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Article

Catalyst-Free Synthesis of Novel 4-(Benzofuran-2-yl)-N-phenylthiazol-2(3H)-imines, Crystal Structure Elucidation, and the Effect of Phenyl Substitution on Crystal Packing

by
Bakr F. Abdel-Wahab
1,
Benson M. Kariuki
2,*,
Hanan A. Mohamed
1 and
Gamal A. El-Hiti
3,*
1
Applied Organic Chemistry Department, Chemical Industries Research Institute, National Research Centre, Dokki, Giza 12622, Egypt
2
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
3
Department of Optometry, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Crystals 2023, 13(8), 1239; https://doi.org/10.3390/cryst13081239
Submission received: 25 July 2023 / Revised: 7 August 2023 / Accepted: 9 August 2023 / Published: 11 August 2023
(This article belongs to the Special Issue Characterisation and Study of Compounds by Single Crystal X-Ray Diffraction)
Browse Figures
Versions Notes

Abstract

:
A one-pot reaction of an equimolar mixture of 4-methoxyaniline, phenyl isothiocyanate, and 2-bromoacetylbenzofuran in absolute ethanol in the absence of any catalysts afforded 4-(benzofuran-2-yl)-3-(4-methoxyphenyl)-N-phenylthiazol-2(3H)-imine with an 83% yield. Under similar conditions, 4-flouroaniline provided a mixture of the expected 4-(benzofuran-2-yl)-3-(4-fluorophenyl)-N-phenylthiazol-2(3H)-imine and unexpected 4-(benzofuran-2-yl)-N-(4-fluorophenyl)-3-phenylthiazol-2(3H)-imine at an overall 73% yield. The structures of the synthesized heterocycles were confirmed using NMR spectroscopy. The products were recrystallized from dimethylformamide to afford samples suitable for structural determination via single-crystal diffraction. The molecules of the products share a common backbone and have similar conformations. They also display some common intermolecular interactions, including C–H···X (X = N, O, π) and π···π contacts. The molecules differ due to the methoxy and fluoro substituents on their phenyl rings, resulting in variations in the extended network in the crystals. Electron density maps and Hirshfeld surfaces have been used to rationalize the intermolecular contacts.

1. Introduction

Heterocyclic compounds are used in many medical applications due to their various biological activities [1,2,3]. Among other reasons, heterocycles are attractive because of their amiability to molecular structure modification. In addition, their lipophilicity, solubility, polarity, and capacity for hydrogen bond formation can be manipulated to suit various applications. Consequently, heterocycles play a significant role in drug design and comprise most (85%) biologically active compounds [4]. The requirement for heterocycles for medicinal applications has increased the demand for the design and synthesis of new compounds. A range of heterocycles have exhibited antibacterial, antitumor, antifungal, and anti-inflammatory properties [5]. Nitrogen-based heterocycles are particularly compelling because of their potential in salient applications [6,7,8,9,10]. Notably, these compounds are found in natural products with unique pharmacological properties [11,12,13].
Heterocycles containing the thiazol-2-imine moiety are of interest for medicinal and agricultural uses [14,15,16]. The thiazole ring system is an essential core scaffold in many natural products; for example, it serves as a crucial component of penicillin and some of its derivatives. These compounds exhibit anticancer, antifungal, anti-inflammatory, kinase inhibition, plant growth regulation, insecticidal, and acaricidal properties [17,18,19,20,21,22,23,24,25,26].
Benzofurans are widely distributed in nature [27] and have been accredited with biodynamic and therapeutic qualities [28,29]. These compounds exhibit antibacterial, antitumor, antioxidant, antiparasitic, and anti-inflammatory properties [30,31,32]. The possible uses for these compounds have led to increased attention toward synthesizing heterocycles containing benzofuran [33,34,35]. The design, synthesis, and structural determination of heterocycles containing thiazole and benzofuran moieties (Figure 1) have been a focus of continued interest, and the characterization of related heterocycles has been reported [36,37,38].
As part of our ongoing research into the design of heterocyclic molecules and the utilization of simple synthetic procedures, three new 4-(benzofuran-2-yl)-N-phenylthiazol-2(3H)-imines, namely, 5a, 5b, and 6, that incorporate thiazole and benzofuran units have been obtained. Part of the work involved crystal structure characterization, enabling a detailed study of the intermolecular contacts in the solid state [39]. Molecules 5a, 5b, and 6 have a common backbone, and their crystal structures enable the exploration of the effect of different substituents on molecular packing in the solid state.
The understanding of molecular interactions in crystalline materials is fundamental to crystal engineering. The desired goal of crystal engineering is to understand intermolecular interaction leading to the eventual exploitation of this knowledge in designing and generating materials for specific functions [40,41,42]. The arrangement of molecules in the crystal structure depends on a combination of factors which include steric effects and electrostatic interactions. The shapes and sizes of molecules and substituents contribute significantly to determining their packing modes because of the need to maximize efficiency in the occupation of space [43]. The molecules under study do not possess strong hydrogen bond donors but can be involved in other types of contacts. Strong and weak hydrogen-bonding interactions [44], including those of the C–H···π type [45], are directional and have a structure-directing capacity in crystal structure formation. Other electrostatic interactions, including π···π [46] contacts, also contribute to structural direction and stabilization.

2. Materials and Methods

2.1. General

The chemicals, reagents, and solvents used in this study were purchased from Merck (Merck Life Science UK Limited, Gillingham, UK). The melting points of the synthesized heterocycles were determined using an electrothermal melting point apparatus (Cole-Parmer, Illinois, IL, USA). The IR spectra were recorded on a Bruker Tensor 27 FTIR spectrometer (Bruker, Tokyo, Japan). The NMR spectra (δ in ppm and J in Hz), recorded at 500 MHz for the proton and 125 MHz for the carbon measurements, were obtained in dimethyl sulfoxide (DMSO-d6) using a JEOL NMR 500 MHz spectrometer (JEOL, Tokyo, Japan). The 19F NMR spectrum was recorded on Bruker Avance III HD 400 spectrometer (Bruker, Tokyo, Japan). A CHNS-932 Vario elemental analyzer (LECO Instruments Ltd., Hazel Grove, Stockport, UK) was used to measure elemental content. Compound 4 was obtained from NRC-Fine Organic Chemicals Unit at the National Research Centre, Egypt. It was synthesized using a previously reported procedure [47].

2.2. Synthesis of 4-(Benzofuran-2-yl)-N-phenylthiazol-2(3H)-imines 5a and a Mixture of 5b and 6

Scheme 1 shows the synthetic routes. A mixture of 1a or 1b (5 mmol) and 2 (5 mmol, 0.68 g) in dry EtOH (15 mL) was refluxed for 15 min, followed by the addition of 4 (5 mmol, 1.2 g). The reaction mixture was refluxed for four hours and then left to stand overnight. The resulting solid was filtered, dried, and recrystallized from DMF, yielding 5a or a mixture of 5b and 6.

2.2.1. 4-(Benzofuran-2-yl)-3-(4-methoxyphenyl)-N-phenylthiazol-2(3H)-imine (5a)

Yield: 83%, mp 182–183 °C. IR (KBr): 3131 (CH), 1618 (C=N), and 1577 (C=C) cm–1. 1H NMR: 3.81 (s, 3H, OMe), 5.63 (s, 1H, thiazolyl), 6.87 (d, 7.7 Hz, 2H, Ar), 6.95 (s, 1H, Ar), 6.98 (t, 7.7 Hz, 1H, Ar), 7.07 (d, 8.6 Hz, 2H, Ar), 7.16 (t, 7.7 Hz, 1H, Ar), 7.27 (app t, 7.7 Hz, 3H, Ar), 7.39 (d, 8.6 Hz, 2H, Ar), and 7.48 (t, 7.7 Hz, 2H, Ar). 13C NMR: 60.0, 100.4, 104.7, 111.3, 115.3, 121.4, 122.2, 123.6, 124.0, 126.0, 128.0, 130.1, 130.3, 130.7, 131.0, 146.5, 151.8, 153.9, 159.8, and 159.9. Anal. Calcd. for C24H18N2O2S (398.46): C, 72.34; H, 4.55; N, 7.03. Found: C, 72.58; H, 5.09; N, 7.11%.

2.2.2. 4-(Benzofuran-2-yl)-3-(4-fluorophenyl)-N-phenylthiazol-2(3H)-imine (5b) and 4-(Benzofuran-2-yl)-N-(4-fluorophenyl)-3-phenylthiazol-2(3H)-imine (6)

Yield: 73%, mp 157–158 °C. IR (KBr): 3129 (CH), 1616 (C=N), and 1576 (C=C) cm–1. 1H NMR: 5.60, 5.74 (2 s, 2H, thiazolyl), 6.87–6.99 (m, 4H, Ar), 7.08–7.17 (m, 5 H, Ar), 7.25–7.29 (m, 5H, Ar), and 7.41–7.54 (m, 14H, Ar). 13C NMR: 100.9, 101.0, 104.9, 105.1, 111.3, 116.6, 116.7, 116.9, 117.1, 121.4, 122.14, 122.3, 123.0, 123.0, 123.7, 123.7, 124.0, 126.1, 127.9, 128.0, 129.6, 129.8, 130.1, 132.0, 132.1, 134.4, 138.1, 146.2, 146.3, 148.2, 151.6, 153.9, 157.9, 159.9, 159.5, 159.8, 160.0, 161.4, and 163.3. 19F NMR: 112.1, 120.4. Anal. Calcd. for C23H15FN2OS (386.43): C, 71.49; H, 3.91; N, 7.25. Found: C, 71.53; H, 4.08; N, 7.39%.

2.3. X-ray Crystal Structure

Diffraction data for 5a and the mixed crystal of 5b and 6 were recorded at 296 K on an Agilent SuperNova Dual Atlas single-crystal diffractometer with mirror-monochromated Mo radiation. Structure solution calculations were carried out using SHELXS [48] and refinement via SHELXL [49]. Anisotropic displacement parameters were utilized for non-hydrogen atoms during refinement. A riding model was used for hydrogen atoms with idealized geometry, and Uiso was set to 1.2 or 1.5 times the value of Ueq for the atom to which the hydrogen atoms were bonded. The para positions of the benzene rings in the molecule of 5b/6 were treated as disordered H/F with final occupancies of 0.332(4)/0.668(4) for F1/H15b and 0.668(4)/0.332(4) for F2/H21. The crystal and structure refinement data are shown in Table 1. The crystal structures of 5a and 5b/6 have been deposited in the CSD under the reference numbers CCDC 2283522 and 2283523 (Supplementary Material).

2.4. Electrostatic Potentials and Hirshfeld Surface Calculations

The two components of the mixed crystal of 5b and 6 were treated as independent ordered structures for the calculations. The input files for electrostatic potential calculation were prepared using Avogadro [50]. The electron density calculation was performed using the RHF/631G(dp) basis set in Gamess [51] and analyzed using Macmolplot [52]. The Hirshfeld surface was generated using CrystalExplorer17 [53].

3. Results and Discussion

A method that is frequently used for synthesizing thiazole ring systems is the reaction of haloketones with thioamides [54,55,56]. Other methods include the reaction of N,N-diformylaminomethyl aryl ketones with phosphorus pentasulfide in a basic medium [57] and the reaction of oximes and anhydrides with potassium thiocyanate and a copper catalyst [58]. Amines and aldehydes can also be used through a reaction with sulfur and oxygen [59], while active methylene isocyanides and carbodithioates are synthesized with sodium hydride [60].

3.1. Synthesis of 5 and 6

Thiazol-2-imines are commonly synthesized through a one-pot three-component reaction of aromatic α-bromoketones, primary amines, and phenyl isothiocyanate in ethanol (EtOH) in the presence of a catalytic amount of triethylamine [17,61]. In this study, two commercially available and easily accessible anilines, namely, 4-methoxyaniline (1a) and 4-flouroaniline (1b), were used. The procedure used resulted in high yields after optimization of the reaction conditions (including the solvent, time, and temperature). The progress of the reaction was observed using thin-layer chromatography. A one-pot reaction of equimolar amounts of 1a (R = OMe), phenyl isothiocyanate (2), and then 2-bromoacetylbenzofuran (4) in dry ethanol (EtOH) afforded 4-(benzofuran-2-yl)-3-(4-methoxyphenyl)-N-phenylthiazol-2(3H)-imine (5a) at an 83% yield (Scheme 1). It should be noted that no catalysts were used. The reaction of 1b (R = F), 2, and 4, under reaction conditions similar to those used for the production of 5a, afforded the expected 4-(benzofuran-2-yl)-3-(4-fluorophenyl)-N-phenylthiazol-2(3H)-imine (5b) and the unexpected 4-(benzofuran-2-yl)-N-(4-fluorophenyl)-3-phenylthiazol-2(3H)-imine (6; Scheme 1) at a 73% overall yield as a 1:2 mixture. Several attempts were made to separate the two compounds through crystallization using different solvents, but these efforts were unsuccessful.

3.2. IR and NMR Spectroscopy of 5 and 6

The chemical structures for 5a and the mixture of 5b and 6 were verified using IR, 1H, and 13C NMR spectroscopy (For further details, refer to the Supplementary Materials for the corresponding spectra.) In the IR spectra of 5a (Figure S1) and the mixture containing 5b and 6 (Figure S2), distinct absorption bands were observed at the 1616–1618 cm−1 and 1576–1577 cm−1 regions. These bands can be attributed to the stretching vibrations of the C=N and C=C groups, respectively. A distinct singlet signal was observed in the 1H NMR spectrum of 5a (Figures S3 and S4), indicating the presence of the thiazolyl proton at 5.63. In addition, the 1H NMR spectrum of compound 5a displayed a singlet signal at 3.80 ppm corresponding to the three protons from the OMe group. The 1H NMR spectrum of the mixture containing 5b and 6 (Figure S5) showed the thiazolyl proton at 5.75 and 5.60 ppm, respectively. Upon analyzing the 13C NMR spectrum of 5a (Figures S6–S8), it was confirmed that all carbons were detected at the anticipated locations following their chemical shifts. The 13C NMR spectrum of the mixture containing 5b and 6 (Figure S9) was complex and showed signals for both compounds. It was difficult to precisely determine the coupling constants between the carbon and fluorine atoms. The 19F NMR spectrum of the mixture displayed two signals at 112.1 and 120.4, which corresponded to 5b and 6, respectively. Furthermore, there was indication of the existence of two additional minor isomers.

3.3. Proposed Mechanisms for the Formation of 5 and 6

A proposed mechanism for the formation 5a and 5b is shown in Scheme 2. It involves the addition of 1a,b to 2 to yield the corresponding thiourea 3a,b. Thiourea 3a,b tautomerizes to yield 7a,b which reacts with 2-bromoacetylbenzofuran (4) to give the corresponding ketone 8a,b and hydrobromic acid (HBr) as a side product. The tautomerization of 8a,b yields 9a,b, which loses H2O to afford 5a,b.
The mechanism through which 6 is produced involves the addition of 1b to 2 to yield thiourea 3b (Scheme 3). The tautomerization of 3b leads to the formation of 10 and 11, which, on reaction with 4, yield 12 and HBr as a side product. The tautomerization of 12 leads to 13, which affords product 6 via the loss of H2O (Scheme 3).

3.4. X-ray Crystal Structures

3.4.1. Crystal Structure of 5a

The crystal structure of 5a is orthorhombic, space group P212121, and an ortep representation of the molecule is shown in Figure 2a. The molecule comprises the following groups: benzofuran (A5a, C1–C7, and O1), thiazole (B5a, C9–C11, N1, and S1), methoxybenzene (C5a, C12–C17, O2, and C24), and aminobenzene (D5a, C18–C23, and N2). Rings A5a and B5a are almost co-planar in the molecule, with a twist angle A5a/B5a of ca. 17°. In contrast, twist angles B5a/C5a and B5a/D5a are greater: they are in the range of 49–78° (Table 2).
Molecule 5a does not possess strong hydrogen bond donors, but its crystal structure displays weaker C–H···X (X = N, O) interactions (Table 3). In the crystal structure, C13–H13···N2 interactions (Figure 3a,b) between the methoxybenzene and aminobenzene groups of neighboring molecules form chains parallel to the direction of the a-axis. Within the chain, the furan group is involved in π–π contact with the thiazole group of a neighbor with a ring centroid-to-centroid distance of 3.93 Å (red dotted lines in Figure 3a,b).
Each chain is linked to adjacent chains via the oxygen of the methoxybenzene group of a molecule accepting one C19–H19···O2 contact and the aminobenzene group donating another. The thiazole group also donates a C10–H10···O1 contact to a neighboring benzofuran group (shown in green in Figure 3a,b). Edge-to-face C–H···π contacts between the benzene rings of the benzofuran group with an H···ring centroid distance of 2.85 Å complete the extended 3D network in the structure (shown in blue in Figure 3a,b).

3.4.2. Structure of the Mixed Crystal of 5b and 6

Structure determination of the crystals obtained after synthesis showed that the substituents in the para positions of the phenyl rings were shared by H and F atoms, and this finding is consistent with the mixture of compounds obtained during synthesis (Scheme 1). The compounds were 4-(benzofuran-2-yl)-3-(4-fluorophenyl)-N-phenylthiazol-2(3H)-imine (5b) and 4-(benzofuran-2-yl)-N-(4-fluorophenyl)-3-phenylthiazol-2(3H)-imine (6), and the ratio of 5b:6 in the crystal was 0.33:0.67. Thus, the crystal structure contains a mixture of molecules 5b and 6 with fluoro substituents on two different benzene rings. Despite the differences in the electronic properties of the benzene and fluorobenzene groups, solid solutions of compounds containing these groups can be formed due to the similar sizes of the groups, as observed in the case of benzoic acid and 4-fluorobenzoic acid [62].
The crystal structure of the mixed crystal of 5b and 6 is monoclinic, space group P21/c, and an ortep representation of the asymmetric unit is shown in Figure 2b. The molecule consists of benzofuran (A6, C1–C7, and O1), thiazole (B6, C9–C11, N1, and S1), benzene/fluorobenzene (C6, C12–C17, and F1), and aminobenzene/aminofluorobenzene (D6, C18–C23, and F2) groups. In the molecule, the planes of rings A6 and B6 are close, with a twist angle A6/B6 of ca. 18°, whereas twist angles B6/C6 and B6/D6 are in the range of 54–78° (Table 2).
As in the observation regarding the crystal structure of 5a, C13–H13···N2 interactions (Figure 4a,b) between methoxybenzene and aminobenzene groups of neighboring molecules form chains parallel to the b-axis in the crystal of 5b/6. The furan groups are also involved in π···π contact with the thiazole groups of neighboring molecules within the chain, with ring centroid-to-centroid distances of 3.99 Å.
Also, comparably with 5a, the thiazole groups donate C10–H10···O1 interactions to neighboring benzofuran groups of adjacent chains (Table 3). Edge-to-face C–H···π connections between the benzene rings of the benzofuran groups with H···ring centroid distances of 2.98 Å are also observed (Figure 4a,b).
The chains are also linked through C–H···F interactions involving the aminofluorobenzene group. The group accepts a contact from the benzofuran group of a molecule from an adjoining chain and donates a contact to the fluorobenzene group of another chain. Interchain C2–H2···S1 contact also occurs.

3.4.3. Comparison of Crystal Packing

Generally, the arrangement of molecules in crystal packing depends on a combination of factors, including steric effects and electrostatic interaction. Steric effects influence molecular arrangement because the shapes and sizes of molecules and substituents largely determine the most efficient way the molecules can occupy space efficiently. The molecules of 5a, 5b, and 6 are identical, apart from the methoxy group in 5a and the fluoro groups in 5b and 6. The similarity in the core of the molecules is reflected in the similarity in the twist angles between groups A/B, B/C, and B/D in the molecules (Table 2).
Electrostatic interactions, such as hydrogen bonding, may be directional and can thus steer molecules so that they pack in a specific way. It is noted here that there are no strong hydrogen bond donors in molecules 5a, 5b, and 6. For ease of analysis and discussion, the two molecules in the mixed crystal of 5a and 6 have been treated separately, retaining the packing obtained from the structural refinement of the mixed crystal structure.
The electron density isosurfaces for the molecules are shown in Figure 5. The positive regions, shown in red and clearly visible around the hydrogen atoms of the molecules, can donate weak hydrogen bonds. The negative regions, shown in blue, can accept hydrogen bonds. The main negative regions that are common to all the molecules are located on the benzofuran oxygen (O1) and the aminobenzene nitrogen (N2) atoms. Additionally, the methoxy oxygen in 5a and the fluorine atoms in 5b and 6 are negative.
The segments that are common to molecules 5a, 5b, and 6 (i.e., all atoms except methoxy and F) participate in similar intermolecular interactions in the structures. The Hirshfeld surfaces, which show close contact between molecules, are presented in Figure 6. The distribution of the close contacts (highlighted in red) is similar for all the common parts of the molecules. As already discussed, the similar intermolecular contacts in the structures involve C13–H13···N2 interactions between the benzene and aminobenzene groups of neighboring molecules, leading to the formation of chains, and the thiazole groups donating C10–H10···O1 contacts to neighboring benzofuran groups. Additionally, the furan groups are involved in π···π contact with the thiazole groups of neighboring molecules, and edge-to-face contacts between the benzene rings of the benzofuran groups also occur.
The electron density isosurfaces are negative for the regions around the methoxy oxygen and F atoms (the different substituents in 5a and 5b/6), and these atoms are involved in intermolecular hydrogen-bonding contact. Thus, the methoxybenzene group accepts a C19–H19···O2 interaction from an aminobenzene group, and C–H···F contacts are also observed for both the F atoms of molecules 5b and 6 in the mixed crystal. Molecules 5a and 5b have methoxy and fluoro substituents, respectively, on the same benzene ring (C5a and C6, respectively) and accept hydrogen bonds. However, it is observed that the methyl on the methoxy group sterically hinders the oxygen atom and limits the direction of hydrogen bonding.

4. Conclusions

The successful synthesis of 4-(benzofuran-2-yl)-3-(4-methoxyphenyl)-N-phenylthiazol-2(3H)-imine in good yields was induced through one-pot reactions of an equimolar mixture of 4-methoxyaniline, phenyl isothiocyanate, and 2-bromoacetylbenzofuran in the absence of any catalysts. Under similar reaction conditions, the use of 4-fluroaniline led to the formation of a mixture of the expected 4-(benzofuran-2-yl)-3-(4-fluorophenyl)-N-phenylthiazol-2(3H)-imine and the unexpected 4-(benzofuran-2-yl)-N-(4-fluorophenyl)-3-phenylthiazol-2(3H)-imine. The structures of the newly synthesized heterocycles were determined using nuclear magnetic resonance spectroscopy and X-ray diffraction.
The crystal structures of 5a and the mixed crystal of 5b and 6 have been established. The identical segments of the molecules participate in similar intermolecular contacts of the C–H···N type between benzene and aminobenzene groups of neighboring molecules that result in the formation of chains, and thiazole groups donate C–H···O contacts to neighboring benzofuran groups. Furan groups are involved in π···π contact with the thiazole groups of neighboring molecules, and edge-to-face contacts occur between benzene rings of adjacent benzofuran groups. The different substituents, methoxy and fluorine, also accept C–H hydrogen-bonding contacts.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cryst13081239/s1, Figure S1: IR spectrum of 5a; Figure S2: IR spectrum for the mixture containing 5b and 6; Figure S3: 1H NMR spectrum of 5a; Figure S4: 1H NMR spectrum (expansion) of 5a; Figure S5: 1H NMR spectrum for the mixture containing 5b and 6; Figure S6: 13C NMR spectrum of 5a; Figure S7: 13C NMR spectrum (expansion) of 5a; Figure S8: 13C NMR spectrum (expansion) of 5a; Figure S9: 13C NMR spectrum for the mixture containing 5b and 6; Figure S10: 19F NMR spectrum for the mixture containing 5b and 6; Figure S11: 19F NMR spectrum for the mixture containing 5b and 6; Supplementary Files: SF1: CIF for 5a, SF2: CIF for the mixed crystal of 5b and 6; SF3: CheckCIF report for 5a; SF4: CheckCIF report for the mixed crystal of 5b and 6.

Author Contributions

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

Funding

G.A.E.-H. acknowledges the support from the Researchers Supporting Project (number RSP2023R404), King Saud University, Riyadh, Saudi Arabia.

Data Availability Statement

Data are contained within the article and the Supplementary Material.

Acknowledgments

We thank the National Research Centre and Cardiff University for technical support.

Conflicts of Interest

The authors have no conflict of interest to declare.

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Crystals 13 01239 g001
Figure 1. Important heterocycles containing thiazole and benzofuran moieties.
Figure 1. Important heterocycles containing thiazole and benzofuran moieties.
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Crystals 13 01239 sch001
Scheme 1. Synthetic routes for the preparation of thiazol-2(3H)-imines 5a and b and 6. Equal amounts (5 mmol) of 1, 2, and 4 were used in boiling dry EtOH. The crystallization (DMF) of crude products resulted in 5a (83%) and a mixture of 5b and 6 (73%).
Scheme 1. Synthetic routes for the preparation of thiazol-2(3H)-imines 5a and b and 6. Equal amounts (5 mmol) of 1, 2, and 4 were used in boiling dry EtOH. The crystallization (DMF) of crude products resulted in 5a (83%) and a mixture of 5b and 6 (73%).
Crystals 13 01239 sch001
Crystals 13 01239 sch002
Scheme 2. A proposed mechanism for the formation of 5a and 5b.
Scheme 2. A proposed mechanism for the formation of 5a and 5b.
Crystals 13 01239 sch002
Crystals 13 01239 sch003
Scheme 3. A proposed mechanism for the formation of 6.
Scheme 3. A proposed mechanism for the formation of 6.
Crystals 13 01239 sch003
Crystals 13 01239 g002
Figure 2. Ortep representation (at 50% probability atomic displacement parameters) for (a) 5a and (b) the mixed crystal of 5b and 6. Both disorder components are shown for the mixed crystal.
Figure 2. Ortep representation (at 50% probability atomic displacement parameters) for (a) 5a and (b) the mixed crystal of 5b and 6. Both disorder components are shown for the mixed crystal.
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Crystals 13 01239 g003
Figure 3. (a) The crystal packing in the structure of compound 5a; (b) a segment of the structure. Intermolecular contacts are shown as dotted lines: green = C–H···N and C–H···O; blue = C–H···π; and red = π···π.
Figure 3. (a) The crystal packing in the structure of compound 5a; (b) a segment of the structure. Intermolecular contacts are shown as dotted lines: green = C–H···N and C–H···O; blue = C–H···π; and red = π···π.
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Crystals 13 01239 g004
Figure 4. (a) Packing in the structure of the mixed crystal of compounds 5b and 6 and (b) a segment of the structure. Intermolecular contacts are shown as dotted lines: green = C–H···N, C–H···O, C–H···S and C–H···F; blue = C–H···π; red = π···π.
Figure 4. (a) Packing in the structure of the mixed crystal of compounds 5b and 6 and (b) a segment of the structure. Intermolecular contacts are shown as dotted lines: green = C–H···N, C–H···O, C–H···S and C–H···F; blue = C–H···π; red = π···π.
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Crystals 13 01239 g005
Figure 5. Electron density maps for molecules of (a) 5a, (b) 5b, and (c) 6, with negative and positive regions represented in blue and red, respectively.
Figure 5. Electron density maps for molecules of (a) 5a, (b) 5b, and (c) 6, with negative and positive regions represented in blue and red, respectively.
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Crystals 13 01239 g006
Figure 6. Hirshfeld surfaces for molecules (a) 5a, (b) 5b, and (c) 6 with areas of close intermolecular contact highlighted in red.
Figure 6. Hirshfeld surfaces for molecules (a) 5a, (b) 5b, and (c) 6 with areas of close intermolecular contact highlighted in red.
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Table 1. Crystal and structure refinement data of 5a and the mixed crystal of 5b and 6.
Table 1. Crystal and structure refinement data of 5a and the mixed crystal of 5b and 6.
Identification Code5a5b/6
Empirical formulaC24H18N2O2SC23H15FN2OS
Formula weight398.46386.43
T (K)296(2)293(2)
λ Å0.710730.71073
Crystal systemOrthorhombicMonoclinic
Space groupP212121P21/c
a (Å)5.5731(5)10.6289(9)
b (Å)10.2520(9)5.6010(3)
c (Å)34.307(3)30.567(2)
α (°)9090
β (°)9095.645(7)
γ (°)9090
Volume (Å3)1960.1(3)1810.9(2)
Z44
Density (calculated) (Mg/m3)1.3501.417
Absorption coefficient (mm–1)0.1880.205
Crystal size (mm3)0.392 × 0.090 × 0.0490.550 × 0.130 × 0.070
Reflections collected16,40815,447
Independent reflections48784636
R(int)0.04970.0539
Parameters263264
Goodness-of-fit on F21.0551.059
R1 [I > 2σ(I)]0.0500.0584
wR2 [I > 2σ(I)]0.09880.1076
R10.08430.1354
wR20.11430.1410
Largest diff. peak and hole (e.Å−3)0.195 and −0.2140.206 and −0.255
Table 2. Group twist angles (°) for the molecule in the crystal structures of 5a and the mixed crystal of 5b and 6.
Table 2. Group twist angles (°) for the molecule in the crystal structures of 5a and the mixed crystal of 5b and 6.
A/B B/CB/D
5a16.98(16)77.82(1)49.55(12)
5b/617.55(12)77.45(8)54.51(8)
Table 3. Intermolecular contacts (Å, °) in the crystal structures of 5a and the mixed crystal of 5b and 6.
Table 3. Intermolecular contacts (Å, °) in the crystal structures of 5a and the mixed crystal of 5b and 6.
D···AD–H···A
5aC13–H13···N23.523(5)162.8
C10–H10···O13.280(4)120.0
C19–H19···O23.398(5)136.3
5b/6C13–H13···N23.634(3)167.4
C10–H10···O13.261(3)117.2
C7–H7···F23.392(4)142.7
C19–H19···F13.192(6)156.1
C2–H2···S13.812(3)123.0
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Abdel-Wahab, B.F.; Kariuki, B.M.; Mohamed, H.A.; El-Hiti, G.A. Catalyst-Free Synthesis of Novel 4-(Benzofuran-2-yl)-N-phenylthiazol-2(3H)-imines, Crystal Structure Elucidation, and the Effect of Phenyl Substitution on Crystal Packing. Crystals 2023, 13, 1239. https://doi.org/10.3390/cryst13081239

AMA Style

Abdel-Wahab BF, Kariuki BM, Mohamed HA, El-Hiti GA. Catalyst-Free Synthesis of Novel 4-(Benzofuran-2-yl)-N-phenylthiazol-2(3H)-imines, Crystal Structure Elucidation, and the Effect of Phenyl Substitution on Crystal Packing. Crystals. 2023; 13(8):1239. https://doi.org/10.3390/cryst13081239

Chicago/Turabian Style

Abdel-Wahab, Bakr F., Benson M. Kariuki, Hanan A. Mohamed, and Gamal A. El-Hiti. 2023. "Catalyst-Free Synthesis of Novel 4-(Benzofuran-2-yl)-N-phenylthiazol-2(3H)-imines, Crystal Structure Elucidation, and the Effect of Phenyl Substitution on Crystal Packing" Crystals 13, no. 8: 1239. https://doi.org/10.3390/cryst13081239

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