Molecular level interaction of solvents (water, benzene and DMSO) analysis of the 2-Bromo-6-nitrotoluene's reactive charge transfer, docking, and spectroscopic properties

1 Introduction

Several nitro derivatives of toluene or methylated derivatives of nitrobenzene have a number of industrial and pharmaceutical uses (Booth, 2015; Allangawi et al., 2023a, 2023b, 2023c, 2023d, 2023d, 2023e). Nitrotoluene is commonly employed in the production of pigments, anti - oxidants, agro - reagents, and pictorial chemical products. Drug intermediate for substances including thioacetazone, para-aminobenzoic acid, benzocaine, procaine hydrochloride, and folic acid, among others. N-acetyl methyl ester of (±)-clavicipitic acids (Harrington et al, 1987; Allangawi et al., 2023a, 2023b, 2023c, 2023d, 2023d, 2023e) and carbazomadurin, a highly oxygenated carbazole alkaloid that protects neuronal cells (Knölker and Knöll, 2003; Allangawi et al., 2023a, 2023b, 2023c, 2023d, 2023d, 2023e; Kosar et al., 2023), have both been completely synthesized using 2-bromo-6-nitrotoluene as a starting reagent. It serves as a common structural system for a variety of naturally existing chemicals and physiologically active substances. (Segneanu et al., 2017; Atanasov et al.,2021). Heterocyclic aromatic and pyrroles indicator containing bridgehead nitrogen have recently piqued the interest of drug research activities. (Constantinos et al., 2019; Markus et al., 2016; Sun et al., 2020). The preparation of dyes is its main use. Variants derived from 2-Bromo-6-nitrotoluenes have been shown to be useful in a variety of cellular mechanisms, comprising cytotoxic, antimicrobial activity, and anti-inflammatory actions. (Asif, 2016; Ata et al., 2004).

The chemical formula (C₇H₆BrNO₂) and molecular weight (216.03 g/mol) of 2-Bromo-6-nitrotoluene salt are given. The results of a thorough investigation show that substantial research has been done on the synthesis of 2-Bromo-6-nitrotoluene and substituted derivatives as well as their biological features, never received attention on precise pharmacological predictions. It stimulates as to conduct a detailed exploration of 2B6NT. The current study investigates the optimized molecule's chemical structures, solvation effects, and biological activities (Frisch and Fox, 2009). One can transform a collection of digital time samples using the DFT into its frequency domain representation also wide applications in drug development. By accounting for all bonds, the Potential Energy Distribution is generated. Pre-Adme (Lee, 2004) and Gusar (Zakharov, 2010) are online software programs that were used to assess ADMI, drug similarity, and toxicity characteristics also evaluations of UV (ultraviolet) for various solvents have been performed. The interaction of the molecule with various proteins is revealed by molecular docking studies, which explains why it has effective anti-inflammatory capabilities (Sagaama et al., 2020). In the final analysis, the present dissertation gives a thorough evaluation of the solvation effects and pharmacological functionality of selected pharmaceutical substances utilizing quantum computational and spectroscopic techniques. As an outcome, the data gathered are very useful for planning upcoming study.

2 Evaluation of computation

DFT assessment and assimilation for 2B6NT have been performed in this work using the Gaussian 09 W (Trucks et al., 2009) software platforms. The recipient associations in the NBO paradigm were investigated using the new package F O C K matrices. (Reed et al.,1988) Computed parameters included global hardness (g), softness (S), energy gap (DE), chemical potential (m) energies, RDG and molecular orbitals with the most and least occupancy (Arjun et al., 2020). Using Multiwfn (Tian and Chen, 2012; Malar Wezhli et al., 2022) ELF and LOL assessments are conducted. Likewise, the chemical's streamlined shape is studied and therapeutic similarity and ADMET properties have been characterized. The structural modelling tool Auto-Dock (Sangeetha et al., 2021) has been deployed to determine the ideal contractual configuration and affinities.

3 Findings & discussion

3.1

3.1 Geometry - optimization

Title compound's optimized structural parameters were determined employing 6–311++G(d,p) basis set with atom numbering system at B3LYP levels. Fig. 1 displays the outcomes. Bond-length and bond-angles of the compound with the title are provided in Table 1. The number of bonds in this molecule is 8 CC, 6 CH, 2 ON and 1 OH. It is discovered that is (O9-H15) is 2.364 Å, which is an extremely large band length. The average length of CC bonds is 1.419 Å, and the O—N (B-L) is 1.224 Å. O—H (B-A) is 2.364 Å while C—H (B-L) is 1.091 Å on average. Compared to other bond angles, N8-O9-H15has the lowest bond angle (88.10 ^{0 *}) and O9-N8-O10 has the highest bond angle (124.9 ⁰) were determined employing D.F.T technique. While the investigative XRD (Piers et al., 1962; Foster et al., 1950) was performed on the compound in its solid state and the theorized examination was carried out on the compound in its gaseous form, there are only tiny variations among theorized and experiential results.

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Fig. 1

Optimized geometric structure with atom numbering of 2-Bromo-6-nitrotoluene.

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Table 1 Geometrical parameters of 2-Bromo-6-nitrotoluene: bond length (Å) and bond angle(°).

Parameter	B3LYP/6–311 + G(d,p)	Experimental*	Parameter	B3LYP/6–311 + G(d,p)	Parameter	B3LYP/6–311 + G(d,p)	Experimental*
Bond length(Å)
C1-C2	1.405	1.410	C3-C6	1.387	C7-H15	1.087	1.080
C1-C4	1.405	1.410	C3-H12	1.083	C7-H16	1.094	1.090
C1-C7	1.506	1.505	C4-C6	1.391	C7-H17	1.09
C1-C5	1.392		C4-C8	1.482	N8-O9	1.224
C2-Br11	1.921	1.925	C5-H13	1.082	N8-O10	1.224	1.225
C3-C5	1.391	1.390	C6-H14	1.081	O9-H15	2.364	2.360
Bond angle(°)
C2-C1-C4	114.5	114.5	C5-C2-Br11	116.7	C4-C6-H14	119.3	119.5
C2-C1-C7	121.8	12.1.7	C2-C5-C3	119.8	C4-N8-O9	117.9	117.5
C1-C2-C5	123	123.1	C5-C3-H13	119.7	C4-N8-O10	117.2
C1-C2-Br11	120.2		C5-C3-H12	119.6	H15-C7-H16	107.2	107.5
C4-C1-C7	123.7	123.8	C4-C5-C6	120.1	H15-C7-H17	109.1	109.1
C1-C4-C6	124	124	C3-C5-H15	120.5	C7-H15-O9	105.2	105.5
C1-C4-N8	120.5	120.1	C6-C3-H12	120.3	H16-C7-H17	107.7	107.5
C1-C7-H15	112.1	111.1	C5-C6-C4	119	O9-N8-O10	124.9
C1-C7-H16	110.6		C3-C6-H14	121.7	N8-O9-H15	88.10	88.1
C1-C7-H17	109.9	109.5	C6-C4-N8	115.5

* Ref (Kragh-Hansen, 1985).

4 Acceptor-Donar interaction

A complete comprehension of the interactions between molecules on an interorganizational & intra - molecular interconnections is provided by N.B.O investigation. (Weinhold and Landis, 2005; Sidir et al., 2010). Employing the second order Fock matrix donor–acceptor correlations will be calculated. Because of the links, the concentrated Lewis structuring contributes to the utilization of the unoccupied non– Lewis orbitals. (Jayabharathi et al., 2012; Sangeetha et al., 2022a ). In order to elucidate the inter - molecular electron transport, rehybridization as well as depolarization of charge distribution NBO experiments were performed on the title molecule (Issaoui et al., 2016). Table S1 lists the stabilization energy of the donor& acceptor. For non-Lewis’s orbital, use an asterisk. E(2) denotes an intensity of maximal integrins interactions. Once the amount of E(2) increases, the coupling across electron donors and acceptors intensifies (Muthu et al., 2015). Conjugative interactions cause e-n delocalization of (C 1 – C 2) spread to antibonding (C4-N8), π (C 1 – C 2) with antibonding π*(C3-C5), π*(C4-C6), resulting in stabilization energies of 3.24,20.78,15.98 correlatively. A significant e-n shift were seen as antibonding orbital (N8-O10) to the oxygen atoms lone pair LP(2), which has a large stabilization energy of 29.99 kcal/mol. Low stabilization Energy 3.84 and 1.78 kcal/mol for the Br(11) lone pair (LP1) on the anti-bonding σ * (C1-C2) observed correlatively.

Table S2 displays the interactions of electrons for various solvents. At 20.67 and 18.54 kcal/mol, LP (2) O9 with (C4-N8) and π (C1-C2) with π *(C3-C5), in water have substantially greater stabilization energies. Minimal energy was discovered in LP (1) -O9 to σ * (C4-N8) & (C2-C5) with σ *(C1-C2) at 4.78 and 3.08 k cal/mol correlatively. The stabilizing energies of benzene LP (3) Br(11) with π * (C 1 – C 2) and π (C 4 – C 6) with π * (C 1 – C 2), however, are significantly higher, coming in 24.74 and 11.13 kcal/mol, respectively. Enough less energy, measured as 4.23 and 3.84 -k- c a l / m o l, is related towards σ (C3–C6) belongs σ * (C4–N8) and LP(2) of Br(11) to σ * (C 1–C 2) correlatively. Additionally, it was discovered that the stabilizing energy of 30.56,23.74 kcal/mol at LP (2) O9 with σ *(N8-O10) and π(C3-C5) with π*(C4-C6) corresponds to DMSO is significantly higher. A very little amount of stabilizing energy 4.33 and 4.53 kcal/mol was discovered from the reactions (C 7 – H16) corresponds to σ* (C1 - C2) as well as (C7 – H17) to σ*(C 1 – C 4) correlatively.

5 MEP analysis

With expertise of the molecule's changeable charging regions, this was attainable to figure out whether atoms associate with each other and the sort of chemical bond. It also employs color grading to demonstrate the chemical structure, shape, negativity, positively, & unbiased electrically charged possibilities. Consequently, the physiochemical characteristics were examined (Scrocco and Tomasi, 1978). Figure S1 depicts different possible electrochemical ranges solely over the inter-face. Ordered from red to orange to yellow to green to blue, the electrostatic potential rises. The maps' colour code was discovered to be between −4.937 eV (deepest red) and 4.937 eV (blue), whereas red indicates repulsion (electrophilic assault) as well as blue indicates attack (nucleophilic attack). It is used to predict specific activation centers of the molecule indicated in the label in Figure S1, in addition to the hydrogen - bonded relation (Murry et al., 1996; Sebastin and Sundarganesan, 2010; Okulik and Jubert, 2005).

5.3

5.3 Studies of E.L.F and L.O.L

They display the areas of chemical region where gaining a significant electrons combination was more prone to happen via ELF and LOL maps. A surface simulation was also created using predictions focused on covalently bonding (Sangeetha et al., 2021). Since localized orbitals overlap, LOL believes that localized orbital gradients should be strengthened, in contrast to ELF, which sees electron pair density (Silvi and Savin, 1994). In Fig. 2(a), (b) ELF and LOL maps are displayed & which runs from 0.0 to 1.0 and includes stronger ordering around 0.5 and 1.0, indicates areas including both non-bonded and bonding regionalized atoms; delocalization of particles was proved utilizing slight size of 0.5, correspondingly (Savin et al., 1997). When electron localization has an impact on electron density, LOL reaches huge - values (>0.5) (Sangeetha et al., 2022c).

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Fig. 2

(a) Electron Localization Function, (b) Localized Orbital Locator colour filled and contour map of 2-Bromo-6-nitrotoluene.

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6 Biological and pharmacological research

The drug likeness of the reference chemical is investigated to primarily evaluate its ability to be employed as a main ingredient in a novel medication dosage form. Numerous drug similarity parameters that were explored in this work. It must adhere to Lipinski's rule in order to be taken into consideration as a prospective drug (Lipinski et al., 1997; 2004). The anticipated medication similarity for 2A4BSA is shown in Table 5. It demonstrates that these indicators have values that are appropriate for the drug that is being evaluated. The Lipinski's rule of five suggests a cut - off point of 5, while the AlogP, among the most key metrics which reveals how hydrophobic or lipophilic a molecule is, is equivalent to 3.06, which is considerably lesser.

6.3

6.3 Analysis of rama-chandran plot

Using Ramachandran graphing, researchers are examining a unique characteristic of biomolecules. Also, it is employed to identify empirical transmission couple for amino acids. The research outcome (Thomas et al., 2020) and the online PASS predictor (Reddy et al., 2016) were used to collect this data. The Ramachandran plot (Saji et al., 2020), which is one of the molecular docking evaluations, is used to conceal protein molecules because of their homogeneity and durability. The majority of the vestiges that are thus on the green zone are shown in Fig. 3 (a, b and c) to be within the permissible red zone, with only a few minor remnants found close to its banned region. The results show that some proteins (4ZQY, 5 V47 and 6YPE) are structurally stable.

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Fig. 3

Ramachandran plot for receptor protein (a) 4ZQY, (b) 5V47 and (c) 6YPE.

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6.4

6.4 Exploration of docking aspects

Major innovations in clinical applications involve molecular docking, a formidable computer technique for calculating the enforceable propensity of a receptor with enzymes. Precise binding position of the ligand and protein may be studied using this new approach (Kragh-Hansen, 1985). Through this work, we can comprehend how ligands, which are tiny molecules, are transported across biological systems. Auto docking experiments are a great way to get understanding of the underlying chemical processes that enable ligands to bind to receptors with well-known three-dimensional structures. Given that the substance in question is an anti-inflammatory drug, its capacity to lessen inflammation is further investigated through docked its receptor with the high affinity of distinct biological objectives. The protein 4ZQY, which is important for anti-inflammatory disorders, has the title chemical docked into its active site. This protein data bank was retrieved from the Research Collaboratory for Structural Bioinformatics (RCSB) website. The receptor was lodged in the distinct categories of the selected molecule to ascertain the least interaction potential value. For the reason of analyzing the strategy of authoritative, the docked compliance with the least official vitality was chosen. The obtained docking characteristics for the chemical with regard to the focused-on proteins are appeared in Table 6. Fig. 4(a, b and c), it is depicted how the title chemical interacts with the proteins 4ZQY, 5 V47 and 6YPE when used as a ligand. With regard to these, 4ZQY exhibits minimal binding-energy at −5.32 kcal/mol, overall large percentage of docked antagonists reacted with ligand. The LYS'26/HN hydrogen bonds in this protein's four residues have a bond distance of 2.5A⁰. Anti-intemperate protein 4ZQY is successfully bound to 2B6NT, as evidenced by the decreased binding energy.

Table 6 Molecular docking parameters of 2-Bromo-6-nitrotoluene. with proteins 4ZQY, 5 V47 and 6YPE.

Protein (PDB ID)	Bonded residues	Bond distance	Estimated inhibation constant(μm)	Binding Energy(kcal/mol)	Intermolecular energy(kcal/mol)	Reference RMSD (AO)
4ZQY	ARG’65/NH2 ARG’65/NB2 LYS’26/CE LYS’26/HD2	2.2 2.1 1.8 2.5	207.17	−5.32	−5.19	27.54
5 V47	ARG’149/1HH2	2.5	118.0.66	−6.16	−6.45	30.70
	ARG’149/1HH2	2.3
6YPE	ARG’152/1HH2	2.12.2	110.07	−6.06	−6.12	29.55
	LYS’29/HD2

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Fig. 4

Docking of 2-Bromo-6-nitrotoluene with (a)4ZQY, (b)5V47 and (c)6YPE protein.

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7 Conclusion

D F T and the 6 – 311 G + + (d, p) premise set were used to carefully examine the vibrations of 2B6NT. The calculated tool geometry provided a reliable approximation and a basis for determining the other variables in the proposed exploration. In addition to assessing architectural characteristics like bond-angle and bond -length, other metrics for the current investigation are determined. Conjugative interactions cause delocalization for σ (C1-C2) spread to antibonding σ*(C4-N8), π (C 1-C2) with antibonding π*(C3-C5), π*(C4-C6), resulting in stabilization energies of 3.24, 20.78, 15.98 correlatively. A significant interaction were, electron density shift from the antibonding orbital π * (N8-O10) to the oxygen atoms lone pair LP(2), which has a large stabilization energy of 29.99 kcal/mol. Low stabilization Energy 3.84 and 1.78 kcal/mol for the Br(11) lone pair (LP1) on the anti-bonding σ * (C1-C2) observed correlatively. Additionally, the FMO study gave the requisite theoretical justification for believing that the molecule is both biologically active and non-toxic. A significant affinity efficiency of −5.32 k cal / mol was discovered during molecular modelling experiments involving its 4ZQYY protein coupled and the protein receptor antagonist, revealing the usefulness to the therapeutic sector. UV–vis spectra were used to reveal the electrical characteristics of various solvents. Also reported for 2B6NT are L.O.L, E.L.F, R.D.G, pharmacological similarity, A D M E correlatively. The pharmaceutical precautionary properties of the research molecule, which reveal anti-viral, anti-fungal, and anti-oxidant properties, were studied and substantiated by structural modelling computations. In conclusion, the present dissertation offers a thorough investigation employing quantum computational and spectroscopic methodologies to evaluate the solvation effects and physiological functionality of selected pharmaceutical substances. In order to prepare for future study, the data gathered are highly valuable.