Polymorphism and Isostructurality of the Series of 3 - ACS Publications

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Polymorphism and isostructurality of the series of 3-(4,5diaryl-4H-1,2,4-triazole-3-yl)propenoic acid derivatives Liliana Mazur, Anna E. Koziol, Katarzyna N. Jarzembska, Renata Paprocka, and Bozena Modzelewska-Banachiewicz Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00080 • Publication Date (Web): 13 Mar 2017 Downloaded from http://pubs.acs.org on March 19, 2017

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Crystal Growth & Design

Polymorphism and isostructurality of the series of 3-(4,5-diaryl-4H-1,2,4-triazole-3-yl)propenoic acid derivatives

Liliana Mazur,a* Anna E. Koziol,a Katarzyna N. Jarzembska,b Renata Paprocka,c Bożena Modzelewska-Banachiewiczc

a

Faculty of Chemistry, Maria Curie-Skłodowska University, Maria Curie-Skłodowska Sq. 2, 20-031 Lublin, Poland

b

Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warszawa, Poland

c

Department of Organic Chemistry, Faculty of Pharmacy, Nicolaus Copernicus University in Toruń, Jurasza 2, 85-089 Bydgoszcz, Poland

* Corresponding author. E-mail: [email protected].

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Abstract: Polymorphism of four biologically active 3-(4,5-diaryl-4H-1,2,4-triazole-3yl)propenoic acid derivatives has been investigated. Traditional solution-based solidstate forms screening revealed three anhydrous forms of 3-[4-phenyl-5-(2-pyridyl)-4H1,2,4-triazole-3-yl]propenoic acid. Noteworthy, two pairs of concomitant polymorphs were detected for this system. Two other compounds were found to be dimorphic. The molecular and crystal structures of all obtained crystal forms were established by singlecrystal X-ray diffraction. The resulting crystal structures were analysed in terms of molecular conformation, intermolecular interaction patterns and crystal packing motifs. The experimental studies were supported by extended lattice and interaction energy calculations. It was found that the carboxylic group adopts the anti conformation in all studied forms and is involved in the intramolecular O-H…Ntriazole hydrogen bonding. In consequence, the association modes are dominated by the weak C-H…O, C-H…N hydrogen bonds further supported by effective π-stacking interactions between the overlapping triazole-propenoic acid units. Substantial conformational differences between polymorphs result from rotation around the triazole-aryl bonds. The thermodynamic relationships between polymorphs were investigated by variabletemperature powder diffraction and differential scanning calorimetry. The studies revealed four pairs of enantiotropically-related polymorphs. Transformations between the polymorphs occur in the single-crystal-to-single-crystal mode.

Keywords: 4H-triazoles, polymorphism, phase transitions, isostructurality, X-ray diffraction studies, TGA-DSC studies, periodic calculations

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1. Introduction Polymorphism, i.e. the existence of different crystal forms of the same molecule, has been known for nearly 200 years now.1 Nonetheless, this phenomenon is still highly unpredictable. It appears that a great number of compounds can occur in more than one crystal form.2 Identification and characterization of each form, in particular a thermodynamically stable one under given conditions, is essential for manufacturing, storage and intellectual property rights of chemicals commercialized in the form of crystalline materials (drugs, pigments, agrochemicals, food additives).3 Polymorphism has direct implications for physical, thermodynamic, kinetic and mechanical properties of the compound. Any change in the solid structure can lead to variation of its properties.2,3 In many cases, the cohesive energy differences between polymorphs are of the same order of magnitude as the energetics of modest rotations about single bonds.2,4 This allows flexible molecules to adopt different conformations in the solid state, the phenomenon known as conformational polymorphism.2,3 The conformational differences were observed in the case of many multimorphic drugs, e.g. Sulfapyridine,5 Benperidol,6 Trimethoprim,7 Tolbutamide8 or Aripiprazole.9,10 The last one with its 12 reported anhydrous polymorphs and additionally, eight solvatomorphs,11 is the most polymorphic drug currently known and one of the most flexible organic systems so far discovered. In general, conformational polymorphs are more likely to differ in their properties than packing-type polymorphs of rigid molecules as many physicochemical properties are conformation-dependent. Although it is more difficult to crystallize conformational polymorphs (~36% of all reported polymorphic molecules),2 they are fairly common in the case of temperature or pressure induced phase transitions. Crystallization of a given substance can sometimes result in more than one crystal form, appearing under the same crystallization conditions.12 Although the phenomenon of concomitant polymorphism has a long history,13 it is still not well recognized and difficult to control. Like most chemical processes, crystallization of polymorphic systems is governed by combination of thermodynamic and kinetic factors. Based on the laws of thermodynamics, crystallization must result in overall decrease in free energy of a given system. This drive towards free energy minimization will be balanced by the kinetic tendency of the system to crystallize as quickly as possible to reduce the imposed supersaturation.3 In the case of overlapping occurrence domains for polymorphs, there

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might be conditions under which the nucleation rates of two (or more) forms are nearly equal. Under such conditions polymorphs can crystallize concomitantly.12 In this paper we report the preparation of different crystal modifications of some 3(4,5-diaryl-4H-1,2,4-triazole-3-yl)propenoic

acid

derivatives

(Scheme

1).

The

compounds are particularly interesting due to their effect on the central nervous system which we had previously studied.14 The results confirmed their anticonvulsive activity and potent antinociceptive action. The preliminary results of solid forms screening on 1 – 4, using conventional solvent evaporation technique, revealed propensity of the compounds to polymorphism. In the case of derivative 3 two sets of concomitant polymorphs were detected. Considering the potent pharmaceutical relevance of 1 – 4, the structural properties of all detected crystal forms and the relationship between polymorphs were investigated using such experimental techniques as X-ray crystal structure analysis, powder diffraction (PXRD), thermal analysis (TG-DSC) and IR spectroscopy. The experimental studies were supported by theoretical computations of rotational barriers, lattice energy calculations and intermolecular interaction energies, characterizing most important synthons and structural motifs.

Compound

1

2

3

4

R1

phe

2-py

2-py

4-py

R2

phe

2-py

phe

phe

Residue

Scheme 1. Schematic representation of the molecular structures.

2. Experimental section 2.1. Synthesis and materials. All chemicals and solvents were purchased from commercial sources (Sigma-Aldrich Co., USA, or Polish Chemical Reagents, Poland) and used without further purification. The studied compounds were prepared applying the procedure described in the literature14,15 and purified by crystallization using methanol, ethanol or methanol-water (1:1 v/v) mixture as a solvent. IR spectra of the final samples were recorded on a Nicolet 4


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6700 FT-IR spectrophotometer in the ATR mode (more details in Supporting Information). 2.2. X-ray crystallography. The X-ray diffraction intensity measurements were carried out on an Xcalibur CCD diffractometer using graphite monochromated Mo-Kα radiation (λ = 0.71073 Å) or a SuperNova diffractometer (Cu-Kα radiation λ = 1.54184 Å). Data sets were collected at 120 K (3c) or 100 K (all remaining crystals) using the ω scan technique. The CRYSALIS16 suit of programs was used for data collection, cell refinement and data reduction. A multi-scan absorption correction was applied. The structures were solved using direct methods implemented in the SHELXS-9717 and refined with the SHELXL-97 program17 (both operating under WinGX18). All non-H atoms were refined with anisotropic displacement parameters. The hydrogen atoms in 1, 2a, 2b, 3a, 3b, 3c were found in the difference-Fourier maps and refined with isotropic displacement parameters. The H atoms attached to carbon in 4a and 4b were positioned geometrically and refined using the riding model with Uiso(H)=1.2Ueq(C). The carboxyl H-atoms in all structures were found in the difference-Fourier maps and refined with isotropic displacement parameters. The final data collection parameters and refinement statistics are summarized in Table 1. The CIF files for each refinement are available from the Supplementary Materials, or can be retrieved from the Cambridge Structural Database (CSD)19 (deposition numbers: CCDC 1519714 − 1519721).

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Table 1. Crystal data and structure refinement details. Crystal

1

2a

2b

3a

3b

3c

4a

4b

Formula

C17H13N3O2

C15H11N5O2

C15H11N5O2

C16H12N4O2

C16H12N4O2

C16H12N4O2

C16H12N4O2

C16H12N4O2

Formula weight

291.30

293.29

293.29

292.30

292.30

292.30

292.30

292.30

Crystal system

monoclinic

monoclinic

orthorhombic

monoclinic

monoclinic

monoclinic

monoclinic

orthorhombic

Space group

C2/c

P21/n

P212121

P21/n

C2/c

P21/c

P21/n

Pca21

a/Å

15.011(1)

9.915(1)

6.698(1)

10.096(3)

15.101(1)

7.109(1)

15.216(2)

11.900(2)

b/Å

8.294(1)

8.088(1)

9.666(1)

7.999(2)

8.078(1)

10.167(2)

6.315(1)

16.014(2)

c/Å

22.105(3)

17.134(3)

20.451(3)

17.237(4)

22.089(3)

18.424(3)

15.628(2)

14.077(4)

β/°

92.18(1)

105.22(1)

90

105.07(3)

91.83(1)

91.90(2)

101.43(2)

90

Volume / Å3

2750.1(5)

1325.8(3)

1324.1(3)

1344.2(6)

2693.2(6)

1330.9(4)

1471.8(4)

2682.6(9)

Z

8

4

2

4

8

4

4

8

dcalc / g·cm−3

1.407

1.469

1.471

1.444

1.442

1.459

1.319

1.447

Θ range / °

2.7−27.5

2.5−27.5

2.9−28.3

2.7−27.5

2.9−27.5

4.8−73.9

2.7−27.5

3.2-27.5

µ / mm−1

0.095

0.103

0.103

0.100

0.099

0.825

0.091

0.100

Crystal size / mm3 Crystal colour and form Rint

0.54×0.31×0.05 colourless plate 0.0554

0.45×0.29×0.15 orange plate 0.0360

0.57×0.26×0.04 yellow plate 0.0349

0.61×0.34×0.09 colourless plate 0.0431

0.59×0.11×0.03 colourless needle 0.0270

0.28×0.13×0.02 colourless needle 0.0193

0.47×0.15×0.08 yellow prism 0.0352

0.59×0.25×0.08 orange block 0.0476

Refl coll/unique

9976/3151

5552/3044

10258/3238

5370/3080

6114/3089

5068/2606

10639/3376

8724/4492

Refl with I>2σ(I)

2133

2163

2804

1765

2278

2289

2298

3606

Parameters R1; wR2 [I>2σ(I)] R1; wR2 [all data] GOF on F2

251 0.037; 0.076 0.061; 0.080 0.86

243 0.046; 0.106 0.066; 0.112 0.95

243 0.036; 0.077 0.042; 0.079 0.99

247 0.044; 0.075 0.095; 0.085 0.82

247 0.036; 0.082 0.052; 0.086 0.94

247 0.034; 0.080 0.040; 0.085 1.04

203 0.057; 0.152 0.078; 0.162 1.06

405 0.055; 0.101 0.074; 0.111 1.09

−0.21/0.26

−0.24/0.41

−0.24/0.45

−0.24/0.22

−0.22/0.31

−0.25/0.17

−0.20/0.61

-0.25/0.33

/ e·Å−3

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2.3. Thermal analysis. 2.3.1. TG/DSC studies. The thermal stabilities of 1, 2a, 2b, 3a, 3b, 4a and 4b were evaluated using a Setsys 16/18 (Setaram) thermal analyzer recording the TG/DTG/DSC curves. Crystals obtained from the crystallization batches had been air-dried before they were subjected to DSC or TG analysis. The samples (4 − 7 mg) were heated in a ceramic crucible at a temperature 30 − 700°C in [lowing air atmosphere with a heating rate of 10°C min−1. The mass loss was characterized by TG and calculated based on the original sample mass. The melting-point values (onset points) and the enthalpies of fusion were evaluated from the DSC results. 2.3.2. Thermomicroscopic analysis. The Linkam LTS 350 hot-stage and the polarizing microscope Nikon Eclipse 50iPOL were used for the analysis (Table 5S, Supporting Information). The heating rate was 4°/min. 2.4. X-ray powder diffraction. XRPD patterns were recorded on a PANanalytical Empyrean automated diffractometer with the Bragg-Brentano geometry and a PIXcel detector using Cu-Kα radiation (λ = 1.5406 Å). The patterns were recorded from 6 to 50° on the 2θ scale, using a scan speed of 239 s/0.03. 2.5. Theoretical calculations. All crystal structures were optimized in the CRYSTAL0920,21 program package at the DFT(B3LYP)/6-31G**22-24 level of theory. During the optimization procedure unit cell parameters were kept fixed, whereas the atomic coordinates were varied. Such optimized crystal structures were subjected to crystal cohesive energy evaluation. Cohesive energies were calculated using CRYSTAL09 at the DFT(B3LYP)/pVTZ25-27 level of theory. Both Grimme dispersion correction28,29 and correction for the basis set superposition error (BSSE) were applied. Ghost atoms were selected up to 5 Å distance from the studied molecule in a crystal lattice and served for the basis set superposition error estimation. The evaluation of Coulomb and exchange series was controlled by five thresholds, set arbitrary to the values of 10-7, 10-7, 10-7, 10-7, 10-25. The shrinking factor was equal to 8 which assures the full convergence of the total energy. The cohesive energy (Ecoh) was calculated following the procedure described in the literature30,31:

Ecoh =

1 E bulk − E mol Z

where Ebulk is the total energy of a system (calculated per unit cell) and Emol is the energy of an isolated molecule extracted from the bulk (with the same geometry as in the 7



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optimized crystal structure). Z stands for the number of molecules in the unit cell. Additionally, intermolecular interactions were calculated for a selected set of polymorphs. This was achieved using the supermolecular method at the DFT(B3LYP)/6-31G** level of theory corrected for dispersion via the Grimme approach. In turn, the GAUSSIAN package was employed to calculate two rotation barriers for compound 3 at the DFT(B3LYP)/6-31G** level of theory with the empirical Grimme dispersion correction. Geometry optimisations were performed at each rotational step (every 1°) keeping restricted the respective values of torsion angles (i.e. either τN1-C5-C6-N3 or τC3-N4-C11-C12). All input files for either CRYSTAL or GAUSSIAN programs were prepared using the CLUSTERGEN program.32 3. Results and discussion 3.1. Crystal syntheses and introductory remarks. During screening for the polymorphs of 1 – 4 a standard solvent evaporation technique was applied. For this purpose a range of solvents with diverse polarities and different functional groups was used (more details in Table 2S, Supporting Information). Single crystals 1, 2a, 3a, 3b and 4a suitable for X-ray diffraction, were grown by recrystallization of the samples from dry methanol at room temperature. In the case of derivative 3 two polymorphs (3a, 3b) were detected in the resulting crystalline batch. Concomitant crystallization of 3a and 3b was confirmed by the additional experiments using different organic solvents, i.e. pure ethanol (99.8%), 1-propanol, 2-propanol, 1-butanol, acetone, nitromethane, chloroform, DMF, DMSO. Interestingly, after rapid cooling of hot, saturated solution of 3 in 96.0% ethanol a new polymorph (3c) was identified in a mixture with polymorph 3b. The three polymorphs of 3 crystallize in the monoclinic system (Table 1) but there are visible differences in morphology of the respective crystals. Form 3a crystallizes as wellshaped plates, whereas polymorphs 3b and 3c as needle-like crystals (Figure 1b). Crystallization of derivative 2 from DMF resulted in the orthorhombic chiral crystals 2b (space group P212121). The monoclinic and orthorhombic forms 2a and 2b appear as wellshaped and thin plates (Figure 1a), respectively. In turn, recrystallization of derivative 4 from the methanol/water (3:1 v/v) solution led to the mixture of 4a and the prevalent orthorhombic polar form 4b (space group Pca21). The most frequently appearing less

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dense form 4a crystallizes in the monoclinic system giving yellow, prism-like crystals, whereas the denser orthorhombic polymorph 4b forms orange, block-shaped crystals. Apart from structures 2b and 4b, the studied compounds crystallize in the centrosymmetric space groups (Table 1), and except for 4b, with one molecule in the asymmetric unit. There are extensive similarities in the molecular conformations, intermolecular interaction patterns and unit cell parameters of the pairs of crystals 1, 3b, and also 2a and 3a, which suggests some extent of isostructurallity. This was confirmed by the values of the Kalman similarity indices33 equal to 0.0031 and 0.0055, for the pairs 1/3b and 2a/3a, respectively.

(a)

(b)

Figure 1. Polarized light microscopy images of crystals: (a) 2a, 2b; (b) 3a, 3b, 3c.

3.2. Molecular structure. The molecular plots for the studied compounds with the atom-labelling schemes are presented in Figure 2. The selected geometric parameters are given in Table 3S (Supporting Information). The propenoic acid fragment in all nine conformers adopts the cis configuration which enables creation of an intramolecular O-H…N hydrogen bond (HB), involving the carboxylic COOH group as a donor, and triazole N2 atom as an acceptor (Table 4S). The intramolecular HB stabilizes co-planar arrangement of the carboxyl group and the triazole ring. The dihedral angle between their best planes does not exceed 10°, except for 3c and 2b, where the planes adopt an angle of 18.6(1)° and 21.9(1)°, respectively. Nearcoplanarity of the propenoic acid system and the triazole unit may suggest a high level of the π-electron delocalization. However, the corresponding structural data indicate a clear distinction between the single and double bonds in this part of the molecule. The C2=C4 distances (Table 3S) are in a rather good agreement with a standard C(sp2)=C(sp2) bond 9



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length (1.316 Å, International Tables for Crystallography34). Similarly, the carboxyl C1−O1 and C1=O2 distances are within typical ranges for a neutral COOH group.35

1

2a

3a

4a

Figure 2. Labelling of atoms in the selected conformers and estimation of their thermal motion parameters as ADPs (50% probability level). The displacement ellipsoids diagrams for all remaining molecules are given in Figure 1S (Supplementary Information).

fitting 2a/2b

fitting 4a/4b (mol A & B)

fitting 3a/3b/3c

a)

b)

10


c)

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Figure 3. Molecular overlay of (a) two conformers of 2 (2a – full line, 2b – open line), (b) three conformers of 3 (3a – full line, 3b – open line, 3c – dashed line) and (c) three conformers of 4 (4a – full line, 4b-A – open line, 4b-B – dashed line).

The molecular overlay of 3a, 3b and 3c (Figure 3b) indicates that the essential difference between the conformers in polymorphs is in the relative orientation of 2-pyridyl and phenyl rings with respect to the central triazole. The reorientation of the rings can be described by the torsion angles N1−C5−C6−N3 and C3−N4−C11−C12, which reach the following values: 158.2(2)°, 139.3(1)° and 177.0(1)° in the former case, whereas 105.8(2)°, 119.3(1)° and -100.0(1)° in the latter case for 3a, 3b and 3c, respectively (Table 3S). The planes of two aromatic moieties form the dihedral angle of 76.9(1)°, 54.0(1)° and 79.2(1)° for 3a, 3b and 3c. The torsion-angle-(τ)–constrained scans calculated for the mentioned torsion angles are shown in Figure 4. They indicate that the orientation of both aromatic rings is very much coupled. The optimal N1−C5−C6−N3 torsion angle amounts to about 180°, which means that the 2-pyridyl ring is co-planar with the triazole moiety, while the N3 atom is anti oriented with respect to the N1 atom, as shown in the diagram d in Figure 4a. In turn, the most favourable C3−N4−C11−C12 torsion angle is equal to either 90° or -90° (two equivalent orientations), which means that in the ideal case phenyl and pyridyl rings are perpendicularly oriented one to another (diagram c in Figure 4b). This knowledge implies that the conformer 3c is the most energetically stable one, however, being only about 1-2 kJ·mol-1 more advantageous than 3a. 3b is definitely least favoured, with the molecular energy difference of 6-8 kJ·mol-1. Significant conformational differences between some polymorphs (e.g. forms 3b, 3c), visualised by appropriate torsion-angle values as well as molecular energy differences suggest detection of conformational polymorphs.2 Similarly to 3, in the case of compounds 2 and 4, the substantial differences between the polymorphs and two conformers present in the asymmetric unit of the crystal 4b result from the rotation around the C5−C6 and N4−C11 bonds (Table 3S). Noteworthy, the two six-membered substituents are inclined to each other by 66.4(1)° (4a), 66.1(1)° (4b-A) and 58.7(1)° (4b-B).

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(a)

(b)

Figure 4. Torsion-angle-(τ)–constrained scans calculated for: (a) N1-C5-C6-N3 and (b) C3-N4C11-C12 torsion angles in compound 3 at the DFT(B3LYP)/6-31G** level of theory with the empirical Grimme dispersion correction. Letters a, b, c and d indicate the most relevant points on the obtained energy curves and the corresponding optimised molecular structures.

3.3. Supramolecular structure and intermolecular interactions Among the intermolecular interactions involved in stabilization of crystals 1 - 4 the π…π stacking and weak hydrogen bonds of C−H…O/N/π type36 play a dominant role. The only potent donor, viz. the COOH group, adopts the anti conformation and is involved in the very short, intramolecular O-H…Ntriazole (O…N range 2.559(4) – 2.609(2) Å; Table 4S) hydrogen bond. Thus the presence of numerous HB acceptors (heterocyclic N- and carboxyl O-atoms) and highly polarized C−H groups in all molecules stimulates formation of 12


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weak interactions. In addition, the presence of aromatic rings and planar arrangement of the triazole-propenoic acid unit makes the molecules tend to form stacking arrangements. In order to quantify intermolecular interactions in all studied crystals and elucidate similarities and differences between polymorphs, the Hirshfeld surface analysis37 was performed. The 2D fingerprint plots are shown in Figure 5 (for more details see Figures 3S and 4S, Supporting Information). The percentage contribution of the main intermolecular contacts to the Hirshfeld surfaces is given in Figure 6.

Figure 5. Hirshfeld surface fingerprint plots for all the observed conformers. Fingerprints of the isostructural forms are given in red and green frames (4b-A and 4b-B represent the two crystallographically independent molecules in the form 4b). The plots were prepared using CrystalExplorer.38

An important feature of all fingerprint plots, excluding those for structure 4b, is that they are rather symmetric. This highlights isotropic environment of molecules in the solid state. The two symmetry independent molecules present in crystal 4b are involved in different intermolecular interaction patterns, which is clearly visible from the appropriate 13



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2D plots (Figure 5). In general, two sets of similar structures can be distinguished, i.e. 1 and 3b as well as 2a and 3a, which confirms isostructurality of the corresponding crystals. Another general observation concerns more efficient packing of 2b, 3c and 4b compared to that of other polymorphs, which is reflected by shorter interatomic distances and fewer ‘voids’ in the upper area of the fingerprint plots. In general, it is consistent with the differences in crystal densities (Table 1) calculated from the diffraction data. For all crystal forms, the H…H contacts (33.0 - 40.4%) make the most significant contribution to the total Hirshfeld surfaces (Figure 6), which is a common feature of organic molecular crystals. The moderate double spikes (Figure 5) near de + di ≈ 2.4 Å (where di and de are the distances from the Hirshfeld surface to the nearest atom center inside and outside the surface) illustrate the H…O and H…N contacts resulting from the weak C-H…O and C-H…N hydrogen bonds. Their total contributions range from 15.6% (3a) to 18.5% (4b-B) and from 8.5% (1) to 18.2% (4b-A), respectively. In turn, the wings in the 2D plots constitute a consequence of H…C contacts, corresponding to the C-H…π interactions, which comprise 14.9% (4b-A) – 24.5% (3a) contribution to the Hirshfeld surface. The π…π interactions, which determine the respective molecular orientation, are manifested by short C…N and C…C contacts. The specific C…N interactions, which form characteristic wings with (di + de) ~ 3.3 Å, comprise 2.9% (1) – 6.6% (2a) of the total HS. The meaningful contribution of the C…C contacts is observed only for 3c (7.7%) and 2b (6.1%).

4b

H...H

4a

O...H

3c

N...H C...H

3b

C...C

3a

C...N

2b

C...O

2a

N…N

1

N...O

0%

20%

40%

60%

80%

100%

O...O

Figure 6. Percentage contributions to the Hirshfeld surface for close intermolecular contacts for the molecules in all studied crystals. 14


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The main 1D motif in isostructural crystals 1 and 3b are molecular stacks (Figure 7b), composed of

two

types

of

centrosymmetric

dimers,

propagating

along

the

crystallographic b axis. In the first dimer, the relative orientation of molecules enables short triazole-triazole and aryl-carboxyl contacts. The interaction energy of -72.4 kJ·mol-1 evaluated for such a molecular arrangement in 3b (Supplementary Information) indicates its great stabilizing character. As far as the triazole-triazole contacts are concerned, the interplanar separation (3.592(2); 3.480(1) Å) and the offset values (0.36(1); 0.65(1) Å) suggest antiparallel, slightly displaced π-stacking motifs.39,40 In turn, the aryl-carboxyl interactions manifest themselves by short C1…N3 or C1…C11 distances, being about 3.21 and 3.36 Å, respectively. In the second type of a dimer, the triazole ring of one molecule is ‘covered’ by the carboxyl group of the adjacent molecule and the interplanar distance between the best-planes of triazole-propenoic acid units is ca. 3.35 Å. Such a dimer in the case of 3b is characterized by even more stabilizing energy than the former one, i.e., of 85.3 kJ·mol-1. Similarly, the most characteristic 1D substructures in 3c are the stacks composed of two types of centrosymmetric dimers (Figure 7c) with the interaction energy amounting to either -73.0 kJ·mol-1 or -62.1 kJ·mol-1 (Supplementary Information). However, in this case they propagate along the a axis. One of the dimers, stabilized by the short triazole-triazole (d = 3.307(2) Å) and aryl-carboxyl contacts, resembles the motif observed in crystals 1 and 3b. In the other one the triazole-propenoic acid moieties overlap with the pyridyl rings. The resulting 1D motifs are reinforced by weak C12−H12…N1 (3.545(2) Å, 157(1)˚) and C16−H16…N1 (3.620(2) Å, 145(1)˚) interactions (Table 4S, Figures 7b,c). The crystal network of 3a and 2a can be considered as overlapping double layers. In both structures the n-glide plane related molecules are linked by Caryl−H…Ocarboxyl (3.180(2) – 3.585(3) Å, 134(1) – 149(2)˚; Table 4S) hydrogen bonds into chains propagated along the b axis (Figure 7a). The chains constitute ‘building blocks’ of flat (101) molecular layers, which assemble in an antiparallel and offset manner. Regarding the interactions responsible for stabilization of the double-layer architectures, the π-stacking forces between the overlapping triazole-triazole, triazole-propenoic acid and pyridyl-carboxyl units (Figure 7a) seem to play a dominant role (the corresponding dimer interaction is equal to -69.1 kJ·mol-1, Supplementary Information). Among them the triazole-triazole interactions are most noticeable. The contacts geometry i.e. the interplanar distance (ca. 3.23 Å) and the offset of the ring centers (ca. 1.8 Å) are indicative of slipped stacking 15



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motifs.39,40 A significant contribution to the overall stabilization of the resulting dimers is accomplished by the C12−H12…O1 (3.434(3) Å, 163(3)˚ and 3.435(3) Å, 152(1)˚, respectively) hydrogen bonds. Among the interactions responsible for linking the double layers into the stable 3D supramolecular net, the dipole-dipole interactions between the antiparallel carbonyl groups (Figure 7a) seem to be noticeable. The latter contacts, with the C…O distance of 3.049(2) Å (3a) or 3.066(2) Å (2a) and the O…C=O angle, being 93.8(1)° (3a) and 96.7(1)° (2a), could be associated with the overlapped antiparallel C=O…C=O motifs.41 Noteworthy, these are the only structures in the present work where the carbonyl-carbonyl interactions are observed. These contacts are characterized by a rather significant interaction energy of -23.2 kJ·mol-1 (3a).

(a)

(b)

(c)

16


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Figure 7. Crystal structure of: (a) 3a - π-stacking contacts and C=O…C=O interactions, (101) molecular layer in view along the a axis and crystal packing in view along the b axis showing the inversion related (101) molecular layers interconnected by π…π stacking (grey – green) or C=O…C=O (green - blue) interactions; (b) 3b - molecular stacking motif stabilized by C-H…O/N and π-π interactions, molecular ribbon stabilized via weak C-H…O/N hydrogen bonds, crystal packing viewed along the a axis - one of the (001) molecular layers given in blue; (c) 3c - stacking dimers, part of (100) molecular layer by weak C-H…O/π intermolecular interactions and crystal packing along the b axis.

The most characteristic structural motifs observed in the non-centrosymmetric chiral crystal 2b are the molecular ribbons propagated along the b axis (Figure 8b). The ribbons are constructed by the 21 screw axis related molecules linked by the weak C4−H4…O1,O2 (3.375(3) Å, 123(1)˚ and 3.482(3) Å, 145(1)˚) and C2−H2…O1 (3.375(3) Å, 124(1)˚) hydrogen bonds (Table 4S). It is worth noting that there are short directional contacts between the carbonyl O2 atoms and the pyridyl N5>C15 rings [d(O…πcent(C12-C13)) = 3.282(2) Å; 3b > 3c. Although the form 3c is characterized by the most stable conformation (Figure 4), whereas 3b by the most advantageous cohesive energy, the form 3a is the most stable, because of the overall stability of its crystal lattice (Table 2). The unit cell total energy of 3a exceeds the corresponding values derived for 3b and 3c by about 15 kJ·mol-1, which is not much but probably enough to overcome any differences resulting from the entropy increase in the studied temperature range if these effects are not most favourable for 3a.

22


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Figure 12. PXRD overlay of experimental patterns of sample 2b, recorded at 40°C, 120°C and 165°C. Reference patterns of 2a and 2b (simulated from SC XRD) are given in red and dark blue.

Figure 13. PXRD overlay of experimental PXRD patterns of concomitant polymorphs 3a and 3b at 40°C, 120°C and 180°C as well as reference patterns of polymorphs 3a and 3b (simulated from SC XRD).

Figure 14. PXRD overlay of experimental patterns of sample 4b, recorded at 40°C, 80°C, 120°C, 160°C and 180°C. The reference patterns of 4a and 4b (simulated from SC XRD) are given in red and dark blue.

4. Conclusions In this work extensive solid-forms screening on four 3-(4,5-diaryl-4H-1,2,4-triazole-3yl)propenoic acid derivatives has been performed. For this purpose the standard solvent

23



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evaporation technique was applied using a wide spectrum of common organic solvents. The experiments did not result in any solvates/hydrates formation, however, they revealed propensity of the compounds to polymorphic modifications. Two derivatives were found to exist in two polymorphic forms while for one compound three crystal forms were detected. To the best of our knowledge, this is the first example of trimorphism of 3,4,5-trisubstituted-4H-triazole derivatives. Furthermore, the structural data demonstrated significant differences in some torsion angles values between conformers which suggests detection of conformational polymorphs.2 As indicated by the variable-temperature XRPD data in all cases the polymorphic systems are enantiotropically related. The differences in the cohesive energy evaluated for the related polymorphs are small, i.e., up to a few kJ·mol-1, and less informative than the energies calculated for the whole unit cell. The mutual stabilities of the related polymorphs were, thus, well confirmed by the latter energy trends. It seems that the entropic factors play the most crucial role in the case of forms 4a and 4b characterized by the least significant total unit cell energy difference (only about 4 kJ·mol-1), where 4b is the denser form and more energetically stable one as far as the static structure is concerned. However, when the temperature increases, it transforms to the 4a form. In spite of the propensity to concommitant crystallization, the polymorphic outcomes can be controlled by crystallization conditions to some extent. The presence of water molecules in solution appears to be one of the main reasons for polymorph diversity during screening. Although the compounds crystallize solely in their solvent-free forms, crystallization of a given form seem to be driven by specific intermolecular interactions in solution, in particular those involving water molecules. This can be explained by the imbalance in the total number of hydrogen-bond donor and acceptor groups. Noteworthy, the only one potent donor, the carboxyl group, is excluded from the intermolecular interactions by its involvement in the O-H…Ntriazole intramolecular hydrogen bond. As a result, the association modes in the studied crystals are dominated by the weak C-H…O, CH…N and C-H…π interactions. A signifficant contribution of the π-stacking contacts, involving the aromatic substituents and planar triazole-propenoic acid units, to the total crystal lattice energy was observed. On the other hand, the lack of specific, hydrogenbonded synthons, directing the supramolecular organization toward a given polymorph, together with conformational flexibility, due to the rotation around the triazole-aryl bonds, can explain the propensity of the compounds to the solid-state modifications. 24


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References

1.

Mitscherlich, E. Ann. Chim. Phys. 1822, 19, 350-419.

2.

Cruz-Cabeza, A. J.; Bernstein, J. Chem. Rev. 2013, 114, 2170-2191.

3.

Bernstein, J. Polymorphism in Molecular Crystals, Oxford University Press, Oxford, UK, 2002.

4.

Nyman, J.; Day, G. M. CrystEngComm. 2015, 17, 5154-5165.

5.

Bar, I.; Bernstein, J. J. Pharm. Sci. 1985, 74, 255-263.

6.

Berzins, A.; Skarbulis, E.; Actins, A. Cryst. Growth Des. 2015, 15, 2337-2351.

7.

Maddileti, D.; Swapna, B.; Nangia, A. Cryst. Growth Des. 2015, 15, 1745-1756.

8.

Thirunahari, S.; Aitipamula, S.; Chow, P. S.; Tan, R. B. H. J. Pharm. Sci. 2010, 99, 2975-2990.

9.

Zeidan, T. A.; Trotta, J. T.; Chiarella, R. A.; Oliveira, M. A.; Hickey, M. B.; Almarsson Ö.; Remenar, J. F. Cryst. Growth Des. 2013, 13, 2036-2046.

10.

Zeidan, T. A.; Trotta, J. T.; Tilak, P. A.; Oliveira, M. A.; Chiarella, R. A.; Foxman, B. M.; Almarsson Ö.; Hickey, M. B. CrystEngComm. 2016, 18, 1486-1488.

11.

Brittain, H. G. Profiles Drug Subst., Excipients, Relat. Methodol. 2012, 37, 1-29.

12.

Bernstein, J.; Davey, R. J.; Henck, J. O. Angew. Chem., Int. Ed. Engl. 1999, 38, 3440-3461.

13.

Wohler, F. Annal. Pharm. 1832, 3, 249-282.

14.

Modzelewska-Banachiewicz, B.; Banachiewicz, J.; Chodkowska, A,; Jagiello-Wojtowicz, E.; Mazur, L. Eur. J. Med. Chem. 2004, 39, 873-877.

15.

Kutkowska, J.; Modzelewska-Banachiewicz, B.; Ziolkowska, G.; Rzeski, W.; Urbaniak-Sypniewska, T.; Zwolska, Z.; Prus, M. Acta Pol. Pharm. 2005, 62, 303-306.

16.

CrysAlis PRO, Agilent Technologies Ltd, Yarnton, Oxfordshire, 2013.

17.

Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112-122.

18.

Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837-838.

19.

Allen, F. H. Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 380-388.

20.

Dovesi, R.; Saunders, V. R.; Roetti, C.; Orlando, R.; Zicovich-Wilson, C. M.; Pascale, F.; Civalleri, B.; Doll, K.; Harrison, N. M.; Bush, I. J.; D’Arco, P.; Llunell, M. CRYSTAL09 (CRYSTAL09 User's Manual), University of Torino, Torino, 2009.

21.

Dovesi, R.; Civalleri, B.; Orlando, R.; Roetti, C.; Saunders, V. R. Rev. Comput. Chem. 2005, 21, 1-125.

22.

Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785-789.

23.

Becke, A. D. Phys. Rev. A: At., Mol. Opt. Phys. 1988, 38, 3098-3100.

24.

Glukhovtsev, M. N.; Pross, A.; McGrath, M. P.; Radom, L. J. Chem. Phys. 1995, 103, 1878-1885.

25.

Dunning, T. H. J. Chem. Phys. 1989, 90, 1007-1023.

26.

Treutler, O.; Ahlrichs, R. J. Chem. Phys. 1995, 102, 346-354.

27.

Schafer, A.; Horn, H.; Ahlrichs, R. J. Chem. Phys. 1992, 97, 2571-2577.

28.

Grimme, S. J. Comput. Chem. 2006, 27, 1787-1799.

29.

Grimme, S. J. Comput. Chem. 2004, 25, 1463-1473.

30.

Civalleri, B.; Zicovich-Wilson, C. M.; Valenzano, L.; Ugliengo, P. CrystEngComm. 2008, 10, 405-410.

25



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

31.

Jarzembska, K. N.; Kubsik, M.; Kamiński, R.; Woźniak, K.; Dominiak, P. M. Cryst. Growth Des. 2012, 12, 2508-2524.

32.

Kamiński, R.; Jarzembska, K. N.; Domagała, S. J. Appl. Crystallogr. 2013, 46, 540-534.

33.

Kalman, A.; Parkanyi, L.; Argay, G. Acta Crystallogr., Sect. B: Struct. Sci. 1993, 49, 1039-1049.

34.

International Tables for Crystallography, Vol. C, Wilson J. A. C., Dordrecht, 1992.

35.

Leiserowitz, L. Acta Crystallogr., Sect. B: Struct. Sci. 1976, 32, 775-802.

36.

Desiraju, G.; Steiner, T. The Weak Hydrogen Bond in Structural Chemistry and Biology. Oxford University Press, Oxford, 1999.

37.

Spackman, M. A.; Jayatilaka, D. CrystEngComm. 2009, 11, 19-32.

38.

Wolff, S. K.; Grimwood, D. J.; McKinnon, J. J.; Turner, M. J.; Jayatilaka, D.; Spackman, M. A. CrystalExplorer (Version 3.1). University of Western Australia, 2012.

39.

Hobza, P.; Selzle, H. L.; Schlag, E. W. J. Am. Chem. Soc. 1994, 116, 3500-3506.

40.

Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K. J. Am. Chem. Soc. 2002, 124, 104-112.

41.

Allen, F.; Baalham, Ch. A.; Lommerse, J. P. M.; Raithby, P. R. Acta Crystallogr., Sect. B: Struct. Sci. 1998, 54, 320-329.

42.

Mazur, L.; Koziol, A. E.; Modzelewska-Banachiewicz, B. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2008, 64, o574-577.

43.

Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Pharm. Res. 2001, 18, 859866.

44.

Brittain, H. B. Am. Pharm. Rev. 2002, 5, 74-80.

45.

Brittain, H. G. Polymorphism in Pharmaceutical Solids; Marcel Dekker, Inc., New York, 1999.

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ASSOCIATED CONTENT Supporting Information Synthetic and spectral characteristics of all studied crystals, selected geometric parameters, geometries of hydrogen bonds, interaction energy values for selected molecular pairs in crystals 3a, 3b and 3c, 3D Hirshfeld surfaces for polymorphs 3a, 3b and 3c, additional Hirshfeld surface fingerprint plots, TG/DTG/DSC plots for studied forms, variable temperature XRPD patterns for 2a, 3b and 3c.

Accession Codes CCDC 1519714 − 1519721 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033

AUTHOR INFORMATION Corresponding Author *Liliana Mazur. E-mail: [email protected]. Telephone: (+48) 815375743. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS LM would like to thank the Polish Ministry of Science and Higher Education/National Science Centre for financial support (grant No. N N204 546839).

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For Table of Contents Use Only Polymorphism and isostructurality of the series of 3-(4,5-diaryl-4H-1,2,4-triazole-3-yl)propenoic acid derivatives Liliana Mazur, Anna E. Koziol, Katarzyna N. Jarzembska, Renata Paprocka, Bożena Modzelewska-Banachiewicz

Synopsis: Comprehensive X-ray crystallographic studies, thermal analysis and variable-temperature powder diffraction investigations on polymorphs of 3,4,5trisubstituted-4H-triazole derivatives are reported. The experimental results were supported by theoretical computations of rotational barriers, lattice energy and intermolecular interactions. The aim of this work was to gain insight into the influence of experimental conditions on the resulting crystal forms and to study the relative stability of the polymorphs, intermolecular interaction patterns and energetics of their crystals.

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Polymorphism and Isostructurality of the Series of 3 - ACS Publications

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