Journal Information
Journal ID (publisher-id): chemical
Title: Journal of the Korean Chemical Society
Translated Title (ko): 대한화학회지
ISSN (print): 1017-2548
ISSN (electronic): 2234-8530
Publisher: Korean Chemical Society대한화학회
INTRODUCTION▼
Over the past decades, research has been focused on α,β-unsaturated ketone which have numerous therapeutic effects, such as, cytotoxicity,1−3 antimitotic,4 antimutagenic,5 antibacterial, antiviral,6 anti-inflammatory,4,7,8 and hepatoprotective activities.9 Some researchers studied the properties of pyrazolines and pyrazole derivatives forming a cyclic moiety of hydrazine and found high activity.10,11 Moreover chalcones, are considered as a key to flavones in flavonoid biosynthesis that is because, in open chain flavonoids two aromatic rings are joined by three carbons with α-β unsaturated system.12 Also, implementation a pyrazole ring in the chalcones increases the cytotoxic activity towards a series of human cancer cell lines.13 In general, acid- or base-catalyzed Claisen-Schmidt condensation of aldehyde and ketone, followed by dehydration is commonly used to synthesize chalcones.14 In the aromatic chalcones which contain keto-ethenyl group (-CO-CH=CH) may exist either in cis or trans form.15 Delocalization of π electrons in the conjugated double bond system reduces its electron density and makes it an intermediate for the synthesis of distinct heterocycles. On the other hand, density functional theory (DFT) was known as an effective tool for providing theoretical guidance into chemical reactivity, and it can help in the expectation of the reaction mechanism as it generate mechanical quantity descriptors used in quantitative structure-activity relationship.16−28
Such findings have led us to synthesize a novel of phenylthiophene chalcones and its corresponding pyrazoline derivatives and to focus on the reaction mechanism depending on DFT calculations. DFT calculations will be discussed to foresee the molecular confirmations23−25 as well as their thermal parameters. In addition, these calculations will be used to explain mechanistic steps for the formations of pyrazoline derivatives. Density functional theory (DFT) is recognized as an important tool to provide theoretical response to chemical reactivity, which affects the biological properties of many drugs, on the other hand, DFT has been shown to illustrate valuable descriptions of molecular structure, mechanistic study, vibrational frequencies, and the energetics of chemical reactions to investigate the electronic properties of many chalcones. Many DFT studies routinely provide chemical reactivity, but no such studies have been performed on thiophene chalcones.27,28
EXPERIMENTAL▼
Computational Method
Gaussian 09 software was used for DFT calculations for the studied compounds.29 DFT methods using B3LYP 6-31G (d, p) basis set was selected for the calculations. The geometries were optimized by minimizing the energies with respect to all geometrical parameters without imposing any molecular symmetry constraints. The structures of the optimized geometries had been drawn with Gauss View.30 Also, calculations of frequencies were carried out by the same level of theory. The frequency calculations showed that all structures were stationary points in the geometry optimization method with none imaginary frequencies.
Materials and Instrumentations
All melting points were measured using Gallenkamp melting point device. Fourier Infrared (Ft-IR) Spectra were recorded using Perkin Elmer FT-IR Spectrum Nicolet IS10. Nuclear Magnetic Resonance Spectra were recorded on a Bruker NMR spectrometer, 1H spectrum was run at 300 MHz in deuterated DMSO as a solvent, the chemical shift (δ) was reported in ppm and the coupling constant (J) values in Hertz and the 13C NMR spectrum was run at 75MHz in deuterated DMSO. The reaction courses were monitored by thin layer chromatography (TLC) on silica gel plates and spots were visualized by UV lamp at 250-380 nm. All the chemicals were purchased from Sigma–Aldrich.
Synthesis of 3-(5-phenylthiophen-2-yl)prop-2-en-1-ones 3(a, b)
To a solution of 5-phenylthiophene-2-carbaldehyde (1) (0.01 mol, 1.9 mL) and 1-(biphenyl-3-yl) ethanone (2a) or 1-(4-(piperidin-1-yl) phenyl) ethanone (2b) (0.01 mol, 2 mL) in absolute ethanol (40 mL), potassium hydroxide solution (3 mL, 40%) was added portion-wise. The mixture was stirred for 2 h. The solid product was collected by filtration, washed with water, dried and finally crystallized from ethanol to give compounds 3a and 3b, respectively.
1-(biphenyl-4-yl)-3-(5-phenylthiophen-2-yl) prop-2-en-1-one (3a). Yellow crystals (yield 82%), m.p. > 300 °C; IR (KBr, ν cm-1): 1638 (C=C) and 1677 (C=O); 1H NMR (DMSO-d6) δ ppm: 7.17-8.49 (m, 14H, ArH), 7.29-7.51 (d, 1H, J = 7.2 Hz, olefinic hydrogen), 7.85-7.87 (d, 1H, J = 7.2 Hz, olefinic hydrogen), 7.94-7.97 (d, 1H, J = 7.6 Hz, thiophene H), 8. 20-8.23 (d, 1H, J = 10.0 Hz, thiophene H); m/z: 365.47 (M-1, 26.13%), Anal. Calcd for C25H18OS (366.1): C, 81.93; H, 4.95. Found: C, 81.91; H, 4.90.
3-(5-phenylthiophen-2-yl)-1-(4-(piperidin-1-yl)phenyl) prop-2-en-1-one (3b). Yellow crystals (yield 78%), m.p. 210-2 °C; IR (KBr, ν cm-1) : 1630 (C=C) and 1657 (C=O); 1H NMR (DMSO-d6) δ ppm: 1.53-1.60 (m, 6H, piperidine H), 3.34-3.41 (m, 4H, piperidine H), 6.97-7.03 (d, 2H, J = 8 Hz, ArH), 7.45-7.67 (m, 5H, ArH), 7.37-7.39 (dd, 1H, J = 8 Hz, olefinic H), 7.77-7.83 (d, 2H, J = 8 Hz, ArH), 7.95-7.97 (dd, 1H, J = 8 Hz, olefinic H), 7.82-7.84 (d, 1H, J = 7.6 Hz, thiophene H), 7.99-8.01 (d, 1H, J = 10 Hz, thiophene H) ; 13C NMR (75 MHz, DMSO-d6) δ ppm: 185.94 (C=O), 154.34, 146.56, 146.10, 139.95, 139.11, 135.04, 134.04, 133.57, 131.05 (2C), 129.76, 128.98, 126.60, 126.07, 125.57, 121.12, 113.49, 108.87, 48.17 (2C), 25.37(2C), 24.44; m/z: 372.18 (M-1, 7.01%); Anal. Calcd for C24H23NOS (373.5): C, 77.18; H, 6.21; N, 3.75. Found: C, 77.21; H, 6.30; N, 3.77.
Synthesis of 4, 5-dihydro-1H-pyrazole-1-carbothioamide 4(a, b)
To a solution of KOH (0.025 mol) and chalcone 3 (a, b) (10 mmol, 3.7 g) in ethanol (50 ml), thiosemicarbazone (10 mmol, 0.9 g) was added. The reaction mixture was refluxed for 6 hrs. The resulting solid was filtered, washed with water, dried and recrystallized from EtOH/DMF to give pyrazole derivatives 4 (a, b).
5-(biphenyl-4-yl)-3-(5-phenylthiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (4a). Yellow crystals (yield 70%), m.p. 210-212 °C; IR (KBr, ν cm-1): 3241 & 3134 (NH2), 1584 (C=N) and 1259 (C=S); 1H NMR (DMSO-d6) δ ppm: 3.8-4.0 (m, 1H, Ha of pyrazole), 4.8-5.0 (m, 1H, Hb of pyrazole), 6.2-6.4 (m, 1H, Hc of pyrazole), 7.02-7.90 (m, 14H, ArH), 7.94-7.96 (d, 1H, J = 7.6 Hz, thiophene H), 8.01-8.03 (d, 1H, J = 10 Hz, thiophene H), 8.5 (s, 2H, NH2); m/z: 438.52 (M-1, 4.62%); 13C NMR (75 MHz, DMSO-d6) δ ppm: 198.51 (C=S), 161.13, 146.06 (2C), 137.01 (2C), 135.06 (2C), 129.90 (2C), 129.63 (2C), 127.82 (6C), 126.31 (4C), 121.19 (2C), 120.13, 40.62; m/z: 372.18 (M-1, 7.01%); Anal. Calcd for C26H21N3S (439.6): C, 71.04; H, 4.82; N, 9.56. Found: C, 71.14; H, 4.83; N, 9.50.
3-(5-phenylthiophen-2-yl)-5-(4-(piperidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (4b). Brown crystals, (yield 87%), m.p. 160-162 °C; IR (KBr, ν cm-1): 3376 & 3266 (NH2) and 1532 (C=N) and 1242 (C=S); 1H NMR (DMSO-d6) δ ppm: 1.56-1.60 (m, 6H, pipridine H), 3.28-3.34 (m, 4H, pipridine H), 4.1-4.49 (m, 2H, Ha & Hb of pyrazole), 5.10-5.3 (m, 1H, Hc of pyrazole), 6.94-6.97 (d, 2H, J = 8.0 Hz, ArH), 7.36-7.56 (m, 5H, ArH), 7.70-7.73 (d, 2H, J = 8.0 Hz, ArH), 7.93-8.09 (d, 1H, J = 7.6 Hz, thiophene H) , 8.28-8.29 (d, 1H, J =10.0 Hz, thiophene H), 8.63 (s, 2H, NH2); m/z: 446.2 (M+, 1.02%), Anal. Calcd for C25H26N4S2 (446.6): C, 67.23; H, 5.87; N, 12.54. Found: 67.20; H, 5.85; N, 12.51.
RESULTS AND DISCUSSION▼
Two new chalcones were synthesized by condensing 5-phenylthiophene-2-carbaldehyde (1) with 1-(biphenyl-3-yl)ethanone (2a) or 1-(4-(piperidin-1-yl) phenyl)ethanone (2b) in ice bath in absolute ethanol (40 mL), potassium hydroxide solution (3 ml, 40%) was added portion-wise. The mixture was stirred for 2 h. The solid product was collected by filtration, washed with water, dried and finally crystallized from ethanol to give prop-2-en-1-ones 3a and 3b in pure state and high yield. The structure of the new synthesized chalcones was confirmed by spectroscopic data as well as elemental analysis. FT-IR data revealed that the absorption bands in the region 1630-1677 cm-1 corresponding to the conjugated carbonyl system of chalcones. The 1H NMR spectra of 3a, 3b exhibit the presence of doublet signals at δ = 7.29-7.97 ppm due to the olefinic hydrogen.
Four conformers have been suggested as products of Aldol condensation reactions, four isomers for 3a, Scheme 2, and two for 3b, Scheme 3. DFT calculations have been performed to study the stability of the estimated conformers [3a (i-iv), 3b (i, ii)]. The DFT calculations were carried out in gas phase with B3LYP 6-311G basis set. The absence of the imaginary frequency for all optimized structures is an evidence of their stability. The thermal parameters have been summarized in Table 1. The results of the theoretical calculations for the four conformers 3ai-iv revealed that the conformer 3aii is the most stable isomer and 3bii for the other derivative. However, the energy difference between the most stable isomer and the least stable one is 2.03 Kcalmol-1 for 3a and 157.71 Kcalmol-1 for 3b. The lower enthalpy value (ΔH) between isomers of 3a is an evidence of their presence in equilibrium. Both compounds showed the same geometrical structure of the stable isomer, syn geometrical configuration of the C=O with aryl group and anti-configuration of the thiophene ring with the β-unsaturated bond. These results could be explained in terms of the formation of the proper geometrical structure for the maximum conjugation. Fig. 1 (in Supplementary Material) shows the geometrical structures of the most stable conformers of 3aii and 3bii. The figure emphasizes the twisting of the phenyl ring of the biphenyl part as well as the phenyl ring attached to the thiophene, this could illustrate the non co planarity of the investigated chalcones.
Compound 3a and 3b were treated with thiosemicarbazide in presence of NaOH in refluxing ethanol to afford thioamide derivatives 4a and 4b, Scheme 4. The IR spectra of the latter compounds showed absorption bands at 1584-1532 cm-1 corresponding to C=N group and at 1242-1259 cm-1 stretching band of C=S group, and the absorption band of NH2 group at 3376-3134 cm-1. Its 1H-NMR spectrum showed the signals of Ha, Hb, and Hc of pyrazole ring as multiplet in the region of 3.26-3.40, 3.95-4.8 and 5.88-6.4 ppm, respectively, and the weak signals at 8.5-8.6 due to NH2 protons.
The reaction mechanism of the addition of thiosemicarbazide to chalcones is studied for 3a as representative example. The mechanism could involve the intermediate formation of thiosemicarbazone and subsequent nucleophilic addition of N–H to the β-unsaturated carbon to give the pyrazole ring; condensation followed by Michael type reaction mechanism, Scheme 5.31 Moreover, there is another reaction mechanism that could compete, Michael type reaction on the β-unsaturated carbon atom followed by nucleophilic attack on the carbonyl group, Scheme 6.
It has been reported by Hawaiz et al.32 that the preparation of thiocarbamoyl pyrazoline derivatives from substituted chalcones and thiosemicarbazide were achieved in high yields on the basis of the condensation then Michael type addition reaction mechanism. The DFT calculations have been used to confirm the reaction mechanism. The atom polar tensor (APT) charges are calculated at the same method with the same base set, Table 2, Fig. 2 (in Supplementary Material). According to the calculated APT charges, the most significant variations of the APT charges at the different atomic sites of the studied chalcones are due to change in the position and the type of the attached ring of the ketone. The highest positively charged centers is the C1, carbonyl carbon, of compounds 3aii (1.542513) and 3bii (1.694828). Consequently, the nucleophilic attack of the NH2 of the thiosemicarbazide might be started on the carbon of the carbonyl group of the highest positive charge rather than the β-unsaturated carbon atom (C4), then by the elimination of one water molecules affords the thiosemicarbazone. Successfully, a second nucleophilic addition of the NH group to the β-unsaturated carbon atom (C4) gives the corresponding pyrazole derivatives 4aii and 4bii. This mechanism is a good evidence of the condensation then Michael type mechanism, Scheme 5, rather than Michael type then the condensation mechanism, Scheme 6.
The reaction of chalcones with thiol compounds is reported to give two diastereomeric adducts.33 Stereochemical investigation of thiol addition reaction of hydroxychalcone and its bis-Mannich derivative was studied. In these reactions, the nucleophilic addition to the beta-carbon atom of the enone moiety generates a new chiral centre. Due to the chiral centres, formation of the enantiomeric forms of the new chiral centre results in formation of two diastereomeric adducts. Accordingly, the observed diasteroselectivity is reflecting enantioselectivity of the addition reactions. A series of bi- and tricyclic 4,5-dihydropyrazoles were reported to afford two diastereoisomers. The reaction of chalcones with semicarbazide gave only one diastereoisomer.10,32 In our present investigation, many isomers (conformational as well as stereo-isomers) could be expected as products of this reaction. Compound 4a is expected to be in four major conformers 4a (i-iv) Scheme 7, however, 4b is expected to be in only two, 4b (i, ii) Scheme 8. Since the reaction created a chiral centre, each conformer could exist in two stereoisomers R and S. The thermal parameters tabulated in Table 3 were calculated by DFT method at B3LYP 6-31G (d, p) basis set. The S and R configurations of 4a have been calculated, and only the S isomer of 4b was calculated. The results of the DFT calculations of the thermal parameters revealed that the pyrazoles 4aiv and 4bii are the least in energy. Regardless of the position of the ring A or its saturation issue, the same geometrical isomer was obtained for both compounds 4aiv and 4bii. This result might be explained in terms of the steric and strain effects, Fig. 3 (in Supplementary Material). Moreover, the absolute configuration of these diastereoisomers has insignificant effect on the stability. However, the S isomer is more stable than the R one by 7.7 Kcalmol-1. This DFT result is confirmed by the reported X-ray structure of its analogues pyrazoles [10], as single crystal X-ray analysis showed the absolute (S)-configuration of the products of these reactions.
Table S4 (in Supplementary Material) showed selected structure parameters of optimized geometry of stable S isomers of 4aiv and 4bii calculated by B3LYP/6-311G method. The bond length of C1-C2 is also affected by the conjugation of the phenyl ring B to have double bond characted that decreases the bond length to be in the range of 1.46 Å. Niether the attachement of the saturated pipridine ring nor its position has a signeficant effect on the bond length. Moreover, there is insigneficant effect of the absolute configuration of the chiral center. Additionally, C2-N6 has a single bond character, its bond length is in between 1.30 Å instead of 1.25 Å for an un-conjugated C=N bond. The long bond lengths of C10-C12 and C22-C26 (1.46 Å) is an evidence of the twisting of the phenyl rings A and E of compounds 4aiv R and 4aiv S. The co-planarity of the aromatic π-bonds decreases the C-C bond length to be lower than 1.4 Å. Another confirmation of these results is achieved by calculations of bond angles for the studied compounds. They showed deviation from the normal trigonal planer for all the unsaturated groups which confirm some single bond character for those gruops. Moreover, the dihedral angles showed the degree of twisting of the rings A and E with respect to the conjugated rings B and D; respectively.
On the other hand, a detailed study of the spectrophotometric absorption of the most stable compounds has been achieved either experimentally or theoretically. The experimental UV-Vis spectrum of the most stable conformers of the prepared compounds 3a, b and 4a, b in alcoholic solutions was recorded in the region of 200-550 nm, Fig. S4 (in Supplementary Material). Moreover, energy levels of the frontier molecular orbitals (FMOs), the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were calculated by the same method at the same set. The calculated energy gap between HOMO and LUMO orbitals was tabulated in Table S5 (in Supplementary Material). The maximum absorbance wavelengths (λmax) were also calculated and compared with the experimentally measured one. The experimental and the theoretical results of the spectrophotometric data were in comparable values. It is obvious that the attachment of pyrazine ring of compound 3a and 4a afforded bathochromic shift in case of the chalcone derivatives 3 and hypsochromic shift for pyrazoline derivatives 4, this result could be illustrated in terms of the degree of conjugation.
CONCLUSIONS▼
Aldol condensation of 5-phenylthiophene-2-carbaldehyde (1) with 1-(biphenyl-3-yl)ethanone (2a) or 1-(4-(piperidin-1-yl)phenyl)ethanone (2b) in ice bath using basic condition produced in pure state and high yield of prop-2-en-1-ones 3a and 3b, which then reacted with thiosemicarbazide to form its pyrazoline derivatives (4a) and (4b). The structures of the newly synthesized compounds were confirmed by spectroscopic data as well as elemental analysis. The DFT calculations revealed that the most stable conformers are (3aii) and (3bii), also confirmed the reaction mechanism. The stability and the structural parameters of the predicted conformers revealed that orientation of the biphenyl and the phenylthiophene moieties affect the stability of the estimated conformers of the synthesised chalcones and pyrazoline.