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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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Crystal Growth & Design

Interplay of inter- and intramolecular interactions in crystal structures of 1,3,4-thiadiazole 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

1

Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warszawa, Poland 2 Department of Chemistry, Maria Curie-Skłodowska University, pl. Marii Curie-Skłodowskiej 2, 20-031 Lublin, Poland 3 Department of Chemistry, University of Life Sciences in Lublin, Akademicka 15, 20-950 Lublin, Poland 4 Department of Biophysics, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland 5 Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warszawa, Poland 6 Department of Cell Biology, Institute of Biology and Biotechnology, Maria Curie-Skłodowska University, 20-033 Lublin, Poland

* Corresponding authors:

Anna A. Hoser ([email protected]), Krzysztof Woźniak ([email protected])

Keywords: 1,3,4-thiadiazole, structure, intermolecular interactions, resonance light scattering, crystal growth mechanism, theoretical calculations

Abstract 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 substituent on molecular geometry and the 3D arrangement of molecules has been studied by means of single crystal X-ray diffraction, fluorescence, UV-Vis spectroscopy and computational methods. The 1,3,4-thiadiazole derivatives occur in two possible conformations in their crystal lattices: with the ortho-hydroxyl group of the resorcyl ring pointing towards the S or the N atoms from the 1,3,4-thiadiazole ring. In the latter conformation, an intramolecular 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 1,3,4-thiadiazole 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 1,3,4-thiadiazole derivatives can be grown form DMSO and are difficult to be grown from methanol solution. 1 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 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

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Introduction Thiadiazole is a five-membered heterocyclic system containing two nitrogen and one sulphur atoms. There are several isomers of thiadiazole including 1,2,3- thiadiazole, 1,2,4thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole. Many thiadiazole derivatives exhibit well documented anti-inflammatory, analgesic activity, and anticancer activity1. They also demonstrate their potential applications in medicine. The 1,3,4-thiadiazole derivatives (TBD) presented in this work (see Figure 1) have antifungal and AChE/BuChE inhibitory activity2 as well as antitumor3, anti-inflammatory4 and antimicrobial5 properties. Additionally, the group of the 1,3,4-thiadiazol 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 1,3,4-thiadiazols are also ligands, forming complexes with metal ions of the d block9. The 1,3,4-thiadiazols 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 co-crystallization12,13. Bis(pirydyl)thiadiazoles were effectively used in MOF synthesis14 to create novel metal–organic architectures. Regarding crystallographic studies of 1,3,4-thiadiazoles: crystal structures of 2-benzamido-5-(4-fluoro-3phenoxyphenyl)-1,3,4-thiadiazoles derivatives have been studied with systematic variation in the functional group at the para position of the benzamido ring15. Crystallisation of the 2-(4fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole

(FABT)

from

DMSO

16

provides two different polymorphic forms of FABT/DMSO solvates , whereas crystallization from water solutions of different alcohols, such as methanol, propan-2-ol, and butanol, with addition of HCl, provides different solvates of 2-(4-fluorophenylamino)-5-(2,4dihydroxy-phenyl)-1,3,4-thiadiazole chloride17. Here, we will focus on (X-1,3,4-thiadiazol-2-yl)benzene-1,3-diols. Depending on the substituent, the (X-1,3,4-thiadiazol-2-yl)benzene-1,3-diol 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 O-H…N. The presence of this pseudo heteroaromatic ring has several consequences on the structure and properties of TBDs, e.g., the O-H…N 2 ACS Paragon Plus Environment

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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 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) Six-membered-ring intramolecular hydrogen bonds are formed in preference to intermolecular hydrogen bonds. (3) The best proton donors and acceptors remaining after intramolecular hydrogen-bond 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 six-membered 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 accomplished23-25, although studied systems were different than ours. The following new derivatives of (1,3,4-thiadiazol-2-yl)benzene-1,3-diols have been studied: (I) 4-[5-phenyl)-1,3,4-thiadiazol-2-yl]benzene-1,3-diol, (II) 4-[5-(4-methylphenyl)1,3,4-thiadiazol-2-yl] benzene-1,3-diol, (III) 4-[5-tert-butylphenyl)-1,3,4-thiadiazol-2-yl]benzene-1,3-diol,

(IV)

4-[5(1,3-benzodioxol-5-yl)-1,3,4-thiadiazol-2-yl]-benzene-1,3-diol,

(V) 4-[5-2-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzene-1,3-diol (see Figure 1). In this work, we present the structures of these compounds and discuss the implications resulting from the interplay between the intra- and intermolecular 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)

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(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 5-substituted-(1,3,4-thiadiazol-2-yl)benzene-1,3-diol derivatives (I - V) were synthesized by the reaction of commercially available hydrazides with sulphinylobis [(2,4-dihydroxyphenyl)methanethion (STB) in methanol at reflux (2.5-3h) 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

2,4-

29

dihydroxybenzenecarbodithioic acid and SOCl2 in diethyl ether to give the 1,3,4-thiadiazole ring. The reaction products were recrystallized from methanol several times until ~95% purity was achieved. The sulphur was removed post-reaction by heating the mixture in hexane at its boiling point. The compounds were crystallized from dimethyl sulfoxide (DMSO) (at room temperature for 2-3 weeks). All solvents used were purchased from Sigma-Aldrich. X-ray diffraction measurements. Single crystal X-ray diffraction data for I and IV were collected on a single-crystal Agilent Technologies SuperNova X-ray diffractometer, whereas II and III on X-ray κ-axis 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 least-square refinements were carried out based on the fullmatrix least-squares 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 multi-scan 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 ortho-hydroxyl group of the resorcyl ring pointing towards the S or the N atoms from the 1,3,4-thiadiazole 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 R

C

H N

NH 2

R

S

STB MeOH, ∆ 2,5 - 3 godz.

5

HO

2

O

N

N

R: O

IV

I

O

II

CH3

V F

III C(CH 3 )3

Scheme 1. Top – one step reaction used in synthesis of 1,3,4-thiadiazoles. Below – formulae of substituent present in the studied 1,3,4-thiadiazoles.

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 PIXEL35-38 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 MP2/6-31G** 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 exchange-repulsion components. The molecular electron density was calculated at the DFT(B3LYP)/6-31G** level of theory using the above-described CRYSTAL-optimised molecular geometries. The dimer interaction energies were further utilized to generate the so6 ACS Paragon Plus Environment

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called energy frameworks. For more details of theoretical computations see the Supporting Materials. Spectroscopic methods. Electronic absorption spectra were recorded at 23oC on a doublebeam UV-Vis 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. 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 1,3,4-thiadiazole ring at the position 2, in all structures. Different substituents are bonded to 1,3,4-thiadiazole ring at position 5 (see Figure 1). The 5-substituted-(1,3,4-thiadiazol-2yl)benzene-1,3-diol 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 ortho-hydroxyl group can be oriented either towards the sulphur atom, as in IV, or towards the nitrogen from the 1,3,4-thiadiazole ring (see structures I, II, III, and previously studied 1,3,4-thiadiazole13). 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 C8-C9 bond length is shorter and the C-OH (ortho hydroxyl group) bond length is longer than in the “S” conformation (see Figure 2 (b)). Also the C8-C9 bond length differs between the “N” and “S” conformations by 0.016 Å. The observed shorter C8C9 bond length of the N conformer is also confirmed by quantum chemical calculations for the isolated molecules. The C12-O1 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 parahydroxyl group and solvent molecule. The average C-S 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 N2-N3 bond of the 1,3,4-thiadiazole 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 C4-C7 bond is 1.468 Å (within the level of errors). The rest of the bond lengths and valence angles in resorcyl and 1,3,4-thiadiazole rings are very similar to the ones previously described16 .


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(a)

(b) Figure 2. A comparison of the 1,3,4-thiadiazole 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 moleculeDMSO - 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 parahydroxyl 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)). 9 ACS Paragon Plus Environment


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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 1,3,4-thiadiazole molecule and DMSO are crucial for the crystal lattice stability: the para-hydroxyl 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 para-OH 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 para-OH 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. Face-to-face π…π stacking and C-H…O or C-H…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 10 ACS Paragon Plus Environment

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by weak dispersive C-H…O or C-H…π interactions with DMSO. In III, the TBD molecule is substituted by a large nonplanar tert-buthyl 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 C-H…C interactions between the tert-buthyl groups from the neighboring molecules and due to the C-H…π interactions. 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.



60

O

H N

HO

N

HO

50

S

R H

Energy kJ/mol

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 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

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40 30 I II III IV V(F-S) V(F-N)

20 10 0 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 o-fluorobeneze ring: fluorine towards S (F-S) or towards N (F-N) 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 14 ACS Paragon Plus Environment

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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).

Table I. Calculated lattice energies for Va and Vb groups from CRYSTAL09 (DFT-D/631G**) and PIXEL. Disordered part id

CRYSTAL09

PIXEL

Va (“S”)

-275.60 kJ/2mol, so it is -137.8 kJ/mol

-136.9 kJ/mol

Vb (“N”)

-222.44 kJ/2mol, so it is -111.2 kJ/mol

-117.6 kJ/mol

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 1,3,4-thiadiazole 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 1,3,4-thiadiazole 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 1,3,4-thiadiazole and DMSO solvent molecules are similar. In this case, the strongest interaction for Va and Vb is observed for the 1,3,4-thiadiazole molecule and the (f) DMSO moiety (see Figure 8 and Table II). This interaction is related to another hydrogen bond 15 ACS Paragon Plus Environment


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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 1,3,4-thiadiazole – 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 – 1,3,4-thiadiazole 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. 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 1,3,4-thiadiazole 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 Å . All energy values are in kJ/mol. Molecule

Rdistt

Ecoul

Epol

Edisp

Erep

Etot

from Figure 8 Va Thiadiazole-

thiadiazole

Thiadiazole-DMSO

Vb Thiadiazole-

thiadiazole

Thiadiazole-DMSO

a b c d e f a b c d e f g a b c d e f a b c d e f g

6.990 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

-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 -3.5 -6 -81.2 -2

-6.1 -5.3 -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 -2.1 -38.5 -2.7

-54.9 -35.1 -38.3 -38.3 -21.2 -83.0 -16.7 -12.6 -4.7 -8.8 -6.8 -19.4 -20.5 -51.8 -34.7 -25.7 -25.7 -31.0 -72.5 -17.2 -12.4 -4.7 -9.3 -7.1 -18.7 -14

40.1 22.6 123.7 123.7 7.3 70.2 15.2 12.7 0.5 8.7 6.1 94.7 23.7 34.6 25.2 18.9 18.9 15.6 53.2 14.7 11.4 0.6 9.7 7.2 88.5 9.7

-31.4 -27.0 -65.0 -65.0 -18.1 -41.3 -12.2 -5.4 -6.0 -4.6 -8.4 -50.7 -18.1 -34.7 -25.0 -16.1 -16.1 -27.9 -37.9 -16.8 -6.6 -4.1 -5.2 -7.9 -49.9 -8.9



ECoulomb

EDispersion

Page 18 of 26

ETotal

Va a

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 18 ACS Paragon Plus Environment

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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.

Differences in crystallisation of V from methanol and DMSO 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 1,3,4thiadiazole (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 chromophore-chromophore 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 19 ACS Paragon Plus Environment


Page 20 of 26

crystallisation process. However, this band is not observed in the saturated solutions of DMSO. This suggests that that 1,3,4-thiadiazole 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.

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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Conclusion The observed structural changes in the 5-substituted-(1,3,4-thiadiazol-2-yl)benzene1,3-diol subunits of thiadiazoles are small and dependent on the substituted group. The resorcyl ring can be oriented with respect to the 1,3,4-thiadiazole 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 C-O bond length (between oxygen from ortho-hydroxyl group and C from the resorcyl ring) and the shortening of the C-C bond length between the resorcyl ring and the 1,3,4-thiadiazole 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 1,3,4-thiadiazoles. In the solution, the dominant “N” conformation of the studied 1,3,4-thiadiazoles 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.

Supporting Materials CCDC 1816158-1816162 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 co-financed 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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For Table of Contents Use Only Interplay of inter- and intramolecular interactions in crystal structures of 1,3,4thiadiazole resorcinol derivatives. Anna A. Hoser, Daniel M. Kamiński, Alicja Skrzypek, Arkadiusz Matwijczuk, Andrzej Niewiadomy, Mariusz Gagoś and Krzysztof Woźniak

TOC GRAPHICS

Synopsis: The 1,3,4-thiadiazole derivatives occur in two possible conformations in their crystal lattices: with the ortho-hydroxyl group of the resorcyl ring pointing towards the S or the N atoms from the 1,3,4-thiadiazole ring. In the latter conformation, an intra-molecular 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.


Interplay of Inter- and Intramolecular Interactions in ... - ACS Publications

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