Next Article in Journal
Comparison of Phase Characteristics and Residual Stresses in Ti-6Al-4V Alloy Manufactured by Laser Powder Bed Fusion (L-PBF) and Electron Beam Powder Bed Fusion (EB-PBF) Techniques
Next Article in Special Issue
Modeling Interactions of Iron Atoms Encapsulated in Nanotubes
Previous Article in Journal
Effect of Poly(Titanium Oxide) on the Viscoelastic and Thermophysical Properties of Interpenetrating Polymer Networks
Previous Article in Special Issue
One Pot Synthesis, Surface and Magnetic Properties of Cu2O/Cu and Cu2O/CuO Nanocomposites
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Crystals
Volume 11
Issue 7
10.3390/cryst11070795
crystals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Benson M. Kariuki
1,
Bakr F. Abdel-Wahab
2 and
Gamal A. El-Hiti
3,*
1
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
2
Applied Organic Chemistry Department, National Research Centre, Dokki, Giza 12622, Egypt
3
Department of Optometry, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia
*
Author to whom correspondence should be addressed.
Crystals 2021, 11(7), 795; https://doi.org/10.3390/cryst11070795
Submission received: 26 June 2021 / Revised: 5 July 2021 / Accepted: 6 July 2021 / Published: 8 July 2021
(This article belongs to the Special Issue New Trends in Crystals at Saudi Arabia)
Browse Figures
Versions Notes

Abstract

:
4-(4-Chlorophenyl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (4) and 4-(4-fluorophenyl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-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, PĪ 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.

Graphical Abstract

1. Introduction

The progressive development of microbial resistance to current drugs is of global concern and, consequently, the design and synthesis of new medications are an ongoing challenge [1]. The majority (85%) of biologically active compounds contain different heterocycles and hence the synthesis of new molecules is important for the quest to generate potential additions to the established heterocyclic systems for therapeutic use [2].
1,2,3-Triazoles are highly stable heterocycles that have a wide range of medicinal applications [3]. They have anti-HIV, anticancer, antibacterial, anti-inflammatory, antitubercular and antiviral activities [4,5,6,7,8,9,10,11,12,13,14,15,16]. The common synthetic routes for 1,2,3-triazoles include 1,3-dipolar cycloaddition between azides and terminal alkynes [17]. However, the procedure results in a mixture of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles due to poor regioselectivity. The use of a copper(I)-catalyzed version of azide–alkyne cycloaddition and click chemistry approaches resulted in the production of various substituted 1,2,3-triazoles in high yields [18,19,20,21,22].
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].
1,3-Thiazoles exist in nature and have diverse pharmacological applications as bioactive compounds. For example, tiazofurin, ritonavir, ravuconazole, nitazoxanide, fanetizole, meloxicam, fentiazac, nizatidine and thiamethoxam act as antimicrobial agents [29,30]. The synthesis of compounds containing the thiazole system is therefore a useful venture due to their potential for medicinal applications. Recent synthetic procedures for 1,3-thiazoles include a copper-catalyzed oxidative reaction of aldehydes and amines in the presence of sulfur [31]. Furthermore, the Hantzsch condensation of thiourea and 2-bromoacetophenones provided 2-aminothiazoles [32]. Recently, we have synthesized a number of heterocycles containing pyrazole, thiazole and 1,2,3-triazole moieties [33,34] and some crystal structures have been established [35,36].
This work involved the synthesis of 4-(4-chlorophenyl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (4) and 4-(4-fluorophenyl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (5). The crystal structures obtained enabled a comparison of the structural properties of the materials; the structures are identical in this case. The study of isostructurality in crystalline solids contributes to the general understanding of the factors that may be important in the design of solid materials for particular applications [37]. Investigation of the properties of isostructural materials containing different substituents continues to attract interest [38,39,40,41], including compounds in which different halogens have been exchanged [42,43,44]. Although it is not surprising that two similar molecules can display similar structural properties, it is not a certainty that this will be the case. Thus, for example, 3-chlorocinnamic acid and 3-bromocinnamic acid can display different crystal structures [45] and, indeed, one molecule can crystallize in more than one crystal structure type, as observed for 3-chlorobenzoic acid [46,47].
Compounds 4 and 5 allow a comparison of isostructural chloro and bromo derivatives of 4-(4-aryl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol -4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole. Rationalization of intermolecular contacts may, for example, reveal information about possible interactions with binding sites in therapeutic application. A potential application of 4 and 5 and related compounds is as therapeutics. An example is 4-(4-chlorophenyl)-2-(5-(4-fluorophenyl)-3-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole, which displays antimicrobial activity [48]. However, the focus of this work was the synthesis and characterization of new materials.

2. Materials and Methods

2.1. General

IR spectra of compounds 4 and 5 were recorded on a AIM-9000 Shimadzu spectrometer. 1H (500 MHz) and 13C NMR (125 MHz) spectra of compounds 4 and 5 were recorded on JEOL spectrometers in DMSO-d6 as solvent. Compound 1 was synthesized following a reported procedure [49]. The IR, 1H and 13C NMR spectra, CIFs and checkcif reports for compounds 4 and 5 are available in the supplementary material.

2.2. Synthesis of 2

A mixture of 1 (1.20 g, 5.0 mmol) and 4-fluorobenzaldehyde (0.62 g, 5.0 mmol) in EtOH (15 mL) containing NaOH (0.8 g) was stirred for 4 h at room temperature. The solid obtained was added to an ice/water (100 mL) mixture, filtered, dried and recrystallized from dimethylformamide to produce colorless crystals of 2 (M.p. 168–170 °C) in 90% yield.

2.3. Synthesis of 3

A mixture of 2 (0.97 g, 3.0 mmol) and thiosemicarbazide (0.30 g, 3.0 mmol) in EtOH (15 mL) containing NaOH (0.30 g, 2.5 mol) was refluxed for 2 h. The solid formed upon cooling was filtered, dried and recrystallized from dimethylformamide to produce colorless crystals of 3 (M.p. 229–231 °C) in 87% yield.

2.4. Synthesis of 4 and 5

A mixture of 3 (0.40 g, 1.0 mmol) and 4-chloro- or 4-bromophenacyl bromide (1.0 mmol) in dry EtOH (15 mL) was refluxed for 2 h. The solid produced was filtered, dried and recrystallized from dimethylformamide to produce 4 (M.p. 267–268 °C) in 82% yield or 5 (M.p. 275–276 °C) in 85% yield, respectively, as pale-yellow crystals. Compound 4: IR (KBr) νmax: 1544 (C=N) and 1604 (C=C) cm−1. 1H NMR: δ 2.47 (s, 3H, Me), 3.42 (dd, J = 3.5 and 17.2 Hz, 1H), 4.16 (dd, J = 11.3 and 17.2 Hz, 1H), 5.66 (m, 1H), 7.18 (t, J = 7.7 Hz, 2H, Ar), 7.36–7.39 (m, 3H, Ar), 7.46–7.49 (m, 4H, Ar) and 7.70–7.71 (m, 4H, Ar). 13C NMR: δ 10.47, 44.85, 63.16, 105.78, 115.91 (d, JC–F = 21.5 Hz), 117.25 (d, JC–F = 22.7 Hz), 127.71, 128.31 (d, JC–F = 8.4 Hz), 129.08, 129.34 (d, JC–F = 8.3 Hz), 132.34, 132.53, 134.69 (d, JC–F = 88.2 Hz), 137.86 (d, JC–F = 78.7 Hz), 148.28, 149.86, 161.58 (d, JC–F = 121.6 Hz), 162.55 (d, JC-F = 122.5 Hz) and 165.18. Compound 5: IR (KBr) νmax: 1572 (C=N) and 1602 (C=C) cm−1. 1H NMR: δ 2.47 (s, 3H, Me), 3.43 (dd, J = 3.6 and 18.1, 1H), 4.15 (dd, J = 11.4 and 18.1 Hz, 1H), 5.65 (m, 1H), 7.18 (t, J = 7.8 Hz, 2H, Ar), 7.38 (s, 1H, Ar), 7.49–7.52 (m, 6H, Ar), 7.62 (d, J = 7.8 Hz, 2H, Ar) and 7.64–7.65 (m, 2H, Ar). 13C NMR: δ 10.48, 44.84, 63.14, 105.87, 115.91 (d, JC–F = 21.5 Hz), 117.25 (d, JC–F = 22.7 Hz), 121.12, 128.01, 128.30 (d, JC–F = 8.3 Hz), 129.36 (d, JC–F = 8.3 Hz), 131,99, 132.33, 134.36 (d, JC–F = 45.3 Hz), 137.86 (d, JC–F = 78.7 Hz), 148.29, 148.29, 149.90, 161.57 (d, JC–F = 120.4 Hz), 163.53 (d, JC–F = 121.3 Hz) and 165.17.

2.5. X-ray Crystal Structure

Single-crystal XRD data were recorded at ambient temperature on an Agilent SuperNova 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].

3. Results and Discussion

3.1. Synthesis of Compounds 4 and 5

Compounds 4 and 5 were synthesized using a multi-step reaction from 1-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (1) via 3-(4-fluorophenyl)-1-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)prop-2-en-1-one (2) and 5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3) as intermediates. Reaction of 3 and 2,4’-dibromoacetophenone or 2-bromo-4’-chloroacetophenone under reflux in ethanol (EtOH) produced 4-(4-chlorophenyl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (4) or 4-(4-bromophenyl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (5) in 82% or 85% yield, respectively (Scheme 1).
The structures of compounds 4 and 5 were confirmed using IR, 1H and 13C NMR spectroscopy. The IR spectra showed characteristic absorption bands in the 1544–1572 cm−1 and 1602–1604 cm−1 regions due to the stretching vibrations of the C=N and C=C groups, respectively. The 1H NMR spectra showed separate peaks for the methylene protons in the pyrazoline moiety, indicating that they are diastereotopic. In addition, the 13C NMR spectra confirmed the coupling between carbon and fluorine atoms and showed overlap between the signals of some carbons.

3.2. 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 molecules of 4 and 5 comprise linked systems of rings (Figure 1). The rings are chloro/bromo-phenyl [A (C1-C6, Cl1/Br1), (C28-C33, Cl2/Br2)], thiazolyl [B (C7-C9, N1, S1), (C34-C36, N7, S2)], pyrazolyl [C (C10-C12, N2, N3), (C37-C39, N8, N9)], fluorophenyl [D (C13-C18, F1), (C40-C45, F3)], methyltriazolyl [E (C19-C21, N4-N6), C46-C48, N10-N12)] and a second fluorophenyl [F (C22-C27, F2), (C49-C54, F4)].
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-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.
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.
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. 8) and (4 vs. 6) results in different crystal structures, as does the replacement of Cl by F (7 vs. 9). In contrast, the crystal structures in which Cl and Br are exchanged (6 vs. 8) are identical, which is an observation consistent with the results obtained in this work for 4 and 5.
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.

4. Conclusions

Two materials, 4-(4-chlorophenyl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5- methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (4) and 4-(4-fluorophenyl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole (5), have been synthesized in high yields and characterized spectroscopically. The materials have been recrystallized using dimethylformamide as the solvent and their structures have been established by single crystal diffraction. The two materials are isostructural and contain two independent molecules in the asymmetric unit. The two independent molecules in each structure have similar conformations although they are not identical. The crystal structures of 4 and 5 are identical but with slight adjustments necessary to accommodate the different halogen (Cl and Br) substituents. Comparison with related materials shows similarity in molecular conformation but with different crystal packing.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/cryst11070795/s1, IR, 1H and 13C NMR spectra, CIFs and checkcif reports for compounds 4 and 5.

Author Contributions

Conceptualization: B.M.K. and G.A.E.-H.; methodology: B.M.K., B.F.A.-W. and G.A.E.-H.; X-ray crystal structures: B.M.K.; investigation: B.M.K., B.F.A.-W. and G.A.E.-H.; writing—original draft preparation: B.M.K., B.F.A.-W. and G.A.E.-H.; writing—review and editing: B.M.K. and G.A.E.-H. All authors have read and agreed to the published version of the manuscript.

Funding

The authors thank the Researchers Supporting Project number (RSP-2021/404), King Saud University, Riyadh, Saudi Arabia.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Acknowledgments

We thank Cardiff University for their technical support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Abu-Hashem, A.A. Synthesis of new furothiazolo pyrimido quinazolinones from visnagenone or khellinone and antimicrobial activity. Molecules 2018, 23, 2793. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Jampilek, J. Heterocycles in medicinal chemistry. Molecules 2019, 24, 3839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Dheer, D.; Singh, V.; Shankar, R. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg. Chem. 2017, 71, 30–54. [Google Scholar] [CrossRef] [PubMed]
  4. Gondru, R.; Kanugala, S.; Raj, S.; Kumar, C.G.; Pasupuleti, M.; Banothu, J.; Bavantula, R. 1,2,3-Triazole-thiazole hybrids: Synthesis, in vitro antimicrobial activity and antibiofilm studies. Bioorg. Med. Chem. Lett. 2020, 33, 127746. [Google Scholar] [CrossRef] [PubMed]
  5. El Malah, T.; Nour, H.F.; Satti, A.A.E.; Hemdan, B.A.; El-Sayed, W.A. Design, synthesis, and antimicrobial activities of 1,2,3-triazole glycoside clickamers. Molecules 2020, 25, 790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Ellouz, M.; Sebbar, N.K.; Fichtali, I.; Ouzidan, Y.; Mennane, Z.; Charof, R.; Mague, J.T.; Urrutigoïty, M.; Essassi, E.M. Synthesis and antibacterial activity of new 1,2,3-triazolylmethyl-2H-1,4-benzothiazin-3(4H)-one derivatives. Chem. Cent. J. 2018, 12, 123. [Google Scholar] [CrossRef] [PubMed]
  7. López-Rojas, P.; Janeczko, M.; Kubiński, K.; Amesty, Á.; Masłyk, M.; Estévez-Braun, A. Synthesis and antimicrobial activity of 4-substituted 1,2,3-triazole-coumarin derivatives. Molecules 2018, 23, 199. [Google Scholar] [CrossRef] [Green Version]
  8. Da Silva, F.D.C.; De Souza, M.C.B.V.; Frugulhetti, I.I.P.; Castro, H.C.; Souza, S.L.D.O.; De Souza, T.M.L.; Rodrigues, D.Q.; Souza, A.M.T.; Abreu, P.A.; Passamani, F.; et al. Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates. Eur. J. Med. Chem. 2009, 44, 373–383. [Google Scholar] [CrossRef]
  9. Doiron, J.; Soultan, A.H.; Richard, R.; Touré, M.M.; Picot, N.; Richard, R.; Cuperlović-Culf, M.; Robichaud, G.A.; Touaibia, M. Synthesis and structure activity relationship of 1- and 2-substituted-1,2,3-triazole letrozole-based analogues as aromatase inhibitors. Eur. J. Med. Chem. 2011, 46, 4010–4024. [Google Scholar] [CrossRef]
  10. Sert, Y.; El-Hiti, G.A.; Gökce, H.; Ucun, F.; Abdel-Wahab, B.F.; Kariuki, B.M. DFT, molecular docking and experimental FT-IR, laser-Raman, NMR and UV investigations on a potential anticancer agent containing triazole ring system. J. Mol. Struct. 2020, 1211, 128077. [Google Scholar] [CrossRef]
  11. Abd-Rabou, A.A.; Abdel-Wahab, B.F.; Bekheit, M.S. Synthesis, molecular docking, and evaluation of novel bivalent pyrazolinyl-1,2,3-triazoles as potential VEGFR TK inhibitors and anti-cancer agents. Chem. Pap. 2018, 72, 2225–2237. [Google Scholar] [CrossRef]
  12. Abdel-Wahab, B.F.; Khidre, R.E.; Awad, G.E.A. Design and synthesis of novel 6-(5-methyl-1H-1,2,3-triazol-4-yl)-5-[(2-(thiazol-2-yl)hydrazono)methyl]imidazo[2,1-b]thiazoles as antimicrobial agents. J. Heterocycl. Chem. 2017, 54, 489–494. [Google Scholar] [CrossRef]
  13. Abdel-Wahab, B.F.; Alotaibi, M.H.; El-Hiti, G.A. Synthesis of new symmetrical N,N′-diacylhydrazines and 2-(1,2,3-triazol-4-yl)-1,3,4-oxadiazoles. Lett. Org. Chem. 2017, 14, 591–596. [Google Scholar] [CrossRef]
  14. Penthala, N.R.; Madhukuri, L.; Thakkar, S.; Madadi, N.R.; Lamture, G.; Eoff, R.L.; Crooks, P.A. Synthesis and anti-cancer screening of novel heterocyclic-(2H)-1,2,3-triazoles as potential anti-cancer agents. Med. Chem. Commun. 2015, 6, 1535–1543. [Google Scholar] [CrossRef] [Green Version]
  15. Stefely, J.A.; Palchaudhuri, R.; Miller, P.A.; Peterson, R.J.; Moraski, G.C.; Hergenrother, P.J.; Miller, M.J. N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl) arylamide as a new scaffold that provides rapid access to antimicrotubule agents: Synthesis and evaluation of antiproliferative activity against select cancer cell lines. J. Med. Chem. 2010, 53, 3389–3395. [Google Scholar] [CrossRef] [Green Version]
  16. Jiang, B.; Huang, X.; Yao, H.; Jiang, J.; Wu, X.; Jiang, S.; Wang, Q.; Lu, T.; Xu, J. Discovery of potential anti-inflammatory drugs: Diaryl-1,2,4-triazoles bearing N-hydroxyurea moiety as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase. Org. Biomol. Chem. 2014, 12, 2114–2127. [Google Scholar] [CrossRef] [Green Version]
  17. Huisgen, R.; Szeimies, G.; Möbius, L. 1.3-Dipolare cycloadditionen, XXXII. Kinetik der additionen organischer azide an CC-mehrfachbindungen. Chem. Ber. 1967, 100, 2494–2507. [Google Scholar] [CrossRef]
  18. Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Click chemistry: Diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 2001, 40, 2004–2021. [Google Scholar] [CrossRef]
  19. Seus, N.; Gonçalves, L.C.; Deobald, A.M.; Savegnago, L.; Alves, D.; Paixão, M.W. Synthesis of arylselanyl-1H-1,2,3-triazole-4-carboxylates by organocatalytic cycloaddition of azidophenyl arylselenides with β-keto-esters. Tetrahedron 2012, 68, 10456–10463. [Google Scholar] [CrossRef]
  20. Schmieder, P.; Khne, R.; Rademann, J. Metal-free, regioselective triazole ligations that deliver locked cis peptide mimetics. Angew. Chem. Int. Ed. 2009, 48, 5042–5045. [Google Scholar] [CrossRef]
  21. Dey, S.; Pathak, T.A. General route to 1,5-disubstituted 1,2,3-triazoles with alkyl/alkyl, alkyl/aryl, aryl/aryl combinations: A metal-free, regioselective, one-pot three component approach. RSC Adv. 2014, 4, 9275–9278. [Google Scholar] [CrossRef]
  22. Cai, Z.-J.; Lu, X.-M.; Zi, Y.; Yang, C.; Shen, L.-J.; Li, J.; Wang, S.-Y.; Ji, S.-J. I2/TBPB mediated oxidative reaction of N-tosylhydrazones with anilines: Practical construction of 1,4-disubstituted 1,2,3-triazoles under metal-free and azide free conditions. Org. Lett. 2014, 16, 5108–5111. [Google Scholar] [CrossRef]
  23. Shaaban, M.R.; Mayhoub, A.S.; Farag, A.M. Recent advances in the therapeutic applications of pyrazolines. Expert. Opin. Ther. Pat. 2012, 22, 253–291. [Google Scholar] [CrossRef] [PubMed]
  24. Varghese, B.; Al-Busafi, S.N.; Suliman, F.O.; Al-Kindy, S.M.Z. Unveiling a versatile heterocycle: Pyrazoline—A review. RSC Adv. 2017, 7, 46999–47016. [Google Scholar] [CrossRef] [Green Version]
  25. Tok, F.; Abas, B.I.; Çevik, O. Koçyiğit-Kaymakçıoğlu, B. Design, synthesis and biological evaluation of some new 2-Pyrazoline derivatives as potential anticancer agents. Bioorg. Chem. 2020, 102, 104063. [Google Scholar] [CrossRef] [PubMed]
  26. Yusuf, M.; Jain, P. Synthetic and biological studies of pyrazolines and related heterocyclic compounds. Arab. J. Chem. 2014, 7, 553–596. [Google Scholar] [CrossRef] [Green Version]
  27. Lellek, V.; Chen, C.-Y.; Yang, W.; Liu, J.; Ji, X.; Faessler, R. An efficient synthesis of substituted pyrazoles from one-pot reaction of ketones, aldehydes, and hydrazine monohydrochloride. Synlett 2018, 29, 1071–1075. [Google Scholar] [CrossRef] [Green Version]
  28. Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Zinc-catalyzed synthesis of pyrazolines and pyrazoles via hydrohydrazination. Org. Lett. 2008, 10, 2377–2379. [Google Scholar] [CrossRef]
  29. Ayati, A.; Emami, S.; Asadipour, A.; Shafiee, A.; Foroumadi, A. Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery. Eur. J. Med. Chem. 2015, 97, 699–718. [Google Scholar] [CrossRef]
  30. Sharma, P.K.; Amin, A.; Kumar, M. A review: Medicinally important nitrogen sulphur containing heterocycles. Open Med. Chem. J. 2021, 14, 49–64. [Google Scholar] [CrossRef]
  31. Wang, X.; Qiu, X.; Wei, J.; Liu, J.; Song, S.; Wang, W.; Jiao, N. Cu-catalyzed aerobic oxidative sulfuration/annulation approach to thiazoles via multiple Csp 3-H bond cleavage. Org. Lett. 2018, 20, 2632–2636. [Google Scholar] [CrossRef] [PubMed]
  32. Facchinetti, V.; Avellar, M.M.; Nery, A.C.S.; Gomes, R.B.; Vasconcelos, T.R.A.; de Souza, M.V.N. An eco-friendly, Hantzsch-based, solvent-free approach to 2-aminothiazoles and 2-aminoselenazoles. Synthesis 2016, 48, 437–440. [Google Scholar] [CrossRef]
  33. Mohamed, H.A.; Alshammari, M.B.; El-Hiti, G.A. Synthesis of new 6-(1H-1,2,3-triazol-4-yl)-5-(1-(thiazol-2-yl)-4,5-dihydro-1H-pyrazol-5-yl)imidazo[2,1-b]thiazoles. Indian J. Heterocycl. Chem. 2018, 28, 529–533. [Google Scholar]
  34. Abdel-Wahab, B.F.; Khidre, R.E.; Mohamed, H.A.; El-Hiti, G.A. A simple process for the synthesis of novel pyrazolyltriazole and dihydropyrazolylthiazole derivatives as antimicrobial agents. Arab. J. Sci. Eng. 2017, 42, 2441–2448. [Google Scholar] [CrossRef]
  35. Ghabbour, H.A.; Abdel-Wahab, B.F.; Alamri, M.; Al-Omar, M.A.; El-Hiti, G.A. Crystal structure of 2-(5-(4-fluorophenyl)-3-p-tolyl-4,5-dihydro-1H-pyrazol-1-yl)-4-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)thiazole, C29H25FN6S. Z. Kristallogr. New Cryst. Struct. 2017, 232, 21–23. [Google Scholar] [CrossRef] [Green Version]
  36. El-Hiti, G.A.; Mohamed, H.A.; Abdel-Wahab, B.F.; Alotaibi, M.H.; Hegazy, A.S.; Kariuki, B.M. 4-(4-Bromophenyl)-2-(3-(4-chlorophenyl)-5-{3-[5-methyl-1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl]-1-phenyl-1H-pyrazol-4-yl}-4,5-dihydro-1H-pyrazol-1-yl)thiazole. IUCrData 2018, 3, x180036. [Google Scholar] [CrossRef] [Green Version]
  37. Braga, D.; Desiraju, G.R.; Miller, J.S.; Orpend, A.G.; Price, S.L. Innovation in crystal engineering. CrystEngComm 2002, 4, 500–509. [Google Scholar] [CrossRef]
  38. Ebenezer, S.; Muthiah, P.T.; Butcher, R.J. Design of a series of isostructural co-crystals with aminopyrimidines: Isostructurality through chloro/methyl exchange and studies on supramolecular architectures. Cryst. Growth Des. 2011, 11, 3579–3592. [Google Scholar] [CrossRef]
  39. Chia, T.S.; Quah, C.K. Temperature-induced order-disorder structural phase transitions of two-dimensional isostructural hexamethylenetetramine co-crystals. Acta Crystallogr. Sect. B 2017, 73, 879–890. [Google Scholar] [CrossRef]
  40. Panicker, L. Thermal, spectroscopic and structural characterization of isostructural phase transition in 4-hydroxybenzaldehyde. Phase Transit. 2018, 91, 530–536. [Google Scholar] [CrossRef]
  41. Galcera, J.; Friščić, T.; Hejczyk, K.E.; Fábián, L.; Clarke, S.M.; Day, G.M.; Molinsa, E.; Jones, W. Isostructural organic binary-host frameworks with tuneable and diversely decorated inclusion cavities. CrystEngComm 2012, 14, 7898–7906. [Google Scholar] [CrossRef]
  42. Reddy, C.M.; Kirchner, M.T.; Gundakaram, R.C.; Padmanabhan, K.A.; Desiraju, G.R. Isostructurality, polymorphism and mechanical properties of some hexahalogenated benzenes: The nature of halogen···halogen interactions. Chem. Eur. J. 2006, 12, 2222–2234. [Google Scholar] [CrossRef]
  43. Saraswatula, V.G.; Saha, B.K. The effect of temperature on interhalogen interactions in a series of isostructural organic systems. New J. Chem. 2014, 38, 897–901. [Google Scholar] [CrossRef]
  44. Cincic, D.; Friscic, T.; Jones, W. A cocrystallisation-based strategy to construct isostructural solids. New J. Chem. 2008, 32, 1776–1781. [Google Scholar] [CrossRef]
  45. Kanao, S.; Kashino, S.; Haisa, M. Topochemical studies. XIII. Structures of 3-bromocinnamic acid and 3-chlorocinnamic acid. Acta Cryst. 1990, C46, 2436–2438. [Google Scholar] [CrossRef]
  46. Gougoutas, J.Z.; Lessinger, L. Solid state chemistry of organic polyvalent iodine compounds. IV. Topotactic transformations of 2-iodo-3′-chlorodibenzoyl peroxide and the crystal structure of m-chlorobenzoic acid. J. Solid State Chem. 1975, 12, 51–62. [Google Scholar] [CrossRef]
  47. Hursthouse, M.B.; Hibbs, D.E.; Ramachandran, V.N. 3-Chlorobenzoic acid. Private communication to the Cambridge Structural Database. 2003; MCBZAC01. [Google Scholar]
  48. Abdel-Wahab, B.F.; Abdel-Latif, E.; Mohamed, H.A.; Awad, G.E.A. Design and synthesis of new 4-pyrazolin-3-yl-1,2,3-triazoles and 1,2,3-triazol-4-yl-pyrazolin-1-ylthiazoles as potential antimicrobial agents. Eur. J. Med. Chem. 2012, 52, 263–268. [Google Scholar] [CrossRef]
  49. Kamalraj, V.R.; Senthil, S.; Kannan, P. One-pot synthesis and the fluorescent behavior of 4-acetyl-5-methyl-1,2,3-triazole regioisomers. J. Mol. Struct. 2008, 892, 210–215. [Google Scholar] [CrossRef]
  50. Sheldrick, G.M. A short history of SHELX. Acta Crystallogr. Sect. A 2008, 64, 112–122. [Google Scholar] [CrossRef] [Green Version]
  51. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C 2015, 71, 3–8. [Google Scholar] [CrossRef]
  52. Turner, M.J.; McKinnon, J.J.; Wolff, S.K.; Grimwood, D.J.; Spackman, P.R.; Jayatilaka, D.; Spackman, M.A. CrystalExplorer17; The University of Western Australia: Perth, Australia, 2017. [Google Scholar]
  53. MacKenzie, C.F.; Spackman, P.R.; Jayatilaka, D.; Spackman, M.A. CrystalExplorer model energies and energy frameworks: Extension to metal coordination compounds, organic salts, solvates and open-shell systems. IUCrJ 2017, 4, 575–587. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Dong, W.-J.; Cui, F.-H.; Gao, Z.-L.; Li, R.-S.; Shen, G.-L.; Dong, H.-S. An efficient synthesis of 5-aryl-4,5-dihydro-3-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)-1-(4-phenylthiazol-2-yl)pyrazoles. J. Heterocycl. Chem. 2011, 48, 1154–1160. [Google Scholar] [CrossRef]
  55. Abdel-Wahab, B.F.; Mohamed, H.A.; Ng, S.W.; Tiekink, E.R.T. 4-{1-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]- 5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-3-yl}-5-methyl-1-(4-methylphenyl)-1H-1,2,3-triazole. Acta Crystallogr. Sect. E Struct. Rep. Online 2012, 68, o1956–o1957. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Abdel-Wahab, B.F.; Ng, S.W.; Tiekink, E.R.T. 4-[5-(4-Fluorophenyl)-1-(4-phenyl-1,3-thiazol-2-yl)-4,5-dihydro-1H-pyrazol- 3-yl]-5-methyl-1-(4-methylphenyl)-1H-1,2,3-triazole. Acta Crystallogr. Sect. E Struct. Rep. Online 2013, 69, o618. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Crystals 11 00795 sch001 550
Scheme 1. Synthesis of 4 and 5.
Scheme 1. Synthesis of 4 and 5.
Crystals 11 00795 sch001
Crystals 11 00795 g001 550
Figure 1. Ring systems in compounds 4 and 5.
Figure 1. Ring systems in compounds 4 and 5.
Crystals 11 00795 g001
Crystals 11 00795 g002 550
Figure 2. Ortep representation of the asymmetric unit showing 50% probability ellipsoids for (a): 4 and (b): 5.
Figure 2. Ortep representation of the asymmetric unit showing 50% probability ellipsoids for (a): 4 and (b): 5.
Crystals 11 00795 g002
Crystals 11 00795 g003 550
Figure 3. The crystal structure packing in 4 viewed down the a-axis.
Figure 3. The crystal structure packing in 4 viewed down the a-axis.
Crystals 11 00795 g003
Crystals 11 00795 g004 550
Figure 4. The crystal structure of 4 viewed down the b-axis with hydrogen atoms omitted for clarity.
Figure 4. The crystal structure of 4 viewed down the b-axis with hydrogen atoms omitted for clarity.
Crystals 11 00795 g004
Crystals 11 00795 g005 550
Figure 5. A segment of the crystal structure of 4 viewed approximately along the c-axis showing the stacking of molecules with ring centroid separation shown as red dashed lines.
Figure 5. A segment of the crystal structure of 4 viewed approximately along the c-axis showing the stacking of molecules with ring centroid separation shown as red dashed lines.
Crystals 11 00795 g005
Crystals 11 00795 g006 550
Figure 6. (a): Two-dimensional fingerprint plot for one independent molecule of 4 with Cl interactions highlighted; (b): the associated Hirshfeld surface. (c): Two-dimensional fingerprint plot for the second independent molecule with Cl interactions highlighted; (d): the associated Hirshfeld surface.
Figure 6. (a): Two-dimensional fingerprint plot for one independent molecule of 4 with Cl interactions highlighted; (b): the associated Hirshfeld surface. (c): Two-dimensional fingerprint plot for the second independent molecule with Cl interactions highlighted; (d): the associated Hirshfeld surface.
Crystals 11 00795 g006
Crystals 11 00795 g007 550
Figure 7. (a): Two-dimensional fingerprint plot for one independent molecule of 5 with Br interactions highlighted; (b): the associated Hirshfeld surface. (c): Two-dimensional fingerprint plot for the second independent molecule with Br interactions highlighted; (d): the associated Hirshfeld surface.
Figure 7. (a): Two-dimensional fingerprint plot for one independent molecule of 5 with Br interactions highlighted; (b): the associated Hirshfeld surface. (c): Two-dimensional fingerprint plot for the second independent molecule with Br interactions highlighted; (d): the associated Hirshfeld surface.
Crystals 11 00795 g007
Table
Table 1. Crystal and structure refinement data for 4 and 5.
Table 1. Crystal and structure refinement data for 4 and 5.
45
FormulaC27H19ClF2N6SC27H19BrF2N6S
Formula weight532.99577.45
Temperature/K293(2)293(2)
Wavelength/Å0.710730.71073
Crystal systemTriclinicTriclinic
Space groupPĪPĪ
a/Å7.7344(6)7.7607(3)
b/Å18.2778(12)18.2950(11)
c/Å19.4909(12)19.5252(14)
α/°116.181(6)115.910(6)
β/°96.410(6)96.971(4)
γ/°92.091(6)92.567(4)
Volume/Å32445.9(3)2460.2(3)
Z44
Density (calculated)/Mg m−31.4471.559
μ/mm−10.2871.801
F(000)10961168
Crystal size/mm30.270 × 0.065 × 0.0260.623 × 0.148 × 0.118
Reflections collected23,27523,703
Independent reflections11,54611,617
R(int)0.04960.0448
Data/parameters11,546/67011,617/669
Goodness-of-fit on F21.0141.032
R1 [I > 2σ(I)]0.06520.0669
wR2 [I > 2σ (I)]0.12390.1722
R1 (all data)0.18020.1364
wR2 (all data)0.16660.2137
Extinction coefficient0.0012(3)n/a
Largest diff. peak and hole/e.Å−30.238 and −0.2430.689 and −0.680
Table
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).
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 Angle4(i)4(ii)5(i)5(ii)
A–B9.44 (11)13.38 (10)9.68 (13)13.36 (14)
B–C3.58 (14)5.30 (15)5.17 (17)5.03 (20)
C–D88.15 (1)84.53 (13)88.15 (16)84.17 (16)
C–E10.39 (15)10.78 (16)10.86 (18)10.53 (21)
E–F33.09 (9)32.59 (10)35.39 (11)31.86(13)
Centroid-centroid distance45
d13.75(1)3.73(1)
d24.05(1)4.09(1)
d33.81(1)3.79(1)
d44.14(1)4.20(1)
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Kariuki, B.M.; Abdel-Wahab, B.F.; El-Hiti, G.A. Synthesis and Structural Characterization of Isostructural 4-(4-Aryl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles. Crystals 2021, 11, 795. https://doi.org/10.3390/cryst11070795

AMA Style

Kariuki BM, Abdel-Wahab BF, El-Hiti GA. Synthesis and Structural Characterization of Isostructural 4-(4-Aryl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles. Crystals. 2021; 11(7):795. https://doi.org/10.3390/cryst11070795

Chicago/Turabian Style

Kariuki, Benson M., Bakr F. Abdel-Wahab, and Gamal A. El-Hiti. 2021. "Synthesis and Structural Characterization of Isostructural 4-(4-Aryl)-2-(5-(4-fluorophenyl)-3-(1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles" Crystals 11, no. 7: 795. https://doi.org/10.3390/cryst11070795

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop