Weak intermolecular interactions play crucial role in molecular assembly and crystal packing. Though C-H‧‧‧O, C-H‧‧‧π interactions have received much attention, the S‧‧‧π interactions have received little attention. Present paper explores the relative importance of C-H‧‧‧O, C-H‧‧‧π and S‧‧‧π interactions in the crystal packing of 2H -1-benzopyran − 2-one phenyl sulfoxide, a coumarin molecule. Investigation of intermolecular interactions and crystal packing through Hirshfeld surface analysis reveals that the maximum of the close contacts are due to weak interactions. Furthermore, their structures were optimized using density functional theory (DFT) calculations with the M062X hybrid functional and the 6-311G++(d,p) basis set. We investigated the Mulliken charges, molecular electrostatic potential (MEP), and frontier molecular orbitals (HOMO-LUMO). Further the molecular docking studies with Human Serum Albumin (HSA) revealed that the compound exhibits better binding affinity compared to Coumarin, suggesting that it may serve as a more effective inhibitor.
Research Article
On Relative importance of C-H‧‧‧O, C-H‧‧‧π and S‧‧‧π interactions in the crystal of 2H-1-benzopyran-2-one phenyl sulfoxide - A coumarin derivative
https://doi.org/10.21203/rs.3.rs-5217455/v1
This work is licensed under a CC BY 4.0 License
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Hydrogen bonding
π-stacking interaction
C-H‧‧‧π interaction
S‧‧‧π interaction
Density functional theory (DFT)
Hirschfield
Molecular Docking
Molecular self-assembly[1, 2] through weak non-covalent forces[3, 4] is a defining characteristic of biological systems[5]. Understanding how various non-covalent forces interact in the self-assembly of molecules and ions is crucial for effectively applying these forces in fields such as crystal engineering[6, 7], supramolecular electronics[8, 9], nanotechnology[10], and host-guest chemistry[11]. Key non-covalent interactions include hydrogen bonding[12], π‧‧‧π interactions[13], S‧‧‧π interactions[14], and C-H‧‧‧π interactions[15]. Among these, hydrogen bonding and π‧‧‧π interactions are particularly important in forming supramolecular architectures[16]. Effective use of hydrogen bonding requires the strategic placement of complementary donor and acceptor atoms on molecules, which promotes stable hydrogen bond formation and directs molecular assembly. Similarly, π‧‧‧π interactions between aromatic systems provide directional forces that aid in the creation of stacked molecular arrangements. Mastery of these non-covalent forces is essential for designing and controlling supramolecular structures with specific properties and functions. Coumarin molecules and their derivatives have been extensively studied due to their significant applications in synthetic chemistry[17], medicinal chemistry[18], and photochemistry[19]. These derivatives exhibit a range of biological activities, including spasmolytic[20], antiarrhythmic[21], cardiotonic[22], and antitumor effects[23]. Some coumarin derivatives also possess weak estrogenic activity[24], making them useful as therapeutic agents for preventing menopause-related diseases[25]. Additionally, coumarin derivatives are employed in solid-state photochemical reactions[26] and dye-laser studies[27].
So, it is important to make a systematic structural and interaction studies of these types of coumarin derivatives (including 2H -1-benzopyran − 2-one phenyl sulfoxide molecule) in their crystals. These results of structural, packing and noncovalent molecular interaction (such as H-bonds, aromatic π‧‧‧π interaction) in the crystal may help to design the more potent bio-active compounds[28] with unique feature and activity. We have analyzed the structure of 2H -1-benzopyran − 2-one phenyl sulfoxide molecule by single crystal x-ray crystallography methods and also analyzed the conformational and electronic structure of this compound by DFT -methods.
2.1. Material and Methods:
Synthesis
The compound was prepared by the reaction of 3-thiophenyl coumarin and CrO3 –montmorillonite clay K-10 in dichloromethane.
After completion of the reaction for 6 hours, the mixture was filtered and chromatographed through silica gel when the pure product of 2H-1-benzopyran-2-one phenyl Sulfoxide was obtained as oil with 45% yield. From the elemental analysis and molecular weight determination of the compound by mass spectroscopy (M = 270), the molecular formula of the compound was assigned as C15H10O3S.
2.2. X-ray Crystallography studies:
X ray diffraction data for the crystalline compound of chemical formula C15H10SO3 were collected at temperature of 114K on a diffractometer equipment with Bruker Kappa Apex -II CCD area detector using CuKα (1.54178Å) X-ray source. The structure was solved by direct method and refined with a full-matrix least squares refinement (total number of refined reflections 2098) using SHELXL-2017 program[29] with R value 0.056.
3.1. Quantum Chemical Calculations:
The optimization with frequency calculation and single point energy calculation has been carried out with M062X/6-311 + + G (d,p) level of theory using Gaussian 09 software package[30]. Absence of any negative frequency at same level of theory confirmed the global optimization of the compound. The basis set correction has been taken into consideration during the single point calculation under the counterpoise correction method in Gaussian 09. Geometry optimization was carried out using the Gaussian 09 package. Initial geometry of the synthesized molecule was adopted from the crystal structure. AIM, RDG and NCI analysis were carried out using the Multiwfn3.7[31] program package, and graphics has been prepared using VMD software[32].
3.2. Molecular Docking studies:
The optimized ligand molecules were docked into the apo-protein (PDB ID: 1AO6) with help of Autodockvina v 1.1.2[33]. The required PDBQT files for protein was generated using AutoDock Tools v.1.5.4[34] by assigning Kollman united charges[35]. Again, the PDBQT for ligand molecule was generated by adding atomic charges using Gasteiger method. The entire protein was selected by setting the grid spacing point at 1 Å and 16 grid points were taken in each direction. All other parameters were assigned to their default values. The best docked structure was selected for analysis. The binding conformation and hydrogen bond interaction of the ligand molecule within the active site cavity is visualized and reported.
4.1. X-ray crystal structure:
4.1.1. Description of the coordination complex:
Single crystal X-ray diffraction (SCXRD) reveals that the title compound crystallizes in Monoclinic P21/c (No. 14) space group and the unit cell constants are: a = 4.6038(4)Å, b = 11.5300(12)Å, c = 23.073(2)Å, and Z = 4. The asymmetric contains a 2H -1-benzopyran − 2-one phenyl sulfoxide molecule. The ORTEP diagram and layered packing arrangement of the molecules have been depicted in Fig. 1a and Fig. 1b respectively. The molecular structure can be best visualized as a combination of three units, coumarin, phenyl and sulphoxy unit where sulphoxy unit act as bridging unit between coumarin and phenyl groups. The molecule has a ‘L’ shape with an angle of 101.73° between the coumarin unit and the phenyl unit which form two arms of ‘L’ with the sulfur atom acting as the pivot atom. The molecules are organized in successive layers, (110) planes, which are stacked along crystallographic c-axis (Fig. 1b). Detailed description of the ‘L’ shaped molecules in a particular layer through weak intermolecular interactions is given in the next section.
|
Crystal Data |
|
|---|---|
|
CCDC |
2385786 |
|
Formula |
C15 H10 O3 S |
|
Formula Weight |
270.29 |
|
Crystal System |
Monoclinic |
|
Space group |
P21/c (No. 14) |
|
a, b, c [Å] |
4.6038(4) 11.5300(12) 23.073(2) |
|
alpha, beta, gamma [˚] |
90.00 92.407(5) 90.00 |
|
V [Å3] |
1223.7(2) |
|
Z |
4 |
|
D(calc) [g/cm3] |
1.4671 |
|
Mu(CuKα) [ /mm ] |
2.366 |
|
F(000) |
560.0 |
|
Crystal Size [mm] |
0.01 × 0.02 × 0.20 |
|
Data Collection |
|
|
Temperature (K) |
114 |
|
Radiation [Å] |
CuKα 1.54178 |
|
Theta Min-Max [ ˚] |
3.8, 66.3 |
|
Dataset |
-5: 5 ; -13: 13 ; -27: 24 |
|
Tot., Uniq. Data, R(int) |
19499, 2098, 0.089 |
|
Observed Data [I > 2.0 σ(I)] |
1845 |
|
Refinement |
|
|
Nref, Npar |
2098, 173 |
|
R, wR2, S |
0.0498, 0.1340, 1.08 |
|
Max. and Av. Shift/Error |
0.01, 0.00 |
|
Min. and Max. Resd. Dens. [e/Å3] |
-0.46, 0.56 |
| W = 1/[S2 (F0)2+(0.0717P) 2+0.7156P] where P=(F02 + 2Fc2)/3 | |
Table 2
Selected bond distances (Å) and angles (ᵒ) degrees of the synthesized crystal.
|
Bond Distances (Å) |
||
|
Bond between |
X-ray crystallography |
DFT computational |
|
S1-O3 |
1.487(2) |
1.516 |
|
S1-C3 |
1.793(2) |
1.834 |
|
S1-C11 |
1.802(2) |
1.838 |
|
O1-C2 |
1.377(3) |
1.388 |
|
O1-C6 |
1.384(3) |
1.367 |
|
O2-C2 |
1.209(3) |
1.205 |
|
C2-C3 |
1.455(4) |
1.455 |
|
C3-C4 |
1.347(3) |
1.349 |
|
C4-C5 |
1.433(3) |
1.437 |
|
C5-C6 |
1.397(4) |
1.406 |
|
C5-C10 |
1.399(3) |
1.407 |
|
C6-C7 |
1.385(4) |
1.393 |
|
C7-C8 |
1.388(4) |
1.389 |
|
C8-C9 |
1.390(4) |
1.402 |
|
C9-C10 |
1.379(4) |
1.385 |
|
C11-C12 |
1.371(4) |
1.391 |
|
C11-C16 |
1.390(4) |
1.393 |
|
C12-C13 |
1.387(5) |
1.394 |
|
C13-C14 |
1.378(5) |
1.395 |
|
C14-C15 |
1.376(4) |
1.395 |
|
C15-C16 |
1.384(4) |
1.394 |
|
Bond Angles(ᵒ) |
||
|
Angle among |
X-ray crystallography |
DFT computational |
|
O3-S1-C3 |
104.71(11) |
104.02 |
|
O3-S1-C11 |
106.10(11) |
106.23 |
|
C3-S1-C11 |
97.53(11) |
98.35 |
|
C2-O1-C6 |
121.4(2) |
123.04 |
|
O1-C2-O2 |
118.0(2) |
118.31 |
|
O1-C2-C3 |
116.9(2) |
115.48 |
|
O2-C2-C3 |
125.1(2) |
126.21 |
|
S1-C3-C2 |
115.76(17) |
118.49 |
|
S1-C3-C4 |
121.7(2) |
118.62 |
|
C2-C3-C4 |
122.4(2) |
122.54 |
|
C3-C4-C5 |
119.5(2) |
120.14 |
|
C4-C5-C6 |
118.2(2) |
117.51 |
|
C4-C5-C10 |
123.5(2) |
123.95 |
|
C6-C5-C10 |
118.3(2) |
118.53 |
|
O1-C6-C5 |
121.6(2) |
121.23 |
|
O1-C6-C7 |
116.4(2) |
117.40 |
|
C5-C6-C7 |
122.0(2) |
121.37 |
|
C6-C7-C8 |
118.5(3) |
118.92 |
|
C7-C8-C9 |
120.5(2) |
120.83 |
|
C8-C9-C10 |
120.5(2) |
119.89 |
|
C5-C10-C9 |
120.2(2) |
120.46 |
|
S1-C11-C12 |
117.6(2) |
117.50 |
|
S1-C11-C16 |
120.84(19) |
120.46 |
|
C12-C11-C16 |
121.5(2) |
121.86 |
|
C11-C12-C13 |
119.0(3) |
118.87 |
|
C12-C13-C14 |
120.2(3) |
120.15 |
|
C13-C14-C15 |
120.4(3) |
120.17 |
|
C14-C15-C16 |
120.2(3) |
120.32 |
|
C11-C16-C15 |
118.7(3) |
118.62 |
Within the unit cell four independent molecules are present that interact with each other by complementary hydrogen bonding (Fig. 3). The complimentary hydrogen bonding is established between the oxygen atoms of pyran unit of coumarin and the hydrogen atoms of sulfoxide phenyl moiety (C-H···O) and also there are another type of hydrogen bond between the sulfoxide atoms and hydrogen atoms of the coumarin (C-H···O). The C-H···π interaction is between the hydrogen atom of the sulfoxide phenyl and the phenyl ring of the coumarin has led to a one-dimensional association of successive molecular complexes along the crystallographic b- axis (Fig. 4).
These supramolecular polymeric chains are further united inversely through hydrogen bond to form the molecular bilayer along b- axis on bc-plane (Fig. 5).The edge-to-edge π···π interaction for the side wise association of the molecular bilayer is between sulfoxidephenyl rings of adjacent 1D supramolecular tape of 2H -1-benzopyran-2-one phenyl sulfoxide molecule. Thus, the mutual cooperation between the hydrogen bonding and edge to edge π···π interactions has led to the formation of a 2D supramolecular bilayer of 2H -1-benzopyran-2-one phenyl sulfoxide derivatives in the bc plane (Fig. 5).
These two supramolecular bilayers are further united side wise through another set of hydrogen bonding between the hydrogen atoms of pyran unit of coumarin and the oxygen atom of sulfoxide phenyl moiety. Thus the mutual cooperation between the hydrogen bonding interaction has led to the formation of a 2D supramolecular sheet of 2H -1-benzopyran-2-one phenyl sulfoxidemolecular complexes in the bc plane (Fig. 6).
Successive 2D supramolecular sheets are further stacked along crystallographic a-axis through π···π interaction, S···π interactions and parallel displaced π···π interactions (Fig. 7) resulting a complete 3D supramolecular assembly like a roofing sheet (Fig. 7) of the molecular complexes.
4.2. Hirshfeld surface analysis and 2D fingerprint plots:
Hirshfeld surface analysis has become a popular tool to understand the relative importance of various atom-atom interactions in crystal packing[36]. We have calculated Hirshfeld surfaces 
and fingerprint (FP) of the crystal by using CRYSTAL EXPLORER program[37]. dnorm can be followed from the equation:
$$\:{\varvec{d}}_{\varvec{n}\varvec{o}\varvec{r}\varvec{m}}\:=\frac{{\varvec{d}}_{\varvec{i}}-{\varvec{r}}_{\varvec{i}}^{\varvec{v}\varvec{d}\varvec{w}}}{{\varvec{r}}_{\varvec{i}}^{\varvec{v}\varvec{d}\varvec{w}}}\:+\frac{{\varvec{d}}_{\varvec{e}}-{\varvec{r}}_{\varvec{e}}^{\varvec{v}\varvec{d}\varvec{w}}}{{\varvec{r}}_{\varvec{e}}^{\varvec{v}\varvec{d}\varvec{w}}}$$
where di and de are the distances form the surface to the nearest nucleus measured from surface inside and outside, respectively and ridwd is the van der Waal’s radii of the atom.The mapping of Hirshfeld surface over the normalized contact distance dnorm was carried out for the compounds illustrated in Fig. 8. This mapping shows three color schemes red, blue, and white. The red (dnorm is negative) and blue (dnorm is positive) colored regions on the surface are from shorter and longer contacts than van der Waals radii respectively; while the white regions are those where distances are comparable to van der Waal’s distances and these have \(\:{d}_{norm}\)value zero[38].
Ten deep red spots (a, b, bʹ, d, e, h, and g) and two set of lighter red spot (c, f) are clearly visible in the dnorm surface of the crystal. The bright red region in the surface marked as a and e are from (C-H···Cph) contacts which is responsible for C-H···π interactions, b, bʹ and h are from C-H···O interactions between the hydrogen atoms of pyran unit of coumarin and the oxygen atom of sulfoxide phenyl moiety for hydrogen bonding. There is another type of C-H···O interactions which are marked by d and g. The lighter red spots c and f on the dnorm surface corresponds to C-S···π interaction with S···Cph distance 3.355Å.
The 2D fingerprint plots were generated to know the percentage of the contributions of intermolecular interactions of each type of contact to the Hirshfeld surface area of the crystal structure. Figure 9 shows the 2D finger plots of the all contacts. H···H interactions, O···H interactions and C···H interactions contribute respectively 39.3%, 23.4% and 16.0% of total interactions. The distinct spikes in the fingerprint plots correspond to the strong intermolecular interactions. Here O···H and C···H interactions appear as two characteristic spikes which have a significant contribution to the crystal packing of the complex where the distance di+ de ≈2.3 and 2.5Å (Fig. 9). The π···π interactions in the C···C fingerprint plot are the broad green region with di+de in between ̴ 3.4 Å to 4.4 Å. The C···H fingerprint plot mainly corresponds to C-H···π interactions and C···C fingerprint plot mainly correspond to π···π interactions. Furthermore, there is a C···S interaction, which is corresponds to C-S···π interactions which has a significant contribution to the crystal packing.
4.3. 3D Energy frameworks analysis:
The study of energy frameworks gives insight into the unique quantitative analysis of interaction energies and supramolecular architecture of molecules in the crystal. The interaction energy between the molecules can be calculated with the most efficient procedure [39] using the CrystalExplorer17.5 software. The total interaction energy was calculated by generating the molecular cluster (Fig. 10) of radius 3.8 Å around the single molecule. The energy framework analysis was performed by using symmetry operations to compute molecular wave functions and to generate electron densities of the cluster of molecules present around the selected molecule.
Table 3 Molecular interaction energies (kJ mol−1) of the cluster of molecules. Each energies should be multiply by the conversion factors kele = 1.057, kpol = 0.740, kdis = 0.871, krep = 0.618 to obtain the total energy (Etot ).
|
Molecule colour |
N |
Symop |
R |
Electron Density |
Eele |
Epol |
Edis |
Erep |
Etot |
|
2 |
x, y, z |
4.60 |
B3LYP/6-31G(d,p) |
-12.7 |
-2.7 |
-67.9 |
50.5 |
-43.4 |
|
|
1 |
-x, -y, -z |
8.83 |
B3LYP/6-31G(d,p) |
6.4 |
-1.1 |
-2.6 |
0.1 |
3.7 |
|
|
1 |
-x, -y, -z |
6.43 |
B3LYP/6-31G(d,p) |
-39.1 |
-11.0 |
-24.5 |
37.0 |
-47.9 |
|
|
2 |
-x, y+1/2, -z+1/2 |
8.14 |
B3LYP/6-31G(d,p) |
-9.2 |
-2.7 |
-15.9 |
12.1 |
-18.2 |
|
|
2 |
x, y, z |
11.53 |
B3LYP/6-31G(d,p) |
-1.1 |
-0.4 |
-9.1 |
8.5 |
-4.1 |
|
|
1 |
-x, -y, -z |
6.86 |
B3LYP/6-31G(d,p) |
-2.3 |
-1.6 |
-27.2 |
16.8 |
-16.9 |
|
|
2 |
-x, y+1/2, -z+1/2 |
8.74 |
B3LYP/6-31G(d,p) |
-11.6 |
-2.5 |
-13.5 |
12.3 |
-18.2 |
|
|
2 |
x, y, z |
12.42 |
B3LYP/6-31G(d,p) |
2.9 |
-0.6 |
-7.7 |
0.0 |
-4.0 |
|
|
1 |
-x, -y, -z |
11.42 |
B3LYP/6-31G(d,p) |
-2.7 |
-0.3 |
-6.4 |
1.0 |
-8.1 |
|
|
1 |
-x, -y, -z |
11.67 |
B3LYP/6-31G(d,p) |
-0.4 |
-0.4 |
-9.5 |
7.9 |
-4.1 |
The scale factors used for the construction of the energy frame-work for B3LYP/6-31G (d,p) electron densities are kele= 1.057, kpol = 0.740, kdisp = 0.871, krep = 0.618. Table 3 represents the crystallographic symmetry operations and the corresponding molecular interaction energies (where R is the distance between molecular centroids (mean atomic position) in Å and N is the number of molecules at that distance, energies are in kJ mol − 1 ) for Fifteen molecules of the complex .The greenish yellow colored molecule located at 6.43Å from the centroid of the selected molecule showing the highest total interaction energy (-47.9 kJmol-1) whereas the orange colored molecule at 8.834Å from the centroid of the selected molecule exhibits the lowest total interaction energy (3.7 kJmol-1). The total interaction energy ( -161.2 kJ mol− 1 ) involving the electrostatic ( -69.8 kJmol− 1 ), polarization ( -23.3 kJmol− 1 ), dispersion ( -184.3 kJmol− 1) and repulsion (146.2 kJ mol− 1 ) energy terms were evaluated by energy frameworks construction using molecular pair interaction energy calculations. It is clear from the Table… that the dispersion energy has the highest value among the all-other interaction energies in the complex. So, the energy calculation points out that interaction in crystals are dominated by dispersion energy framework over the electrostatic Coulomb interaction energy for the complexes. This is because of the presence of sulpher group which has a large electron cloud in each compound. The more electrons an atom or molecule has, the stronger dispersion forces are.
The visualization of different interaction energies like Coulomb interaction energy, dispersion energy and total interaction energy are represented by red, green, and blue color cylinder with scale factor (cylinder tube size) 100 and cut off energy 5.00 kJmol− 1 respectively for the complex along different axes are shown in Fig. 11. The size of the cylinders represents the magnitude of the interaction energy between molecular pairs and these also represent the relative strength of the molecular packing along different directions. The red color cylinders in this energy framework of molecular cluster represents the electrostatic energy (Eelec ), green color cylinders represent dispersive energy (Edis) and blue color cylinders represents the total interaction energy (Etot) Fig. 11. The energy framework diagram also showed that the dispersion energy dominates over the electrostatic and polarization energies in the crystal environment.
4.4. Computational Studies
4.4.1.DFT calculation results:
The quantum chemical calculations, analysis of the frontier molecular orbitals, atomic charges and surface potential studies play an important role to understand the molecular interaction and chemical properties of the compound. The geometrical optimization of the compound and coumarin were carried out by density functional theory (DFT) using M062X functionals with 6-311 + + G(d,p) level basis set[].The optimized structure of the compound and coumarin have been shown in Fig. 12. A comparison of X-ray crystallographic and the optimized data of bond lengths and bond angles of the synthesized molecule have been presented in Table 2. The calculated and experimental values are nearly same as can been seen from Table 2.
Further, the frontier molecular orbitals (HOMO-LUMO)[40] and their energy gap for the compound and coumarin are shown in Fig. 13. The HOMO, LUMO and ΔE for the compound is observed to be -6.3846, -2.3129 and 4.0717 eV respectively whereas the same for Coumarin is observed to be -6.6159, -2.0201 and 4.5958 eV. The 2H -1-benzopyran − 2-one phenyl sulfoxide compound has lower ΔE so donation of electron from HOMO to LUMO would be easier and compound will have higher stability.
The ionization potential (I), the electron affinity (A), the absolute electronegativity (χ), the global hardness (η), the global softness (σ), the chemical potential (µ), the global electrophilicity (ω) and the dipole moment (D)[41] are also calculated and tabulated in Table 4.
|
Parameters |
2H -1-benzopyran − 2-one phenyl sulfoxide (eV) |
Coumarin |
|---|---|---|
|
EHOMO ELUMO ΔEgap Ionization potential (I) Electron affinity (A) Electronegativity ( χ) Chemical hardness ( η) Global softness ( σ) Chemical potential( µ) Electrophilicity ( ω) Dipole moment (Debye) |
-6.601 − 2.608 3.993 6.601 2.608 4.604 1.996 0.250 − 4.604 5.309 4.5437 |
− 6.877 − 2.285 4.592 6.877 2.285 4.581 2.296 0.218 − 4.581 4.570 5.200 |
where, χ = (I + A)/2, η= (I-A)/2, σ = 1/2η and ω = µ2/2η.
The Mulliken atomic charges[42] of all atoms of the compound have been computed and listed in the Table 5. The oxygen atoms have shown negative charges and that can be explained by their participation in the formation of (C-H···O) hydrogen bonds. The C5(1.537) atom has shown high value of electro-positivity and C6 (-1.386) atom has shown the high value of electro-negetivity due to the fused ring of coumarin. The carbon atom with negative charge is ready for electrophilic attack and the carbon atoms with positive charges would be responsible for nucleophilic attack site[43].
Table 5
Mulliken atomic charges of the title compound
The molecular electrostatics potential (MEP)[44] map is an advantageous diagram to visualize the partial atomic charges influence interrelated properties. The MEP map gives us the idea to predict the reactive sites for electrophilic and nucleophilic attack and also to investigate the biological identification as well as hydrogen bonding. Based on the partial atomic charges, ESP diagrams have been drawn with the help of Multiwfn and VMD software[31],[32]. The molecular electrostatic potential (MEP) map of the compound is generated in the color scale range − 0.030 au (deepest red) to + 0.030 au (deepest blue) and is shown in Fig. 15. The blue colors (positive region of ESP) represent the electrophilic reactivity and the green colors (negative region of ESP) related to nucleophilic reactivity of the molecule. The red color indicates the highest negative ESP region related to the electrophilic attack site. The MEP map shows that the highest negative ESP regions are localized over the oxygen atoms of pyran unit of coumarin and the sulfoxide. These are the possible sites for electrophilic attack. The blue regions (positive ESP region) are spread around the hydrogen atoms attached to carbon atoms.
4.4.2. AIM, RDG and NCI analysis:
The stability of the molecular structure can be achieved by its intermolecular or weak intermolecular interactions. To understand the nature of the various intermolecular interactions between hydrogen bond donor and the neutral substrates, the QTAIM[45] analysis were carried outfor model supramolecular associates.The topological parameters of the Bond Critical Point (BCP) such as the electron density (ρ(r)), Laplacian of electron density (\(\:{\nabla\:}^{2}\)ρ), the potential electron density (v(r)) and Lagrangian kinetic electron density (g(r)) have been analyzed from the Baders theory[46], which is accomplished with Multiwfn and VMD software. The topology of electron density of various intra and intermolecular interactions is an interesting melody to substantiate the strength of interactions. The strength of hydrogen bond can also be characterized by evaluating the hydrogen bond energy (EHB).The hydrogen bond energy (EHB) can also be calculated using the QTAIM method as suggested by Espinosa et al.[47] Eq. 1 approximate EHB is the half of VBCP
EHB= \(\:\frac{1}{2}\)VBCP (1)
The topological parameters of interacting atoms are listed in Table 6. The electron density ρ(r) and Laplacian of electron density ∇2ρ of the intermolecular interaction
C-H···O are 0.00790 a.u. and 0.02894a.u.respectively. The positive Laplacian electron density indicates that the interactions exhibit closed-shell interaction[48][49].The bond energy of this interaction has been calculated as -6.48 kJ/mol.
|
Critical point number |
ρ(r) Electron density a.u. |
\(\:{\nabla\:}^{2}\)ρ Laplacian of electron density a.u. |
V(r) Potential energy density a.u. |
G(r) Lagrangian kinetic energy density a.u. |
|V(r)|/G(r) |
G(r)/ ρ(r) |
|---|---|---|---|---|---|---|
|
BCPs(Brown) |
||||||
|
b1 (C-H···O) |
0.00790 |
0.02894 |
-0.00494 |
0.00608 |
0.81117 |
0.77004 |
|
RCPs(Yellow) |
||||||
|
r1 |
0.02094 |
0.16705 |
-0.02679 |
0.03428 |
0.78166 |
1.63542 |
|
r2 |
0.03428 |
0.14854 |
-0.02512 |
0.031127 |
0.80696 |
0.90809 |
|
r3 |
0.00621 |
0.02653 |
-0.00435 |
0.00549 |
0.79168 |
0.88376 |
|
r4 |
0.02213 |
0.17689 |
-0.02917 |
0.03669 |
0.79485 |
1.65854 |
The NCI analysis can provide the useful information about the non-covalent interaction within the compound. The analysis is based on RDG (a basis non dimensional quantity)[50] defined as
RDG(r) =\(\:\frac{1}{2{\left({3\pi\:}^{2\:}\right)}^{\raisebox{1ex}{$1$}\!\left/\:\!\raisebox{-1ex}{$3$}\right.}}\frac{|\nabla\:\rho\:\left(r\right)|}{{\rho\:\left(r\right)}^{\raisebox{1ex}{$4$}\!\left/\:\!\raisebox{-1ex}{$3$}\right.}}\)
where\(\:\:\nabla\:\)ρ(r) is a gradient of the electron density. This investigation enables visualization of regions to understand the interaction is either attractive or repulsive interactions. The NCI-RDG analyses were carried out by an isosurface value of 0.6, and are displayed respectively in for both compounds (Fig. 16.(b)). The RDG scatter graph of the compound was indicated in Fig. 16(c). As seen on the Fig. 16(b), the red color is defined as strong repulsion (steric effect), the blue colors indicate the hydrogen bonding interaction and green colors are Van der Waals interactions. In the NCI-RDG isosurface graphs of compound, the green region between the hydrogen atoms of sulfoxide phenyl moiety and the oxygen atoms of pyran unit of coumarin results from the H-bond like C-H...O, as shown in Fig. 16(c).
In the molecular complex, there is important π···π interaction, S···π interactions and parallel displaced π···π interactions between two molecular units as shown in Fig. 17(a). To understand whether it is a favorable interaction resulting from the crystal packing effect or not and also to understand the nature of this interaction, we have attempted the computational explorations. Interestingly, the computational results reveal that the observed interactions is a stable interactions like structural motif and the geometrical parameters characterizing the interactions estimated from both crystal geometry and computation come quite close to each other (Fig. 17(a,b)).The BSSE corrected complexation energy[51] for this interacting motif is -13.02kcal/mol. Figure 17(c) shows the NCI surface plot and Fig. 17(d) shows the reduced density gradient plot for these interactions. The characteristic broad green spike in the native value range of − 0.01 to 0.006 a.u. for sign(λ2)ρ corresponds to weak noncovalent interactions. In the NCI isosurface plot (Fig..), a flat sheetlike region between molecular units corresponds to π···π interaction, S···π interactions and parallel displaced π···π interactions.
4.4.3. AIM analysis of various hydrogen bonds in crystal packing:
To understand the relative importance of various noncovalent interaction such as hydrogen bonding between two molecular units, the QTAIM analysis were carried out for two basic motifs of molecular synthon (Fig. 18 and Fig. 19). AIM analysis also reveals that the bond critical points (b2 and b3) and bond path joining the O and H atoms between the oxygen atoms of pyran unit of coumarin and the hydrogen atoms of sulfoxide phenyl moiety (C-H···O)are for hydrogen bonds and the bond critical point b4 are for the H···H interaction. The topological parameters of interacting atoms of motif 1 are listed in Table 7. The positive Laplacian indicates that the all interactions exhibit closed-shell interaction. The bond energy of the various Hydrogen bond interactions are shown in Table 7.
|
Critical point number |
ρ(r) Electron density a.u. |
\(\:{\nabla\:}^{2}\)ρ Laplacian of electron density a.u. |
V(r) Potential energy density a.u. |
G(r) Lagrangian kinetic energy density a.u. |
|V(r)|/G(r) |
EHB (kJ/mol) |
|---|---|---|---|---|---|---|
|
BCPs(Brown) |
||||||
|
b1 (C-H···O) |
0.00801 |
0.02940 |
-0.0051 |
0.00623 |
0.81862 |
− 6.694 |
|
b2 (C-H···O) |
0.00727 |
0.02596 |
-0.00452 |
0.00551 |
0.82033 |
− 5.933 |
|
b3 (C-H···O) |
0.00399 |
0.01626 |
-0.00249 |
0.00328 |
0.75915 |
− 3.268 |
|
b4 (H···H) |
0.00263 |
0.01000 |
-0.00135 |
0.00192 |
0.70313 |
− 1.772 |
|
b5 (C···O) |
0.00242 |
0.00929 |
-0.00126 |
0.00179 |
0.70391 |
|
|
b6 (C-H···O) |
0.00808 |
0.02929 |
-0.00514 |
0.00623 |
0.82504 |
− 6.746 |
|
RCPs(Yellow) |
||||||
|
r1 and r9 |
0.02266 |
0.17985 |
-0.03024 |
0.03760 |
0.80426 |
|
|
r2 |
0.00640 |
0.02682 |
-0.00455 |
0.00563 |
0.80817 |
|
|
r3 and r10 |
0.02115 |
0.15107 |
-0.02597 |
0.03187 |
0.81487 |
|
|
r4 and r11 |
0.02142 |
0.16937 |
-0.02767 |
0.03500 |
0.79057 |
|
|
r5 |
0.00305 |
0.01443 |
-0.00194 |
0.00277 |
0.70036 |
|
|
r6 |
0.00248 |
0.01057 |
-0.00141 |
0.00203 |
0.69458 |
|
|
r7 |
0.00167 |
0.00715 |
-0.00082 |
0.00130 |
0.63077 |
|
|
r8 |
0.00645 |
0.02685 |
-0.00459 |
0.00565 |
0.81239 |
|
AIM analysis for motif 2 also reveals that the bond critical points (b2, b3, b4 and b5) and bond path joining the O and H atoms between the sulfoxide oxygen atoms and the hydrogen atoms of coumarin(C-H···O)are for hydrogen bonds. The topological parameters of various interacting atoms for synthon 2 are listed in Table 8. The energy of various non-covalent hydrogen bond interactions are also listed in Table 8. The higher electron density of the BCP (b2 and b5) than the BCP (b3 and b4) corresponds to the stronger hydrogen bond.
|
Critical point number |
ρ(r) Electron density a.u. |
\(\:{\nabla\:}^{2}\)ρ Laplacian of electron density a.u. |
V(r) Potential energy density a.u. |
G(r) Lagrangian kinetic energy density a.u. |
|V(r)|/G(r) |
EHB (kJ/mol) |
|---|---|---|---|---|---|---|
|
BCPs(Brown) |
||||||
|
b1 and b6 (C-H···O) |
0.00802 |
0.02934 |
-0.00509 |
0.00622 |
0.81833 |
− 6.681 |
|
b2 and b5 (C-H···O) |
0.00972 |
0.03846 |
-0.00648 |
0.00803 |
0.80697 |
− 8.505 |
|
b3 and b4 (C-H···O) |
0.00715 |
0.02859 |
-0.00453 |
0.00584 |
0.77568 |
5.946 |
|
RCPs(Yellow) |
||||||
|
r1 and r11 |
0.02263 |
0.17964 |
-0.03017 |
0.03754 |
0.80368 |
|
|
r2 and r10 |
0.00641 |
0.02674 |
-0.00455 |
0.00561 |
0.81105 |
|
|
r3 and r9 |
0.02116 |
0.15101 |
-0.02597 |
0.03186 |
0.81512 |
|
|
r4 and r8 |
0.02151 |
0.16981 |
-0.02784 |
0.03514 |
0.79226 |
|
|
r5 and r7 |
0.00411 |
0.01818 |
-0.00261 |
0.00358 |
0.72905 |
|
|
r6 |
0.00177 |
0.00814 |
-0.00079 |
0.00142 |
0.55634 |
|
4.4.4. Molecular Docking studies:
The Molecular docking studies of the ligand molecules are performed with Human Serum Albumin (HSA) carrier protein. The HAS is well known globular protein known to carry drug molecules to their destined site of action in the physiological system so is used for different experimental studies. The docking studies show that the 2H -1-benzopyran − 2-one phenyl sulfoxide molecule binds to HSA with an affinity of -8.479 kcal/mol and Coumarin has binding affinity of -6.255 kcal/mol. The comparative binding affinities suggest that the 3-phenylsulfoxy coumarin molecule has a better binding ability than the Coumarin molecule and may function as better inhibitor molecule. The binding sites for both the molecules are shown in Fig. 20.
A new coumarin derivative, 2H-1-benzopyran-2-one phenyl sulfoxide, has been synthesized and its crystal structure analyzed. This compound crystallizes in the Monoclinic crystal system, specifically in the space group P21/c (No. 14). The crystal structure reveals that the compound features common C-H···O type intermolecular hydrogen bonds. Additionally, it exhibits intra-molecular C-H···π interactions that contribute to the stabilization of the molecular structure. The analysis also shows that the crystal structure includes edge-to-edge π···π interactions, π···π interactions, and the relatively rare S···π interactions, all of which enhance the stability of the crystal. The simple coumarin based molecules studied here illustrate the intricate interplay of various weak forces in crystal packing. Specifically, the cooperation of C-H···O interactions, C-H···π interactions, π···π interactions, S···π interactions, and dispersive forces demonstrates how these forces collectively contribute to the stability and organization of the crystal structure.
Hirshfeld surface analysis indicates that H···H, O···H and C···H interactions contribute 39.3%, 23.4%, and 16.0%, respectively, to the total interactions. Furthermore, 2D fingerprint plots highlight that C···C and C···S interactions are significant in contributing to the crystal's stability. The structure of the compound was optimized using the M062X functional with the 6-311 + + G(d,p) basis set, yielding excellent correlations between the optimized geometrical parameters and those obtained from X-ray diffraction (XRD) studies. Based on molecular docking studies, it appears that the 2H-1-benzopyran-2-one phenyl sulfoxide compound exhibits superior binding ability compared to Coumarin, potentially making it a more effective inhibitor.
6. Funding:
A. D. J. acknowledges the financial support from the Department of Science, Technology and Biotechnology, Government of West Bengal, India through the project memo no: 250(Sanc.)/ST/P/S&T/16G-47/2017 Date: 25/03/2018 and 349(sanc.)/STBT-11012(19)/10/2021-STSEC dated 14/07/2021.
7. Supplementary data:
CCDC 2385786 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033). CIF data and checkcif report has been provided as ESI material.
8. Credit Author Statement:
P. Joarddar is responsible crystal synthesis, Hirshfeld analysis and draft manuscript preparation. S.C. Halder is responsible for DFT computation. S. Kundu is responsible for XRD data analysis. S. Dasgupta is responsible for Molecular Docking studies. G. Biswas is responsible for crystal synthesis. A. D. Jana has supervised the work and prepared the final manuscript.
9. Competing interests:
The authors declare that there is no conflict of interest.
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No competing interests reported.