Molecular modeling and biological activity analysis of new organic-inorganic hybrid: 2-(3,4-dihydroxyphenyl) ethanaminium nitrate

2.1 Samples preparation

2-(3,4-dihydroxyphenyl) ethanaminium nitrate crystals were synthesized by mixing 1 mmol of HNO3 in 10 ml of water with 1 mmol of dopamine hydrochloride in 10 ml of water. This solution was stirred for 15 min and then left to stand at room temperature. After a few days colorless single crystals of the title compound were obtained. The reaction mechanism for the synthesis is shown in the following Scheme 1:

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Scheme 1

The reaction mechanism of 2DOPN.

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2.2 Materials and physics measurement

Measurement of single crystal X-ray diffractions was registered at the room temperature (T = 150 K) using a Bruker APEXII diffractometer with Mo KWα radiation source (λ = 0.71073 Å). Absorption corrections were performed by the multi scan technique by the means of SADABS software (Ross et al., 2006). The total number of measured reflections was 10,787 which 4339 were independent reflections and 3583 reflections had an intensity I > 2σ (I). SIR97 (Altomare et al., 1999) was used to solve the structure and then refined with full-matrix least- square methods based on F² (SHELXL97) (Sheldrick, 2008) included in WinGX program (Farrugia, 2012). All non hydrogen atoms were refined anisotropically. A final refinement on F² converged at R [F² > 2 σ (F²)] = 0.043 and wR (F²) = 0.113. The Table S1 summarizes all the crystallographic details and results of the structure refinement.

2.3 Theoretical calculations

All the quantum computational calculations were performed for 2DOPN by the DFT method with B3LYP/6-311G++(d,p) basis set using Gaussian 09 (Gaussian 09 et al., 2009) program. Molecular structure was visualized with GaussView 6.0 package (GaussView, 0000). The molecular formula of the target compound is C₈ H₁₂ N₂ O₅. It contains 27 atoms and 114 electrons. It is a neutral molecule with a singlet system. The optimized parameters like bond angles and bond lengths were compared with experimental values reported from crystallographic data. To determine the types of intermolecular interactions, many analyses have been used such as QTAIM, ELF, and LOL. These topological analyses were carried out using Multiwfn (Lu and Chen, 2012) software. The Crystal Explorer package (Wolff et al., 2012) was used to perform the Hirsfeld surface in order to quantify the interactions in the crystal structure. Moreover, the non-covalent interactions were investigated in terms of reduced density gradient (RDG). NBO analysis was studied to establish the energy of intermolecular interactions by computing donor acceptor interaction energy. In addition, the Mullikan charges have been used to process the elctronegativity and charge transfer in molecule. The Molecular electrostatic potential analysis (MEP) and Molecular electrostatic potential (ESP) on the molecular VDW surface were visualized to predict the reactive sites of the molecule title. The energy gap between HOMO-LUMO and the global reactivity descriptors were calculated in order to determine the electronic propriety, stability and reactivity of 2DOPN. Gauss-sum program (O’Boyle et al., 2008) has been used to prepare the plots of density of state (DOS). Furthermore, the non linear optical propriety (NLO) has been carried out on our compound. Biological activities of 2-(3, 4-dihydroxyphenyl) ethanaminium nitrate has been investigated using iGemdock (Visualizer, 2005). Discovery studio (Yang and Chen, 2004) software is used to view and design the docking patterns from standard protein data bank

3.1 Description of the crystal structure

The molecular graphics of 2DOPN single crystals were done using an ORTEP drawing as shown in Figure S1. Dopaminuim nitrate (C₈H₁₂NO₂·NO₃) consists with two units: an organic unit which is the dopaminuim [C₈H₁₂NO₂]⁺ and the inorganic unit which is the nitrate [NO₃]^- .

2DOPN has been crystallized to the triclinic system with space group P1 and the network parameters obtained are a = 8.3066 (4) Å, b = 10.4856 (5) Å, c = 11.2303 (7) Å, V = 953.37 (9) ų and Z = 4. The dopaminuim cation are linked to the nitrate anion by means of an assortment of N-H···O, C-H···O and O-H···O hydrogen bonding (Figure S2). As shown in this figure, in the crystal structure the compound are connected through three H-bonds (N-H···O, C-H···O and O-H···O) involve oxygen atoms of the nitrate anion as acceptors, and the nitrogen atoms, carbon and oxygen atoms of dopaminuim cation as donors. These non-covalent interactions help to increase the stability of the structure.

3.2 Molecular geometry and optimized parameters

In this research, geometry of 2-(3, 4-dihydroxyphenyl) ethanaminium nitrate were optimized using the DFT calculation of a hybrid functional B3LYP and dispersion correction method WB97XD with the level of 6–311++G (d, p) basis set. Imaginary frequency confirms the absence of negative frequencies and that the molecular system was fully optimized and converged. The optimized structure along with the numbering of atoms of C₈H₁₂N₂O₅ is depicted in Fig. 1. Both the geometrical parameters (bond lengths and bond angles) and the experimental data are selected in Table 1 and compared by using the RMSD values. During the DFT calculation, we find that the optimized structure corresponding to the minimum energy (E _B3LYP = -797.568 a.u, E _WB97XD = -797.561 a.u) is obtained with B3LYP / 6–311++G(d, p) method. On the other hand, the RMSD is calculated in order to rigorously compare the most adequate method. The lowest RMSD of the bond angles (RMSD _B3LYP = 0.99°, RMSD _WB97XD = 1.02°) and lengths (RMSD _B3LYP = 0.186 A°, RMSD _WB97XD = 0.194 A°) is obtained with B3LYP / 6–311++G (d, p). As can seen from the table 1, that the calculated bond lengths were greatly then the experimental ones. Usually, the theoretical bond lengths are stronger than the experimental results because in majority of system the molecules are ensured by inter and intramolecular H bonds (Shukla et al., 2020). The molecule title has eight C–C bond lengths, seven C–H bond lengths, four O-N bond lengths, three N–H bond lengths, two O–H bond lengths and one O-C bond lengths. We have six C–C bond lengths present in the phenyl ring lies in the interval 1.517–1.389 A° in DFT and 0.930–1.38 A° in the experiment. The other two bond lengths C4-C7 (1.539 Å) and C7-C10 (1.517 Å) show stronger values than other ring C–C bond lengths. This is explained by the difference in electronegativity between the atoms, the types of bonds (single, double, …) and the chemical environment. The C–H bond lengths are elongated in the interval 1.082–1.093 A° (DFT) and in 0.970–1.520 A° (Exp.). Also, the bond lengths calculated formed between N₃-H₁₉ (1.017 A°), N₃-H₂₀ (1.086 A°) and N₃-H₂₁ (1.033 A°) atoms are approximately similar values. The two bond lengths O₁-H₂₂ and O₂-H₂₃ reported in DFT calculations are equal to 0.976 A° and 0.971 A° respectively. The corresponding bond angles C₁₃-O₁-H₂₂ (110.63°), C₁₄-O₂-H₂₃ (113.82°) demonstrated that the hydrogen bonds which link the crystal stability of our compound are weak types. We note also that all the bond angles calculated are in concord with the experimental bond angles. Moreover, it is observed that the simulated and observed values for the bond angles of the phenyl ring C₇-C₁₀-C₁₁ (120.27°, 120°), C₇-C₁₀-C₁₇ (120.75°, 121.7°), C₁₁-C₁₀-C₁₇ (118.98°, 118.3°), C₁₃-C₁₄-C₁₅(120.48°, 119.6°), C₁₄-C₁₅-C₁₇ (119.48°, 120.3°) and C₁₀-C₁₇-C₁₅ (120.70°, 121°) are very close to the experimental results. In Figure S3 we shows the calculated correlation coefficients (R²) between the experimental and theoretical bond length and angles. We found that the correlation coefficient is very close to 1 for the bond length (R² = 0.958) and bond angle (R² = 0.95). This coefficient showed that the result greatly correlated. From all these results has demonstrated that this method were reliable to reproduce the experimental values. Thus, we continue our calculation by using B3LYP functional at 6–311++G (d, p) level of theory.

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Fig. 1

The optimized geometric structure of C₈H₁₂N₂O₅ compound.

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4.1 Quantum theory atoms in molecule (QTAIM) analysis

The quantum theory of atoms in molecule (QTAM) is one of the appropriate technique to analyze different types of interaction (inter and intramolecular interaction). This approach provides as more effective information about the presence of non covalent interaction in term electron density of a system analyzed (Issa et al., 2020). We have applied this tool using the Multiwfn program to characterize and determine the proprieties of non covalent interaction. The bond critical points (BCPs) of the intra and intermolecular bonds, ring critical points (RCP) and the new ring critical points (NRCP) of C₈H₁₂N₂O₅ are shown in Figure S4. Also, we are presented in Table 2 the calculated electron density (ρ), Laplacien of electron density (∇²ρ(r)), kinetic energy (G(r)), potential energy (V(r)), total energy (H(r)) and interaction energy (E_interaction). These topology parameters are calculated to identify the natures of the bonds that exist in our molecule. The Fig. 4Sa of monomer shows the presence of hydrogen bonds N-H···O types. In addition to this like, we noted in the dimer (Figure S4) the presence of two other types of hydrogen bonds C-H···O and O-H···O. By analyzing the results obtained in table 2, the ∇²ρ(r) > 0 and G(r) + V(r) < 0 indicating that the hydrogen bond is a medium hydrogen bond. In addition, the value of the rapport –G (r_BCP)/V(r_BCP) is between 0.5 < -G(r_BCP)/V(r_BCP) < 1, it indicates that the nature of the H-bond is covalent. Consequently, AIM analysis confirms that these results are in good agreement with the experimental results.

4.2 ELF and LOL

Electron localization descriptors, such as the electron localization function ELF and the localized orbital locator LOL are calculated by using Multiwfn software. These methods are performed by Selvi et al.(Savin et al., 1997) and provide a visual tool for interpreting the results of electronic structure calculations (Clements et al., 2020). ELF and LOL have the same chemical properties, they make it possible to differentiate covalent, ionic and van der Waals bonds, in terms of local kinetic energy. However, ELF allows a partition of the molecular space in basins of electronic localization within which the excess of kinetic energy due to the repulsion of Pauli is minimum. LOL is usually observed during the overlap of localized orbitals, resulting in high gradients of localized orbitals. The pictures of the ELF and LOL for the title compound are presented in color shade map and contour map which illustrated in Fig. 2.a and Fig. 2.b, respectively. These maps show the areas where the probability of finding an electron pair is high (Silvi and Savin, 1994). From Fig. 2.a, the elevated ELF regions (red regions) indicate the highly localized bond and non-bond electrons around the hydrogen atoms (H19). Blue regions around few carbon atoms indicate the delocalized electron cloud. In Fig. 2. b, it can be seen that the LOL map shows a white region around hydrogen atoms. This region designating that the electron density surpasses the high limit of color scale (0.80). In addition, high LOL values are represented by red colors located between carbon (C10, C7 and C4) indicates the covalent nature of the bonds between them. In contrast, the blue regions between organic and inorganic unit are small (0.12～ 0.24 a.u) gave evidence of existence of non covalent interactions leading to hydrogen bonds. The ELF and LOL results correlate very well with those obtained from QTAIM analyses.

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Fig. 2

(a) and (b) electron localization function (ELF) and localized orbital locator (LOL) map for the title compound.

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4.3 Hirshfeld analysis

Hirshfeld surface analysis is a good method for displaying and comprehending of intermolecular interactions present within the crystal structure of the studied compounds (Gatfaoui et al., 2020). The Hirshfeld surfaces of our 2DOPN molecule were generated with different properties: d _norm, d _i, Shap index and Curvedness obtained by the software Crystal explorer (Fig. 3). The normalized contact distance d_norm surface displayed three colors: red (negative d _norm values), white (zero d _norm values) and blue (positive d _norm values) used to recognize the shorter, close and longer intermolecular interaction than the Van der Waals radii (Sagaama et al., 2020). Red spots on the d _norm surface have been localized around oxygen and hydrogen atoms. This situation shows the presence of O…H/ H…O interactions, which are due to hydrogen bonds N-H···O, O-H···O and C-H···O within the crystal packing. The white color representing intermolecular distances close to Van der Waals contact and indicates the H…H interactions. The blue surfaces illustrate the domains where the neighboring atoms are too moved away to interact with each other. Furthermore, d_norm mapping makes it possible to display the different types of intermolecular interactions in our compound (Fig. 4). The circular deep red color displayed on this surface highlight the shortest intermolecular contacts which are attributed to the hydrogen bonds (due to N-H···O, C-H···O and O-H···O). Fig. 3.d and Fig. 3.b illustrate how the shape index and curvedness mapping can be also be used to identify characteristic packing mode existent in the crystal. The absence of red and blue triangles in the Shap index and Curvedness maps excluded the presence of π-π interactions and even if in C-H···π type interactions in our crystal structure. In addition, the fingerprints of the main contact involved in the studied compound are illustrated in Fig. 5. These plots resulting from the distribution of the pairs (di, de) and allow to highlight the mutual contacts of the atoms participating in close contacts in the crystalline structure. We can notice that the maximum contribution is from O…H/H…O (59%) (represents half of the total contribution) followed by H…H and C…H/H…C with 27.2% and 10.1%, respectively. The participation of the contact observed between carbon and hydrogen (C…H/H…C) is equal to 10.1%. The O…H/H…O contacts (Fig. 5.b) between the oxygen atoms located inside the HS and the hydrogen atoms situated outside and vice versa are characterized by two narrow symmetrical pointed wings with de + di = 1.7 A°. These types of contact provide evidence of N-H···O hydrogen bonds. The graphic associated with hydrogen atoms (Fig. 5.c) is described by an end which points towards the origin on the diagonal and that corresponds to the d_e + d_i = 1.1 A°. This result reveals the presence of close H…H contacts within the title compound 2DOPN. The composition of the 2D fingerprint (Fig. 5.e) also shows other contacts such as C…H/H…C (10.1%), O…O (1.8%). This analysis makes it possible to show the different intermolecular interactions obtained by x-ray diffractions, which help to stabilize the molecular structures.

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Fig. 3

Hirshfeld surfaces: (a) d_norm, (b) Curvedness, (c) d_i and (d) Shape index of the title molecule.

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Fig. 4

Different hydrogen bonds N–H…O, C–H…o and O–H…O observed by d _norm mapping.

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Fig. 5

Bidimensional fingerprints of 2DOPN: (a) All intermolecular contact, (b) contact O…H/H…O, (c) H…H, (d) C…H/H…C and (e) percentage contribution to the Hirshfeld surfaces.

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4.4 Reduced density gradient (RDG) visualization of non covalent interaction

In addition to the topology analysis, a visual approach known as Reduced Density Gradient analysis (RDG) has been added to study the non-covalent interactions. This method could be used to visualize different interactions such as hydrogen bonding, Van der Waals (VDW) interaction and steric effects (Tahenti et al., 2020). To probe the existence of weak interactions, it was shown that RDG analysis was able to recognize non-covalent interactions such as the hydrogen bonds, Van der Waals and steric effect. We represented on Fig. 6.a and Fig. 6.b, the RDG plots of 2-(3, 4-dihydroxyphenyl) ethanaminium nitrate in two and three dimensional spaces. There are three different interaction regions shown within our molecule located in the low density and have low RDG spaces, were indicated as blue, green and red spots. The red color indicating the steric repulsion (strong repulsion) between the atoms of molecule, which sign (λ₂) ρ > 0. Green color appears in the area of the sign (λ₂) ρ = 0 correspond to the Van der Waals interaction. The spikes in the region sign (λ₂) ρ < 0 are blue in color, representing the strong electrostatic interaction like hydrogen bonding (Gatfaoui et al., 2020). As shown in Fig. 6.a, clear blue spots are presented between the hydrogen atoms of the NH₃ group and oxygen atoms of nitrate group results from the weak hydrogen bond like N–H…O (strong attractive interaction). Red color was observed inside the center of aromatic rings, which indicate the steric repulsion (repulsive interaction). Furthermore, the C–H…π interaction is shown by the mixture of the red-green color. Green plates between the hydrogen atoms are attributed to Van der Waals interactions. In addition, to determine the nature and strength of the interactions analyzed using RDG surfaces, we have plotted the graphic of the RDG versus sign (λ2) ρ (Fig. 6.b). This graph shows a color code allows to visualize the interaction zones in 3D space. We noted large negative values of sign (λ2) ρ are indicative of stronger attractive and the binding interaction (H-bond). The interaction region marked by red color can explain the repulsive and non binding interaction located in the interval [0.02–0.05] a.u. The green color situated between −0.01 and 0.01 a.u in the RDG scatter graphs of C₈H₁₂N₂O₅, which corresponds the weak non covalent interaction (VDW type interaction).

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Fig. 6

Graphs of RDG versus the sign (λ2) ρ of the molecule title.

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7.1 Molecular electrostatic potential analysis (MEP)

The molecular electrostatic potential (MEP) is a very important propriety for studying and predicting reactive molecular. It is related to the electron density, which is a very useful descriptor for identifying nuleophilic and electrophilic attack sites as well as intermolecular hydrogen bonding (Gatfaoui et al., 2018). We plotted in Figure S7 the three dimensionally map to show the charge distributions of C₈H₁₂N₂O₅. The reactive sites can be located by different color codes situated between −8.480 e^-2 a.u (deepest red) to 8.480 e^-2 a.u (deepset blue). In general, the red and yellow color is a negative region, which indicates an electron rich site showing nucleophilic reactivity (Noureddine et al., 2021). This region is localized around the oxygen atoms of the nitrate anion. The MEP map shown that the blue color is a positive region promoting the site favorable for electrophilic attacks. This regions is situated around the hydrogen atoms of the organic group (precisely around the NH₃⁺), which indicates an electron deficient sites. According to the figure, we find that the region around the hydrogen atoms of the ammonium group are sites for electrophilic activity (the most positive potential) and oxygen atoms of the NO₃⁻ anion group. are sites for nucleophilic attraction (the most negative potential). These sites give details about the region from which the compound can have intermolecular interactions. The MEP analysis affirms the existence of hydrogen bonds between the organic and inorganic groups of our molecule N-H···O type.

7.2 Molecular electrostatic potential (ESP) on the molecular VDW surface

The ESP on the molecular VDW surface helps to investigate the reactive behavior and predict intermolecular interactions. In general, the regions of greatly negative ESP will clearly accept hydrogen bonds, while hydrogen atoms with a positive ESP will be potential donor sites (Noureddine et al., 2021). Furthermore, ESP allows to show that the atom closest to the global ESP minimum on the VDW surface indicating as much as possible to be an active site for electrophilic attack. In this part, we plotted in Figure S8 the molecular structure and surface extrema of our compound and the Summary of surface analysis are given in Table S4. From this figure, the maxima and minima surface are indicated as red and blue spheres respectively. The number of surface maxima 1 has a maximal value equal to 122.86 kcal/mol that correspond to global maximum arising from the positively charged H₁₉. At this point the ESP is much larger than those at other maxima. This is due to the fact of the presence of nitrogen, which attracts the electron from the hydrogen H₁₉. It can be seen that the lone pair of the oxygen O₂ of organic group and O₂₅ of the inorganic group leads to a minimum value equal to −89.17 Kcal/mol (minimum 4). Since, it is also the global minimum on the surface, the oxygen's O₂ and O₂₅ should be the most favorable site for interacting with positively charged species. The surface area in different ESP ranges is shown in Figure S9. From this graph, it can be seen that there is a large part of the molecular surface having a low ESP value. We also notice the existence of small areas with negative and positive ESP values, corresponding to the regions of maximum and minimum global ESP respectively. In conclusion, we find that the maximum energies as well as the minimum energies located on this surface are derive from the interactions between the two organic and inorganic groups via hydrogen bonds N-H···O, C-H···O and O-H···O.

7.3 Global reactive descriptors: HOMO-LUMO analysis

In order to determine the electronic propriety, stability and reactivity of diverse compounds in terms of frontier molecular orbital, a TD-DFT calculation has been realized. HOMO and LUMO are referred to as frontier molecular orbital and acts primarily as an electron donor and acceptor respectively. This energy gap between the highest occupied (HOMO) and the lowest unoccupied molecular orbital (LUMO) plays an important role in the explaining kinetic stability as well as the chemical reactivity of the compound (Noureddine et al., 2021). The literature reveals that molecules having large / small values of energy gap are known as hard / soft molecules (Noureddine et al., 2021). Furthermore, the soft molecules (less reactive) are more polarizable than the hard ones because they need less energy for excitation (Janani et al., 2021). The plot HOMO-LUMO expose the passage of charges within the molecule. Figure S10 displays the HOMO and LUMO for our molecule with the corresponding energies and energy gap ΔE_HOMO-LUMO. It can see that the surfaces for FMOs are indicated with two colors; red and green explain positively (electrophilic sites) and negatively (nucleophilic sites) charged surfaces. From this figure, it is clear that the HOMO is entirely localized on the [C₈H₁₂NO₂]⁺ cation (precisely in phenyl rings) with a small contribution of two oxygen atoms of the NO₃^– anion. LUMO is localized on the NO₃^– anion with a small contribution of a few atoms of the organic group. We are grouped in Table S4 the global reactivity energy descriptor such as E_HOMO, E_LUMO, electron affinity (A), ionization potential (I), energy gap ΔE_HOMO-LUMO, chemical potential (μ), electronegativity (χ), chemical hardness (η), global softness (S) and electrophilicity index (ω) and additional electronic charges (ΔN) (donor and acceptor charge behavior) of our compound. The energy of HOMO and LUMO of the title compound in gas phase ais equal to − 6.17 eV and − 0.61 eV, resp. The absolute value of the energy |ΔE _HOMO-LUMO|is calculated using B3LYP / 6–311++G (d, p) method is equal to 5.56 eV. Besides, the large / small value of the chemical potential and electrophilicity index explain the good electrophilic / nucleophilic approach of molecules, respectively (Nageswari et al., 2018). The electrophilicity index is found to be 2.09 eV, which is small and this value confirmed that our molecule has a character nucleophilic. In addition, the value of ω is positive, which indicates that the system can act as an acceptor of electrons and clearly indicating the interactions between filled and unfilled orbital. The chemical hardness is a useful indicator for scaling the stability and reactivity of the molecules. The η is found to be 2.75 eV, therefore the title compound has much stability and rigidity character. Furthermore, if the molecule possessed an elevated electronegativity number, the studied compound will attract electrons to itself. The electronegativity of our molecule is equal to 3.39 eV (this value is>1.7 eV), in this case the character of chemical bond is changed from covalent to ionic. The density of states (DOS) describes the number of available states of molecular orbitals at a particular energy level. The DOS graph was obtained by using TD-DFT Gaussian output file via Gauss-Sum package and it is shown in Figure S11. From the DOS plot, the red and green lines signify the HOMO (occupied orbitals) and the LUMO (virtual orbitals), respectively. The study of the DOS plot and its energy levels (|ΔE _HOMO-LUMO|= 5.58 eV) also verify the FMOs analysis.