- Research article
- Open Access
Vibrational spectral analysis, XRD-structure, computation, exo⇔endo isomerization and non-linear optical crystal of 5-((5-chloro-1H-indol-2-yl)methylene)-1,3-diethyl-2-thioxodihy-dropyrimidine-4,6 (1H,5H)-dione
© The Author(s) 2019
- Received: 13 June 2018
- Accepted: 16 January 2019
- Published: 2 February 2019
- Thiobarbituric acid
- Exo–endo isomer
Barbituric acid and thiobarbituric acid and their derivatives as hypnotic-compounds containing the active methylene are considered being as a good starting material to prepare specific class of heterocyclic molecules via Knoevenagel mild condensation condition [1–4]. Combination of thiobarbituric acid and different aldehydes via dehydration reactions is a useful synthetic technique to design novel mono-/or poly-substituted thiobarbiturate derivatives [2–8]. Such compounds recently become highly attractive to pharmaceutical chemists, since it is biological very activity, it used as: anticancer, anti-inflammatory, antioxidant, antibacterial, anti-convulsing, antifungal, antihypnotics and antiangiogenic agents [5–14]. Moreover, these compounds were broadly used as enzyme inhibitors , for example, it was good to inhabit tyrosinase enzyme which contributed to the neurodegeneration associated with Parkinson’s disease [15–17]. For such reasons, there is an urgent need to develop novel and active tyrosinase inhibitors; which is considered as a promising breakthrough enzyme-inhibitors compounds.
Many polar-organic crystalline molecules with non-centrosymmetric crystal structures reflected a very high second-order non-linear optical (NLO) properties [18, 19]. Several organic compounds which were prepared through condensation reactions may own NLO-properties; such properties can be enhanced via introducing of π-bridge in between two different functional groups donor–acceptor–donor (D–A–D) in the desired organic compounds .
In this study, 5-((5-chloro-1H-indol-2-yl)methylene)-1,3-diethyl-2-thioxodihydro-pyrimidine-4,6 (1H,5H)-dione compound has been prepared through one pot condensation reaction in a good yield, the structure of exo-isomer was confirmed by XRD-single crystal and spectrally characterized. Several experimental spectral measurements were compared with their corresponding theoretical parameters. Initially, exo–endo isomerization reaction was DFT-computed and its T.S was detected under QTS2 level of calculation.
TOF–MS of the desired compound reflected very good agreement with the C17H16ClN3O2S expected molecular formula; the (MH+) molecular ion peak was detected experimentally to be m/z = 361.3, since the theoretical m/z ion peak found to be 360.2, this seen is consistent with recent result [1, 21].
X-ray crystallographic and optimized structures
Summary of crystallographic data for the target compound
Crystal system, space group
Unit cell dimensions
a, b, c Å
9.1136 (3), 12.7475 (5), 15.6198 (6)
α, γ, β °
67.0300 (10), 81.2960 (10), 79.0530 (10)
1634.36 (11) Å3
Density (calculated) (Mg m−3)
Absorption coefficient (mm−1)
Crystal size (mm)
0.42 × 0.16 × 0.15
θ range for data collection
Final [I > 2σ(I)]
R indices (all data)
In solid state, no solvent molecules were detected in the crystal lattice; the desired thiobarbiturate is composed of thioxodihydro-pyrimidine-4,6(1H,5H)-dione ring bonded to 5-chloro-1H-indole ring via C=C bond, the two ethyl groups which were bonded to the thioxodihydro-pyrimidine-4,6(1H,5H)-dione via the N atoms are in trans positions to each other. The two rings are in one plane which flattens the molecule, XRD structure confirmed such seen since all the atoms in the molecule (except terminal ethyl groups) are with sp2 hybridizations. The structure was solved as dimer, the two molecules connected together via N–H…O strong H-bond in perpendicular planes. The two molecules in the dimer are structurally semi-identical and both solved as exo-isomer stereo-structure (Fig. 2a).
Selected experimental XRD bond lengths and angles compared to the DFT-B3LYP calculated result
Endo/exo DFT-isomerization via sp2–sp2 single flip rotation
Combined crystal interaction, Hirshfeld, MEP and Mulliken charge analysis
Mulliken atomic charges
DFT and experimental 1H NMR
The experimental and theoretical (GIAO and ACD-LAB) in DMSO-d6 were matched as in Fig. 6b and in c. The experimental and calculated protons chemical shifts revealed an excellent correlation, the correlation coefficient determined by GIAO and ACD-LAB against experimental found to be 0.950 and 0.972, respectively.
FT-IR (DFT and experimental)
Electronic, HOMO/LUMO energy and TD-SCF transfer
Experimentally, the UV behavior reflected π → π* electronic transition one sharp peak at λmax = 430 nm in both ethanol and chloroform solvents (Fig. 9a). The TD-SCF/DFTB3LYP/6-311G(d) calculations exhibited one abroad band at λmax = 397 nm in both solvents (Fig. 9b). No significant difference in the electronic behaviors (Uv and TD) were detected by changing solvents which reflecting a high degree of harmony between exp. and DFT analysis. The experimental wavelength showed a very good agreement with TD-B3LYP/6-311G(d) an experimentally bathochromic shift with Δλmax = 33 nm were detected. To understand the electron transfer in FMO of the molecule HOMO and LUMO was computed in ethanol [25–27], ΔELUMO–HOMO = 0.128 a.u. (3.49 eV). Due to TD-B3LYP/6-311G(d) the main electron transfer at λmax = 397 nm can be attributed to HOMO → LUMO (97%), while λ at 362 nm to HOMO-2 → LUMO (96%) and λ at 445 nm to HOMO-1 → LUMO + 1 (95%).
Global reactivity descriptors (GRD)
GRD parameters used by the frontier electron density to explain reactions in conjugated system and predicting the most reactive position in molecule. The conjugated-molecules are detected by a small EHOMO/LUMO, which facilitated the understanding of the structural activities of molecules [22–24].
DFT/B3LYP/6-311G(d)/GRD quantum parameters of exo-isomer in ethanol
The advantage of such quantum parameters have been demonstrated to understand the molecular activities of such compound to be used as metal-coordination ligand or search for other biological applications.
Nonlinear optical (NLO)
The mean polarizability (α), total static-dipole moment (μ), the anisotropy polarizability (Δα) and the mean hyperpolarizability (β) for the studied compounds
Novel 5-((5-chloro-1H-indol-2-yl)methylene)-1,3-diethyl-2-thioxodihydro-pyrimidine-4,6(1H,5H)-dione via Knoevenagel mild condensation condition. Exo–endo isomerization reaction in the desired molecule was computed, T.S structure and energy level was detected under QTS2 level of calculation. The exo-structure was proven by XRD-analysis measurement, several physical analyses like: CHN-EA, MS, IR, UV–Vis., 1H and 13C NMR consisted with such seen. The DFT/B3LYP/6-311G(d) structural optimized data were agreed with the XRD-parameters. The exp. XRD-lattice interactions were computed by HSA, MEP map and Mulliken charge, several H-bonds and π–π stacked short interactions were detected. The DFT/6-311G(d) calculations like B3LYP-IR, TD-SCF, HOMO–LUMO, GRD and GIAO NMR reflected a high agreement with their corresponding experimental parameters. NLO-theoretical calculation showed excellent optical properties of the compound, it is even ~ 20 better than urea-reference. The compound TG/DTG analysis revealed a high thermal stability with one step decomposition reaction.
The XRD-data was collected on a Bruker APEX-II D8 diffractometer. The NMR spectra were run in DMSO-d6 using Jeol-400 spectrometer. All the chemicals were purchased from Sigma.
Synthesis of 1,3-dimethyl-5-(thien-2-ylmethylene)-pyrimidine-2,4,6-(1H,3H,5H)-trione
A mixture of 1,3-diethyl-2-thioxodihydro-pyrimidine-4,6(1H,5H)-dione (1.0 mmol) and 5-chloro-1H-indole-2-carbaldehyde (1.0 mmol) in 50 mL of distilled water was refluxed and stirred for 5 h until a yellow product was precipitated. Water was decanted, and the yellow product was washed with water then left under an open atmosphere for drying (yield, 85%).
The yellow powder product, with a m.p = 360 °C, was collected; molecular formula C17H16ClN3O2S; (Calcd. C, 56.43; H, 4.46 and N, 11.69. Found: C, 56.28; H, 4.41 and N, 11.53). [M+] m/z = 361.3 (360.2, theoretical). 1H NMR (400 MHz, DMSO-d6): (ppm) 1.2 (m, 6H, 2CH3), 4.5 (b, 4H, 2CH2), 7.0–9.0 (4 m, 14H, Ar’s), 9.2 (s, 2H, –HC=N–), 13.1 (s, 1H, –HN–). 13C-NMR (100 MHz, DMSO-d6): (ppm) 13.5 (2C, CH3CH2), 43.1 (2C, CH3CH2), 110.8, 116.1, 117.7, 121.8, 123.4, 126.1, 131.5, 128.8, 130.7, 139.8, 145.6, 146.9 (10 signals, 10C, Ar’s), 160.8 (2C, C=O), 173.8 (1C, C=S). FT-IR main vibrations, VN–H = 3319 cm−1, VC–HAr = 3176 cm−1, VC–H aliph = 2979 cm−1, VC=O = 1669 cm−1, VC=S = 1365 cm−1, VC=C = 1286 cm−1.
Hirshfeld surface analysis (HSA) been performed using the CRYSTAL EXPLORER 3.1 program . All Computational calculations of the desired compound were performed by Gaussian 09 software . The molecule optimization geometries, IR vibrations, HOMO/LUMO, TD-SCF, NLO, GRD analysis were carried on DFT/B3LYP level of theory using 6-311G(d, p) base set, NMR chemical shifts were performed at DFT/B3LYP/level of theory and 6-311++G(d,p) base set via adopting GIAO method .
AB and IW conceived and designed the experiments; MSA performed the experiments; AMA analyzed the data; AB contributed reagents/materials/analysis tools; HAG solved the chemical structure by X-ray single crystal technique; AZ and IW carried out the computational studies; AB and IW wrote the paper. All authors read and approved the final manuscript.
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding this Research group NO (RGP-257).
The authors declare that they have no competing interests.
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