look at these structures reveals some important
differences between the structures. Within a layer, the thiadiazole molecules are shifted in
different directions in both structures, and in the case of II, TBD adopts the “N”
conformation. In the case of V, static disorder is present and both the “S” (Va) and “N” (Vb)
conformations occur in the crystal lattice with the occupancies ca. 80% for Va (the “S”
conformation) and ca. 20% for Vb (the “N” conformation).
There are important questions which arise from structural analysis: why for the structures II
and V, which are stabilized in similar manner, the TBD molecules adopt two different
conformations? Why a static disorder is present in V?
To address these questions, we performed a series of theoretical computations for the isolated
molecules and for the crystal lattices.
(a)
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(b)
(c)
(d)
(e)
Figure 4. Hydrogen bonding and stacking interactions for (a) II (b) III (c) IV (disorder in
DMSO and hydroxyl groups was removed for clarity of presentation) (d) Va (e) Va.
(a)
(b)
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(c)
(d)
Figure 5. Packing of molecules in the crystal structures of: (a) II, (b) III, (c) IV and (d) V. .
Single molecule theoretical calculations in Gaussian09
DFT theoretical calculations for differently substituted TBD isolated molecules show that the
most energetically favourable conformation is the “N” one. The energy for the “S”
conformation is approximately 35 kJ/mol higher than for “N” (see Figure 6). The rotational
barrier between these two forms is 50 kJ/mol. Although the form IV has the highest
calculated energy for the “S” conformation for the isolated molecule, this conformation is
preferred in the crystal lattice. In Figure 6, the arrow indicates the rotation angle for which
the hydrogen from the ortho-hydroxyl group is rotated by 180o.
For all studied compounds, the replacement of a substituent does not significantly change the
energy values for the rotational barrier. Therefore, one may assume that during lattice
formation the change of conformation from N to S may take place when there is a possibility
of creating intermolecular interactions which will compensate the 35 kJ/mol energy difference
between the two conformations.
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0
H
O
N
S
HO
N
HO
R
H
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I
II
III
IV
V(FꢀS)
V(FꢀN)
0
20 40 60 80 100 120 140 160 180
Rotation [deg]
Figure 6. Potential energy changes as a function of the resorcyl group rotation. In the case of
V, one considered two orientations of oꢀfluorobeneze ring: fluorine towards S (FꢀS) or
towards N (FꢀN) atoms.
For the disordered V, in which both the “S” and “N” conformations exist concurrently, we
conducted theoretical computations in order to better understand the nature of disorder.
Electrostatic potentials generated for thiadiazole molecule from V mapped on the Hirshfeld
surface clearly shows that the rotation of the ring mostly affects the dihydroxybenzene ring.
(a)
(b)
Figure 7. Electrostatic potential mapped on Hirshfeld surface for structure V in the “S” (a)
and “N” (b) conformations.
Additionally, we have decided to investigate which interactions stabilize the lattice when the
TBD molecules are in the “S” or “N” conformations. We conducted theoretical computations
of the lattice energies for Va and Vb, in which only one disordered part was used, while the
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second part was artificially removed. Lattice energies computed using CRYSTAL09 and
PIXEL (for calculations details see the Supporting Materials) approaches are presented in
Table I. A comparison of the results obtained for Va and Vb shows that the crystal lattice of
Va with the “S” conformation has 26.6 kJ/mol and 19 kJ/mol lower energy according to
CRYSTAL09 and PIXEL, respectively, than the crystal lattice build of the conformers Vb
(“N”). This result was in line with our expectations, that Va, which we found in the crystal
structure with higher occupancy (80%), is lower in energy despite the energy difference
between Va and Vb being significant. Moreover, this difference was also observed when we
compared the total energies from CRYSTAL09 (see the Supporting Materials).
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Table I. Calculated lattice energies for Va and Vb groups from CRYSTAL09 (DFTꢀD/6ꢀ
31G**) and PIXEL.
Disordered part id
Va (“S”)
CRYSTAL09
PIXEL
ꢀ136.9 kJ/mol
ꢀ117.6 kJ/mol
ꢀ275.60 kJ/2mol, so it is ꢀ137.8 kJ/mol
ꢀ222.44 kJ/2mol, so it is ꢀ111.2 kJ/mol
Vb (“N”)
We have also obtained dimer interaction energies from PIXEL calculations. Table II
shows the values of interaction energies between the neighbouring molecules used for the
total lattice energy estimation.
It appears, that the main difference between Va and Vb is related to the intermolecular
hydrogen bond formed between the 1,3,4ꢀthiadiazole molecules in Va, and which is not
observed in Vb. The importance of this interaction for stability of the lattice is clearly
observed in the energy framework (Figure 8 ꢀ Va and Vb, views along the a and c axes). The
total energy calculated for such dimer interactions was 65 kJ/mol, higher than needed to
change conformation from “N” to “S”.
The energies of other interactions between neighbouring 1,3,4ꢀthiadiazole molecules
in Va and Vb deviate by around 10%, except for the molecule (e) for which the energy of
interactions is 10 kJ/mol lower than for Va (see Figure 8 and Table II).
According to our PIXEL calculations, the total dispersion energy value for Va is ca.
10% higher than for Vb. When the energy of the hydrogen bond in Va is not considered, the
dispersion energy dominates in both crystal lattices. In both of these, the interactions between
1,3,4ꢀthiadiazole and DMSO solvent molecules are similar. In this case, the strongest
interaction for Va and Vb is observed for the 1,3,4ꢀthiadiazole molecule and the (f) DMSO
moiety (see Figure 8 and Table II). This interaction is related to another hydrogen bond
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between the para-hydroxyl of the resorcyl ring and the oxygen from DMSO molecule. Other
interaction energies were less than 5 kJ/mol, except 1,3,4ꢀthiadiazole – DMSO (g) energy of
which is ꢀ9.2kJ/mol lower for Va than for Vb. This deviation is related to the opposite
orientation of the resorcyl group in the crystal lattice. The contribution to the crystal lattice
energy from the solvent – 1,3,4ꢀthiadiazole interaction is ~ꢀ100 kJ/mol and is ꢀ6 kJ/mol lower
for Va. The complementarity of electrostatic and dispersion contributions to the total energy
is visible on the energy frameworks.
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As the packing of II and V is similar and in II, the thiadiazole molecule adopts the
“N” conformation, the energy frameworks generated for this structure appear to be similar to
those generated for Vb (Figure 9). Although the “S” conformation could be energetically
more favourable, due to presence of a methyl group in the para-position in benzene ring of II,
the neighbouring TBD molecules are oriented in such way that formation of a hydrogen bond
between them is impossible.
Va
Vb
Figure 8. (a) Interactions of the central 1,3,4ꢀthiadiazole molecule with the neighbouring
molecules and DMSO solvent in crystal lattice of Va, (b) similar interactions in the
crystal lattice of Vb.
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Table II. Selected energies of interactions between the closest molecules in the crystal lattices
of Va and Vb calculated using the PIXEL program. The Rdist symbol denotes the
distance between the centers of mass of the neighboring molecules in
values are in kJ/mol.
Å . All energy
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Molecule
from
Rdistt
Ecoul
Epol
Edisp
Erep
Etot
Figure 8
a
b
c
d
e
f
6.990
ꢀ10.5
ꢀ9.1
ꢀ95.5
ꢀ95.5
ꢀ0.1
ꢀ16.2
ꢀ5.8
ꢀ1.9
ꢀ0.4
ꢀ2.6
ꢀ5.9
ꢀ84.3
ꢀ14.9
ꢀ12.8
ꢀ10.8
ꢀ3.6
ꢀ3.6
ꢀ8.7
ꢀ11.0
ꢀ8.8
ꢀ2.5
1.1
ꢀ6.1
ꢀ5.3
ꢀ54.9
40.1
22.6
ꢀ31.4
ꢀ27.0
ꢀ65.0
ꢀ65.0
ꢀ18.1
ꢀ41.3
ꢀ12.2
ꢀ5.4
Va
Thiadiazoleꢀ
5.513
7.502
7.502
7.653
3.547
6.000
9.932
9.711
8.552
9.949
9.001
7.490
6.843
5.954
7.502
7.502
7.243
3.682
6.023
9.966
9.640
8.354
9.909
9.062
7.640
ꢀ35.1
ꢀ38.3
ꢀ38.3
ꢀ21.2
ꢀ83.0
ꢀ16.7
ꢀ12.6
ꢀ4.7
ꢀ55.0
ꢀ55.0
ꢀ4.1
ꢀ12.3
ꢀ4.9
ꢀ3.7
ꢀ1.4
ꢀ1.9
ꢀ1.8
ꢀ41.7
ꢀ6.4
ꢀ4.6
ꢀ4.7
ꢀ5.7
ꢀ5.7
ꢀ3.9
ꢀ7.6
ꢀ5.4
ꢀ3.1
ꢀ1.1
ꢀ2
123.7
123.7
7.3
thiadiazole
70.2
15.2
12.7
0.5
ThiadiazoleꢀDMSO
a
b
c
d
e
f
ꢀ6.0
ꢀ8.8
8.7
ꢀ4.6
ꢀ6.8
6.1
ꢀ8.4
ꢀ19.4
ꢀ20.5
ꢀ51.8
ꢀ34.7
ꢀ25.7
ꢀ25.7
ꢀ31.0
ꢀ72.5
ꢀ17.2
ꢀ12.4
ꢀ4.7
94.7
23.7
34.6
25.2
18.9
18.9
15.6
53.2
14.7
11.4
0.6
ꢀ50.7
ꢀ18.1
ꢀ34.7
ꢀ25.0
ꢀ16.1
ꢀ16.1
ꢀ27.9
ꢀ37.9
ꢀ16.8
ꢀ6.6
g
a
b
c
d
e
f
Vb
Thiadiazoleꢀ
thiadiazole
ThiadiazoleꢀDMSO
a
b
c
d
e
f
ꢀ4.1
ꢀ3.5
ꢀ6
ꢀ9.3
9.7
ꢀ5.2
ꢀ2.1
ꢀ38.5
ꢀ2.7
ꢀ7.1
7.2
ꢀ7.9
ꢀ81.2
ꢀ2
ꢀ18.7
ꢀ14
88.5
9.7
ꢀ49.9
ꢀ8.9
g
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ETotal
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Vb
a
II
b
Figure 9. Energy frameworks computed for Va, Vb and II, for structure V along the a
direction, for structure II along the b direction. See Supporting Materials for more directions.
The high difference in energy between these two structures Va and Vb suggests that
only the conformation “S” should be observed in crystal. However structure V consist in 80%
from Va and 20% of Vb components. Obviously, this is not only minimization of lattice
energy or even not minimization of total electronic energy which is the main driving force
formation of a given structure, but minimization of Gibbs free energy. Therefore, important
contributions to Gibbs free energy arises from entropy as well, and in case of disordered
structures conformational entropy, related to disorder can have significant contribution to
Gibbs energy.
Assuming an random distribution among two sites we estimated entropy of mixing of Va and
Vb (see Supporting Materials). According to our considerations, disorder is lowering free
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energy by c.a. 1.2 kJ/mol at room temperature. The difference in electronic energy between
Va and Vb is around 20 kJ/mol. Therefore, we think that disorder in V is more related to
kinetics.
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To rationalise results of crystallisation of V from methanol and DMSO, Resonance
Light Scattering spectroscopy (RLS) measurements were conducted. The RLS effect is
observed as increased scattering intensity at, or very near, the wavelength of absorption of an
aggregated molecular species. RLS is commonly used to investigate chromophore aggregates.
Light scattering experiments are usually performed at wavelengths far away from absorption
bands. However for species that aggregate, a significant enhancements in light scattering of
several orders of magnitude can be observed at the wavelengths characteristic for these
species. The effect can be enhanced by several orders of magnitude when strong electronic
coupling exists among the chromophores. In addition, the wavelength dependence of this
technique allows for selective observation of aggregates, even in multicomponent systems
that include a large fraction of monomers or other aggregates. Resonance light scattering
appears to be both a sensitive and selective method to study electronically coupled
chromophore aggregates. We think that RLS could be an informative method of studying of
crystallisation processes.
A strong band in the RLS spectrum is present only in the presence of intermolecular
chromophore ꢀ chromophore interactions in the solution. The band is a highly sensitive and
selective tool which allows the tracing of the aggregation of molecules and their interactions
with molecules of solvents. The intensity of the band increases with the concentration of the
aggregates. Figure 10 (a) shows an electronic absorption spectra of V with absorption bands
at 337 and 342 nm in methanol and DMSO, respectively. These bands appear at shorter wave
lengths than the bands present in the RLS spectra because they were obtained at low
concentration in appropriate solutions. Figure 10 (b) shows the RLS spectra of 1,3,4ꢀ
thiadiazole (compound V) in methanol as a function of different concentration of V. It can be
seen that for the concentration of 4.48 mmol/l, which is ~50% saturated, a band related to
chromophoreꢀchromophore aggregates is clearly seen around 530 nm. This means that
interactions between moieties of V are stronger than those between V and the methanol
molecules. The impact of this type of interaction leads to the creation of dimers and then of
larger aggregates. As we were unable to crystallise any single crystals of V from methanol,
apparently the created aggregates must be disordered and their formation does not promote
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crystallisation process. However, this band is not observed in the saturated solutions of
DMSO. This suggests that that 1,3,4ꢀthiadiazole in DMSO is mostly in the monomeric state in
the solution. This could be due to stronger interactions with the solvent moieties in this case.
One can see consequences of these strong interactions with solvent molecules in the form of
crystallisation of solvates in the solid state.
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Figure 10 (a) Electronic absorption spectra of molecule V. Resonance light Scattering spectra
of molecule V in (b) methanol and (c) in DMSO. Concentrations are expressed in mmol/l.
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The observed structural changes in the 5ꢀsubstitutedꢀ(1,3,4ꢀthiadiazolꢀ2ꢀyl)benzeneꢀ
1,3ꢀdiol subunits of thiadiazoles are small and dependent on the substituted group. The
resorcyl ring can be oriented with respect to the 1,3,4ꢀthiadiazole ring in two orientations with
the ortho-hydroxyl group directed either to the nitrogen atom “N” conformation or to the
sulfur atom “S” conformation. The exact conformation depends on the creation of
intermolecular hydrogen bonds in the crystal lattice. The calculated energy for the single
molecule differs between the two conformations “S” and “N” around 35 kJ/mol. Due to
presence of intermolecular interactions, this energy difference can be easily overruled.
Additionally, the observed intramolecular hydrogen bonds in II and III are
responsible for elongation of the CꢀO bond length (between oxygen from ortho-hydroxyl
group and C from the resorcyl ring) and the shortening of the CꢀC bond length between the
resorcyl ring and the 1,3,4ꢀthiadiazole ring, which is confirmed by results of the quantum
chemical calculations. Structure I does not include any DMSO molecules in the crystal lattice.
In its crystal lattice, disordered molecules occupy structural channels in the ordered skeleton.
This specific crystal lattice pattern differs significantly from the other ones presented as the
role of intermolecular bonding of the ortho hydroxyl group from resorcyl ring is minimized.
This rationalizes the presence of the “N” conformation in this case. In II, III, IV, and V,
interactions with DMSO molecules significantly stabilize the crystal structure. The DMSO
molecules strongly interact with the para-hydroxyl groups from the resorcyl ring and also
through vdW interactions with the hydrophobic parts of the 1,3,4ꢀthiadiazoles.
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In the solution, the dominant “N” conformation of the studied 1,3,4ꢀthiadiazoles is
energetically more favourable then the other conformation. In the bulk crystal, ring rotation is
forbidden due to specific sandwich like packing and strong interactions between rings. This
suggests that molecules in the structures IV and V transfer to the “S” conformation on the
crystal surface during crystal growth when strong intermolecular hydrogen bond can be
created.
Structure V exhibits static disorder, and both conformations “S” and “N” appear in
the crystal lattice. Such structures are still a challenge for crystal structure prediction methods:
as energy difference between the created lattices for different components is ca 20 kJ/mol in
favour of the “S” conformation. Thus, the structures would be predicted to be in “S”
conformation. However 20% of Vb still appears in crystal V and the effect has to be related to
the crystal growth mechanism.
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We found that DMSO is a good solvent for crystal growth for this group of
compounds. The fact that they can be grown as solvates from DMSO and are difficult to be
grown from methanol can be rationalise on the basis of RLS spectra.
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Supporting Materials
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CCDC 1816158ꢀ1816162 entries contain the supplementary crystallographic data for I, II,
III, IV and V crystals. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
AAH thanks for a financial support from the Polish Ministry of Science and Higher
Education within the Iuventus grant number IP 2011017671. The study was carried out at the
Biological and Chemical Research Centre, University of Warsaw, established within the
project coꢀfinanced by European Union from the European Regional Development Fund
under the Operational Programme Innovative Economy 2007–2013. Calculations were
carried out using resources provided by the Wrocław Centre for Networking and
Supercomputing (Grant 115). KW acknowledges the Polish National Science Centre (NCN)
MAESTRO grant decision number DEC2012/04/A/ST5/00609.
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References
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1. Hu, Y.; Li, C.ꢀY.; Wang, X.ꢀM.; Yang, Y.ꢀH.; Zhu, H.ꢀL., 1,3,4ꢀThiadiazole: Synthesis,
Reactions, and Applications in Medicinal, Agricultural, and Materials Chemistry. Chemical
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Interplay of interꢀ and intramolecular interactions in crystal structures of 1,3,4ꢀ
thiadiazole resorcinol derivatives.
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Anna A. Hoser, Daniel M. Kamiński, Alicja Skrzypek, Arkadiusz Matwijczuk, Andrzej
Niewiadomy, Mariusz Gagoś and Krzysztof Woźniak
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TOC GRAPHICS
Synopsis:
The 1,3,4ꢀthiadiazole derivatives occur in two possible conformations in their crystal
lattices: with the orthoꢀhydroxyl group of the resorcyl ring pointing towards the S or the N
atoms from the 1,3,4ꢀthiadiazole ring. In the latter conformation, an intraꢀmolecular hydrogen
bond is created which is energetically favourable for the isolated. However, for the molecules
in the former conformation, some intermolecular interactions between the neighbouring
molecules are strong enough to overrule the intramolecular OH…N hydrogen bond.
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