INTRODUCTION:

One of the most important groups of a biochemically active compound is a carboxylate, molecule including sulphur, and the carboxylate, find wide application for the synthesis of drug. This drug containing sulphur and carboxylate are component of a treatment of some diseases, and it has application in a research area. therefore, this is a considerable interest synthesis and characterisation of such component¹. Recently density functional theory (DFT) study is the an advanced version of study, via, different parameter like of HOMO, LUMO MEP², and In ADME study pharmacokinetic activity, drug lessness, and it’s egg diagram provide further research.³

As known the wide occurrence of heterocyclic amino thiophene compound which have a great importance, for the preparation of various type of thiophene derivatives⁴.

Five members cyclic thiophene five membered ring coupled with different aliphatic ring compound to form thiophene derivatives. substituted 2- amino thiophene(3) are important in organic compound. Schiff bases were synthesised from different aldehyde and thiophene derivatives(3) are very important, because there stability³¹, chelating properties, and ligand which use use in several areas the substituted 2-amino- thiophene derivatives are formed which are most significant heterocycles which widespread and essentially to be diversity of natural product and medicinal agents⁵ . Tetrazol(3) and it’s derivatives shows a nuemurs bioactive heterocyclic compound and wide applications in natural, pharmaceutical and clinical applications.

We are set a target to synthesis a 2-amino 4,5,6,7-tetrahydrobenzo (b)thiophene-3-carboxylate (3), and it’s different derivatives with starting material like cyclopentanone and dimedone. The schiff base synthesis of tetrazol (3) and (5) with 4-formyl pyrzole (7), salicyaldehyde,4-nitro benzaldehyde, and 4-anisaldehyde.

MATERIAL AND METHODS:

Material:

For newly synthesised molecules reactions were moniterd by thin layer chromatography (TLC) silca gel plate with fluorescencewer54 were used. Boiling points were comformed by Boiling Point apparatus Glass tube Thiele Abron AC-2559 AC-472T. The FT-IR spetra mesuered by (FTAffinity-1S) Spectrometer H-1NMR and C13-NMR spectral measurement is done in DMSO-d6 as solvent, TMS is a internal standard and chemicals shift values measured in ppm.

Methods:

1. Procedure for synthesis of ethyl 2-amino-4,5,6,7-terahydrobenzo(b)thiophene-3-carboxylate.(3)

A mixture of cyclohexanone (1 mmol), an activated nitrile (1 eq.), N-methyl morpholine (1 eq.) and elemental sulfur (1 eq.) in 5 ml of ethanol was stirred at 40–50 C for 5–6 h. After completion of reaction demonstrated by TLC, cool the solutions mixture and then add th Water in it and filter the solutions. (m.p.116-118 °c)

(3b) m.p.115°c,1H NMR: δ 1.00 (6H, s), 1.29 (3H, t, J = 7.1 Hz), 2.33 (2H, d, J = 16.9 Hz), 2.50 (2H, d, J = 13.5 Hz), 4.15 (2H, q, J = 7.1 Hz).13C NMR: δ 14.2 (1C, s), 28.2 (2C, s), 33.1 (1C, s), 38.6 (1C, s), 50.0 (1C, s), 61.2 (1C, s), 105.8 (1C, s), 130.7 (1C, s), 137.1 (1C, s), 161.8 (1C, s), 166.2 (1C, s), 191.7 (1C, s).

2. Synthesis of 4,5,6,7,8-Tetrahydrobenzo[ 4,5]thieno[ 2,3-d]pyrimidine -4(3H)-one(4):

A mixture of (3) (4.5 mmole) and formamide (0.44mmol) was refluxed for 3 hrs. Cooled mixture poured onto cold water, and left at room temperature ovovernight The formed PPT was filtered off and recrystallized from methanol to give brown needle crystal(yield 90%) (m.p 250 - 251 °c)

3. Ethyle-2,amino-4H,5H,6H-cyclopento(b)thiophene-3-carboxylate (3a),(3b).

A mixture of cyclopentanone(1mmlo), ethyl cyanoacetate (1 eq) and activated sulphur (1eq) in methanol was stirred using a magnetic plate shaker at 50-60°c. Ammonia was added drop wise in first 10 mintue of the reaction, after 3 hrs of reaction the resultant precipitated collected by filtration and crystallized from methanol and yielded yellow crystals. (116-118 °c).

4. Synthesis of 2-(3-aryl-4-formylpyrazol-1-yl thiazole (5).¹⁰

To the Vilmeier -Haack reagent prepared from DMF(10 ml) and POCL3 (1.1 ml ,12 mmol) ,hydrazone ( 4 mmol) was added and then reaction mixture stirred at 60 to 65 °C for 3 hr and then poured into ice cold water. The solid that separated on neutralization with your aaNaHCO3 was filtered, washed with water and recrystallize from ethanol.

5. Synthesis of schiff base derivative (6,7,9,10):

Take aldehyde(8a-d) (1 eq.) with thiophene derivative (3) (1 eq.) in Ethanol, reflux the reaction mixture. for 1hr.and between take TLC for monitoring the reaction, after the completion of reaction, the hot mix. Poured into ice cold water. Then product was filtered into under suction was washed with distilled water the product was obtained yellow range.

6. Synthesis of ethyle -2-benzamide-4,5,6,7, tetrahydro-1-benzothiophene-3-carboxylate(8):

Dissolve thiophene derivative (3) in a 5ml 10% sodium hydroxide contained in a conical flask, add one ml of benzoyl chloride in a one portion to the above solution. put a cotton plug on conical flask and shake vigorously for about 10 minute. add crushed ice this reaction mixture, and acidifying with concentric HCL, filter the product and wash with cold water. recrystallization it from water.

Chemical Reaction:

RESULT AND DISCUSSION:

An aldehyde compound 4-formalylpyrazole, salicyaldehyde and anisaldehyde, 4-nitrobenzaldehyde was independently reacted with 2- amino thiophene derivative’s (3) and (3a) respectively, to produce imine derivative(6-10). The solid condensation product of the above chemical components where air stable and dissolved in a DMSO. and its analytical, physical, spectral finding categorized the cocompound. Where the geometry of compound where determined by their FTIR, ¹H-NMR,¹³C-NMR data. The colour of all tetrahydro benzo derivative and its schiff bases as an yellow. All the reactions were monitored by the thin layer chromatography (tlc) via, glass plate with silica gel and aluminium sheet both were stationary phases and solvent like n- hexane and ethyl-acetate is an mobile phases (5%, 10%).¹³

1. FT-IR spectra¹³: For the mesurring the FT-IR spertra of different compound there is used a IRAffinitt -1S instrument. The Fourier Transfrom Infrared specta of a aminothiophene derivative and it’s schiff base derivative indicating a binding mode of a ester group and amino group on a thiophene ring. The aminothiophene derivatives (3),(3a),(3b) and schiff bases derivative (6),(7),(8) shows a ester group stretching frequency at 1730-1740 cm-¹, ir band in the 1648 cm-¹, 3406cm-¹, 3299 cm-¹, 2985-2938 cm-¹, 2840 cm-¹, 781 cm-¹ and 639 cm-¹ region of characteristic of (CH)ring, (CH)Alf,(CS) and (CSC) respectively. In the compound (6), which 4-formyl pyrrole (5) bonded with tetrazole (3), which it show a stretching frequency at28 and 2736 cm-¹ (CH) stretching, 1691 cm-¹ (>C=O) stretch of CHO group. In the compound in (7),(>C=C<) stretching frequency shows at 1600-1500 cm-¹, (CN)1550-1595 cm-¹,and (OH) stretching at 3550 cm-¹.The carbonyl(>C=O<) stretching at 1680 cm-¹ due to additional conjugation eeffect, aromatic benzene ring shows a stretching frequency at 1590-1600 cm-¹and ester group frequency at 1788 cm-¹.due to extra conjugation effect.

2. ¹H NMR spectra¹³: The proton nuclear magnetic resonance fspectral data (¹H NMR) further confirmed the chemical composition and the structure of the synthesised molecules (3). ¹H NMR data for the compound where recording in DMSO-d6 the two multiple observe at 2.60 (m,4H) and 1.75(m.4H) ppm, were assigned to ring proton. The singlet at 6:00 ppm was assigned to amine proton proton. The proton of (CH2) and (CH3) of the (-CO2C2H5) group were observed at 4.32(q,2H) and 1.35(t,3H) ppm respectivelly.

3. 13C NMR spectra¹³: The carbon nuclear magnetic resonance (¹³C-NMR) spectral study in DMSO solvent delivered a strong sign to established proposed structure of compound (3), (3b). The ¹³C-NMR spectra revealed distinguished peak inside the anticipated range, in the compound (3), the carbons of a thiophene ring and the carbonyl appeared at 165.53,163.33,131.80,115.97 and 103.25(4 Cthiophene, C=O), carbon peak of ethoxy group at 59.03 and cyclohexane carbon show value at 26.98,24.41,23.31,22.19 (4 CH2cyhex), and carbon peak of (-CH3) at 14.79.

Figure 1: Molecular structure of Molecule (3b)

Frontier Molecular Orbital Analysis: The analysis of frontier molecular orbital (FMO)may easily determine a chemical system with its optoelectronic ability to absorb light. The energy difference between the highest occupied molecular orbital, and lowest unoccupied molecular orbital (HOMO and LUMO) rerespectively. Both related to each other to be molecule for its chemical reactivity and a kinetic stability. The HOMO and LUMO are the important parameter in a quantum chemistry, constructedon their characteristic, it can be indicated how a molecule would interact with other molecule¹⁴. The HOMO is electron donor, while LUMO is an a free site to accept them.²²^,²³

Transition during the interaction of the orbital. The difference between the both referred as a energy gap. HOMO referred as ionization potential, and LUMO as electron affinity. Energy gap is an important parameter that can determine the reactivity and stability for molecule it also referred as a biological activity of a molecule. The HOMO which are electronically filled orbital, or LUMO is electronically special orbital. The value were determined by using (Gussion (R) 09 program) basic set. In the compound (3b), the special extent of HOMO was on the 5 membered thiophen ring, and amide group and oxygen of carboxylic group of cyclic ring, and LUMO of the sulphur of thiophene ring. and carboxylic group of ester.¹⁵

Figure 2: Frontier Molecular Orbital Analysis of DFT Analysis molecule (3b).

Global chemical reactivity:

To recognise the association between the structural system, consistency and global surface chemistry, interpretive. Density functional theory (DFT), predicted global reactivity identified have been used. The value of the Egap and reactivity described shown that tetrazole derivative have a good reactivity. Any chemical arrangement with a minor FMO energy gap is known for less stable , more reactivity and softer¹⁶.

Molecular Electrostatic Potential (MEP) Analysis:

Any chemical system with its physical and chemical characteristics, may be investigated using a data of molecular electrostatic potential (map) plot. Such map can be used to understand the potential for neucleophilic or electrophilic to engage at more suitable position at chemical species. The MEP surface has distinct hues such as yellow, white, green, red, orange, blue, cyan²⁶. The show magnitude of electrostatic potential within the chemical structure. Oygen in the structure highlighted red coloured in the MEP map sulphur highlighted by yellow coloured in MEP map respectively. The nitrogen atom show by the blue in colour. Red colour of oxygen which it shows the area of negative potential and may be most applicable in nature. and other regions and cyan colour indicate the area of positive potential. And may be appropriate for nucleophilic engagement. The hydrogen and the carbon atom produce electron deficient area and showed by the colour of white and cyan colour. The blue part show the nitrogen atom, ester group of carbonyl oxygen shown the yellow and aromatic one with red in colour respectively.¹⁷

Figure 3: MEP analysis of molecule (3b).

Natural Population analysis:

Atomic charges with molecule can be represented in a variety of way, with a high level of authenticity to about some value only after acknowledging the residual or uncertainty, which is data mulliken charges for the calculation. The mulliken charges is derived through the measurement of mullican population and which it show both positive and negative value of structure, and analytical procedure. The charges is determined, by mean of the DFT. Gaussian (R)09 Programe technique as basic set. The far more positive or most negative values are marker of electron density distribution in the molecule as well as possibility of drawing or a donating electron for formation of covalent bond or a non-covalent bond. The electron density of molecule on way function can evaluated by using national population analysis(NPA).¹⁸ The mullican charges of a tetrazole(3b) of electron distribution density of positive and negative charges shown in figure.

Figure 4: Mulliken charges analysis of molecules (3b).

Theriotical study: The Gaussian(R) 09 program pakage is used to study the DFT and theoretical stimulated based molecular mechanism.

The global reactivity identifier:¹⁹ The global chemical reactivity descriptors (GCRDs) are imperative metrics for understanding the reactivity and structural permanency of any chemical system.

These descriptors are also known as biological activity descriptors. The energy of an FMO(Egap) where used to evaluate global reactivity identifier including that kind of electron affinity (EA), we evaluated the chemical hardness (η), chemical potential (µ), electronegativity (ꭓ), global softness (σ), and electrophilicity index (ꞷ) of the imine dderivative (3,3a,3b) and its schiff base derivative(6-10). The energies of HOMO and LUMO were operated to analyse these promising descriptors and are represented in table (5).

IP = -E_HOMO

EA = -E_LUMO

The ionization potential is denoted by IP (eV), and the electron affinity is denoted by EA (eV).

Koopmans’s theorem was used for the determination of chemical potential (µ) and electronegativity (ꭓ), in addition to chemical hardness (η) which are described and calculated from the following given equations as:

µ = E_LUMO+ E_HOMO/2

ꭓ = [ IP+EA ] /2 = -E_LUMO+E _HOMO/2

η = [IP –EA ]/2 = -E_LUMO– E_HOMO/2

The following relationship was used to define the global softness (σ) as:

σ = 1/2η

Meanwhile, the electrophilicity index (ꞷ) can be explained and calculated by the given equation:

ꞷ = µ²/2η

Figure 5: Calculated quantum chemical reactivity descriptor for ethyl-2-omino-5,5-dimethyle-7-oxo-4,5,6,7-tetrahydo-1-benzothiophene-3-carboxylate.

Figure 6: IR spectroscopy of (3).

Figure 7: IR spectroscopy of (3b)

Figure 8: IR spectroscopy of (3b).

Figure 9: IR spectroscopy of (6)

Figure 10: IR spectroscopy of (7)

Figure 17: ADME study data of a molecule (1-10) i.e synthesised compound.

CONCLUSION:

The new thiophene based derivative synthesised and utilized by physical, spectral analytical methods in this study. Different physical and chemical parameters are studied by DFT study were successfully applied to achieve optimized molecule structure with electronic calculation. The computed value of global hardness is more than the global softness value, which it indicated that molecule (3b) were stable in nature. Antimicrobial test performed on all of the produced compound of thiophene derivatives. In the ADME study all imine (3), (3b), respectively show a high GI absorption, and shiff base imine derivative (6) shows a low GI absorption values. With lead likness and lipinski-violation ratio, 3 and 1 respectively. Similarly pharmacokinetics and pharmacokinetics and bbioavailability The research reveled that on the basis of DFT and ADME of thiophene derivatives, they were addressed in future for the developing medicine based on a variety of newly developed pharmacological specifications.

CONFLICT OF INTEREST:

Declared none.

ACKNOWLEDGMENTS:

AB thanks Department of Chemistry, T. C. College, Baramati for the project under the supervision of RB.

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Received on 27.05.2024 Revised on 12.08.2024

Accepted on 26.10.2024 Published on 25.11.2024

Available online from December 27, 2024

Asian J. Research Chem.2024; 17(6):309-318.

DOI: 10.52711/0974-4150.2024.00053