Synthesis and Structural Characterization of Isostructural 4-(4-Aryl)-2-(5-(4-ﬂuorophenyl)-3-(1-(4-ﬂuorophenyl)-5-methyl-1 H -1,2,3-triazol-4-yl)-4,5-dihydro-1 H -pyrazol-1-yl)thiazoles

: 4-(4-Chlorophenyl)-2-(5-(4-ﬂuorophenyl)-3-(1-(4-ﬂuorophenyl)-5-methyl-1 H -1,2,3-triazol-4-yl)-4,5-dihydro-1 H -pyrazol-1-yl)thiazole ( 4 ) and 4-(4-ﬂuorophenyl)-2-(5-(4-ﬂuorophenyl)-3-(1-(4-ﬂuorophenyl)-5-methyl-1 H -1,2,3-triazol-4-yl)-4,5-dihydro-1 H -pyrazol-1-yl)thiazole ( 5 ) have been synthesized in high yields. Crystallization of 4 and 5 from dimethylformamide solvent produced samples suitable for structure determination by single crystal diffraction. The materials are isostructural with triclinic, P¯I and symmetry and comprise two independent molecules in the asymmetric unit. The two independent molecules in the asymmetric unit assume similar conformation. The molecule is essentially planar apart from one of the two ﬂuorophenyl groups, which is oriented roughly perpendicular to the plane of the rest of the molecule.

Pyrazoline-containing heterocycles are involved in different therapeutic applications. They are used as antimicrobial, anti-inflammatory, analgesic, antidepressant and anticancer agents [23][24][25]. Many pyrazolines exist in vitamins, pigments, alkaloids and cells of many plants and animals [26]. Substituted pyrazolines can be synthesized in one-pot procedures. For example, condensation of carbonyl compounds and hydrazine hydrochloride in methanol for 1 h at 65 • C produced substituted pyrazolines [27]. They can also be produced from 3-butynol and arylhydrazines through hydrohydrazination in the presence of a catalyst containing zinc [28].

General
IR spectra of compounds 4 and 5 were recorded on a AIM-9000 Shimadzu spectrometer. 1 H (500 MHz) and 13 C NMR (125 MHz) spectra of compounds 4 and 5 were recorded on JEOL spectrometers in DMSO-d 6 as solvent. Compound 1 was synthesized following a reported procedure [49]. The IR, 1 H and 13 C NMR spectra, CIFs and checkcif reports for compounds 4 and 5 are available in the supplementary material.

X-ray Crystal Structure
Single-crystal XRD data were recorded at ambient temperature on an Agilent Super-Nova Dual Atlas diffractometer (mirror monochromator, MoKα (λ = 0.71073 Å) radiation). Crystal structures were solved by direct methods using SHELXS [50] and refined using SHELXL2018 [51]. Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were inserted in idealized positions and refined using a riding model with Uiso(H) set to 1.2 or 1.5 times the value of Ueq(C) for the atoms to which they are bonded. CCDC 2077559 and 2077560 contain the supplementary crystallographic data for this paper. Hirshfeld surfaces were calculated using CrystalExplorer [52,53].

Crystal Structures of 4 and 5
Compounds 4 and 5 are isostructural as evidenced by their similar unit cell parameters and triclinic, PĪ, symmetry ( Table 1)

Crystal Structures of 4 and 5
Compounds 4 and 5 are isostructural as evidenced by their similar unit cell parameters and triclinic, PĪ, symmetry ( Table 1)   The asymmetric unit in both structures contains two independent molecules ( Figure  2a,b). Products 4 and 5 were obtained as racemic mixtures and the two molecules in the asymmetric unit are enantiomers with C10 and C37 as chiral centers. In all the molecules, rings A, B, C and E are almost coplanar with twist angles between adjacent rings in the range 3.58(1)° to 13.38(13)° (Table 2). Ring F is twisted by ca 30° and D is almost perpendicular to the plane of A, B, C and E. The two independent molecules in each structure have similar conformations although they are not identical. Additionally, molecular conformations are similar in both crystal structures. The asymmetric unit in both structures contains two independent molecules (Figure 2a,b). Products 4 and 5 were obtained as racemic mixtures and the two molecules in the asymmetric unit are enantiomers with C10 and C37 as chiral centers. In all the molecules, rings A, B, C and E are almost coplanar with twist angles between adjacent rings in the range 3.58(1) • to 13.38(13) • (Table 2). Ring F is twisted by ca 30 • and D is almost perpendicular to the plane of A, B, C and E. The two independent molecules in each structure have similar conformations although they are not identical. Additionally, molecular conformations are similar in both crystal structures.  Table 2. Inter-ring twist angles ( • ) and centroid-to-centroid distances (Å). (The centroid-to-centroid distances shown are longer than is conventionally shown for π-π contacts but are used in this case for ease of comparison of the structures. (i) and (ii) refer to the first and second independent molecules).

Inter-Ring Twist Angle 4(i) 4(ii) 5(i) 5(ii)
A-B 9.44 (11) 13.38 (10)  The following discussion applies to the structures of both 4 and 5, although only the former is used for illustration. In the crystals, the molecules are stacked parallel to the a-axis (Figure 3). In the stack, the mean plane of the fragment containing rings A, B, C and E is parallel to (10-1) in one stack and to (201) in the adjacent stack in the direction of the b-axis (Figure 4). Within a given stack, there is very limited π-π interaction between aromatic rings of neighboring molecules. The closest rings in the stack are fluorophenyl/chlorophenyl in 4 ( Figure 5) and fluorophenyl/bromophenyl in 5 and the distances between the ring centroids are in the range from 3.73 Å to 4.20 Å (d1-d4 in Table 2). The planes of the rings involved are not parallel and the angles between the rings of neighboring molecules are 12.18 • and 14.42 • for 4 and the corresponding angles are 12.95 • and 13.70 • for 5.
The asymmetric unit in both structures contains two independent molecules (Figure  2a,b). Products 4 and 5 were obtained as racemic mixtures and the two molecules in the asymmetric unit are enantiomers with C10 and C37 as chiral centers. In all the molecules, rings A, B, C and E are almost coplanar with twist angles between adjacent rings in the range 3.58(1)° to 13.38(13)° (Table 2). Ring F is twisted by ca 30° and D is almost perpendicular to the plane of A, B, C and E. The two independent molecules in each structure have similar conformations although they are not identical. Additionally, molecular conformations are similar in both crystal structures. The following discussion applies to the structures of both 4 and 5, although only the former is used for illustration. In the crystals, the molecules are stacked parallel to the a-  (Figure 3). In the stack, the mean plane of the fragment containing rings A, B, C and E is parallel to  in one stack and to (201) in the adjacent stack in the direction of the b-axis (Figure 4). Within a given stack, there is very limited π-π interaction between aromatic rings of neighboring molecules. The closest rings in the stack are fluorophenyl/chlorophenyl in 4 ( Figure 5) and fluorophenyl/bromophenyl in 5 and the distances between the ring centroids are in the range from 3.73 Å to 4.20 Å (d1-d4 in Table 2). The planes of the rings involved are not parallel and the angles between the rings of neighboring molecules are 12.18° and 14.42° for 4 and the corresponding angles are 12.95° and 13.70° for 5.   Generally, an asymmetric unit comprising one molecule would be expected in such a structure as the second enantiomer can be generated by inversion symmetry. However, the structures of 4 and 5 comprise two independent molecules with slightly different conformations in order to attain the most efficient molecular packing in the crystal. An alternative method to maximize packing efficiency would be by the incorporation of solvent molecules, for example. Generally, an asymmetric unit comprising one molecule would be expected in such a structure as the second enantiomer can be generated by inversion symmetry. However, the structures of 4 and 5 comprise two independent molecules with slightly different conformations in order to attain the most efficient molecular packing in the crystal. An alternative method to maximize packing efficiency would be by the incorporation of solvent molecules, for example.
The crystals of 4 and 5 are isostructural despite the different halogen substituents, which are Cl and Br, respectively. The difference in the calculated densities of 1.447 Mg m −3 and 1.559 Mg m −3 is consistent with the presence of chlorine and bromine atoms in the structures. Despite the different halogen substituents, the molecules have assumed essentially the same crystal structure but with slight adjustment of conformation and intermolecular contacts by virtue of the larger size of the Br atom rendering the molecular volume of 5 about 1% greater than that of 4.  Table 2. Inter-ring twist angles (°) and centroid-to-centroid distances (Å). (The centroid-to-centroid distances shown are longer than is conventionally shown for π-π contacts but are used in this case for ease of comparison of the structures. (i) and (ii) refer to the first and second independent molecules.)  For the title compounds, the substituents on rings A, D and F are (4: Cl, F and F) and (5: Br, F and F). Crystal structures have also been reported for molecules with other substituents on the same rings, namely (6: Cl, F and Me) [48], (7: H, Cl and Me) [54], (8: Br, F and Me) [55] and (9: H, F and Me) [56]. Molecular conformation in structures 6-9 is similar to that in 4 and 5 since rings A, B, C and E are roughly coplanar, ring F is twisted and ring D is oriented out of the plane. However, unlike 4 and 5, the other crystal structures have just one molecule in the asymmetric unit. Exchanging F for methyl (5 vs The Hirshfeld surfaces show different intermolecular contacts for the two independent molecules of each structure. The surfaces are shown in Figure 6b,d for 4 and Figure 7b,d for 5. The red regions clearly indicate that the intermolecular contacts are not identical for the two independent molecules of the same structure. Conversely, the contacts are essentially the same for the corresponding molecules in 4 and 5. Highlighted in the fingerprint plots in Figure 6a,c for 4 and Figure 7a,c for 5 are the contributions by chlorine and bromine. The plots follow the same pattern as the Hirshfeld surfaces; the two independent molecules of the same structure show differences whereas comparable molecules from different structures have similar characteristics. The contributions in 4 by Cl are 3.7% and 4.1% for the two independent molecules and 3.9% and 4.2% by Br for 5.
Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1, IR, 1 H and 13 C NMR spectra, CIFs and checkcif reports for compounds 4 and 5.