# Biosensitivity and Theoretical Electronic Structure Investigations on 3-(2-Hydroxyphenyl)-2-iminothiazolidin-4-one and Its Zn2+ and Cd2+ Metal Complexes

Authors: Zewdu Bezu Gemechu; Boobalan Maria Susai; Abi M. Taddesse; Endale Teju Bedada; R. Ramamoorthy
Journal: Journal of Chemistry
 (2021)

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## Abstract

A two-step cyclocondensation reaction has been carried out using 2-aminophenol with 2-chloroacetyl chloride to produce o-hydroxyphenyl chloroacetamide followed by treatment with KSCN in CH3COCH3 to produce the heterocyclic ligand 3-(2-hydroxyphenyl)-2-iminothiazolidin-4-one. The Zn2+ and Cd2+ complexes with a metal : ligands ratio of 1 : 4 were synthesized in ethanol using respective metal precursors with the title ligand. Antimicrobial activities of the ligand and its complexes were checked against some bacterial and fungal strains. The result evidenced better bioactive performance of the metal complex (though lower than the standard drug) than the free ligand against Escherichia coli, Staphylococcus aureus, and Salmonella typhi bacteria, as well as Fusarium oxysporum and Aspergillus niger fungal strains. Theoretical investigations on ligand and metal complexes help to infer the electronic structure behavior of them. Molecular geometry and bond order analysis provides detailed information on the nature of chemical structure and bonding. Molecular Electrostatic Potential (MEP) and atomic charge analysis claims evidence on charge distribution and electrophilic, nucleophilic reactive sites. Natural bond orbital analysis provides second-order perturbed stabilization interactions, orbital population, and their energies. Other theoretical properties such as hardness, softness, electron affinities, and ionization potential were derived and discussed in detail.


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## Body

## 1. Introduction

In terms of structural and coordination compound chemistry, most metal complexes containing many heteroatoms in a membered ring receive a lot of attention. Because of their affluence of formation and flexibility, thiazolidinones have played an important role in the development of coordination chemistry, as they readily form stable complexes with most transition metals. Complexes make up a large number of biologically active compounds, and even the simplest forms of complexes have been used as model compounds in studies of bodily processes [1]. Imines are nitrogen carbon double bond compounds owing to their stability and structural similarity to natural biological substances; imines are an essential class of compounds and are used as antipathogenic agents (bacteria, fungal) of which thiazolidinone are derivatives, which play an important role in medical science, and their unique physicochemical properties, which allow them to be used in a variety of other fields, put them ahead of other heterocyclic organics [2].Furthermore, these compounds function as well-liked ligands, and their biosensitivity has been shown to increase with complexation. Thiazolidinones also serve as good ligands in the formation of metal complexes due to the presence of nitrogen, sulfur, and oxygen donors [3]. The strong antibacterial and antifungal properties of thiazolidinones sparked a lot of interest in the development of new compounds in this class. Ligands like thiazolidinones and derivatives constrain certain bacterial and fungal strains to varying degrees [4–8].Henceforth, the present work mainly focuses on the biological and computational probe of phenyl fused thiazolidinones based 3-(2-hydroxyphenyl)-2-iminothiazolidin-4-one ligand (L1) and its Zn2+ and Cd2+ (ZnL1 and CdL1) complexes, respectively. The experimental characterizations such as elemental, thermodynamical, and spectral (FTIR, UV-Vis, and NMR) attributes of the ligand and metal complexes had been reported in our earlier work [9]. In the present work, we are motivated to investigate the biological sensitivity and electronic structure characterization of those title systems in this work.


## 2. Materials and Methods

### 2.1. Synthesis of Ligand (L1) and Metal Complexes (ZnL1 and CdL1)

The synthesis of 3-(2-hydroxyphenyl)-2-iminothiazolidin-4-one named L1 had been reported in our earlier work. The chemical structure of L1 was confirmed by various spectral characterizations. The L1 has been synthesized under double stage synthesis and its synthetic scheme is shown in Figure1. The synthesis of Zn and Cd metal complexes of L1, namely, ZnL1 and CdL1, was reported in our prior work, where L1 was reported. The structure of ZnL1 and CdL1 was confirmed using elemental analysis, chloride test, UV-Vis, conductometric analysis, FTIR, and NMR spectral techniques [9].Figure 1
The synthetic scheme of L1.


### 2.2. Antimicrobial Sensitivity

The antibacterial sensitivity of the synthesized L1 and its ZnL1 and CdL1 complexes was tested in vitro using the paper disc diffusion method [10]. Antibacterial tests were performed on three important bacteria: Escherichia coli (Gram-negative), Staphylococcus aureus (Gram-positive), and Salmonella typhi (Gram-negative), as well as two fungi, Fusarium oxysporum and Aspergillus niger, which were tested using nutrient agar medium, with chloramphenicol and Bavistin standard antibiotic drugs serving as controls in antibactericidal and fungicidal studies, respectively. The diameter of the inhibition zones was measured, and the effectiveness of the synthesized compounds was assessed.


#### 2.2.1. Preparation of Media and Sample Solution

Escherichia coli, Staphylococcus aureus, and Salmonella typhi bacteria were transferred from the culture and streaked for 24 hours at 37°C on Mueller-Hinton agar (MHA) plates. The bacteria were then transferred to autoclaved MHA that had been cooled to 45 degrees Celsius in a water bath and mixed vigorously by swirling the flasks. After that, the medium was poured into sterilized Petri dishes, solidified, and used. From stock cultures, mycelia plugs were transferred to PDA and incubated for 6 days. The fungi spores were then transferred to a 50 mL autoclaved PDA that had been cooled in a water bath to about 45°C. Finally, the spore suspension-containing media was poured into sterilized plates, solidified, and used for biotesting. The ligand and complex solutions were prepared by dissolving their 10 mg samples in 1 ml DMSO, and 10 μl and 20 μl aliquots were used for biotest.


#### 2.2.2. Antimicrobial Sensitivity Testing Procedure

The antibacterial sensitivity includes the following procedure: The Whatman no.1 filter paper was punctured with office puncture to obtain 6 mm diameter paper discs. The discs were sterilized in an oven at 180°C for 1 hour. Then, in two replications, 10μl and 20 μl of compound solution were pipetted to the discs. The sample-impregnated paper discs were transferred with sterile forceps to a nutrient agar plate seeded with bacteria and incubated at 37°C for 24 hours. In antifungal sensitivity examination, similar procedures were followed excluding that paper discs impregnated with samples were transferred with sterile forceps to PDA seeded with spore suspensions of Aspergillus niger and Rhizoctonia bataticola at room temperature for 3 days [11].


### 2.3. Computation Profile

In general, the theoretical and computational investigations on molecular systems could help one to gain quantum chemical insight on the molecular electronic structure properties. The present work has been focused on computing, calculating, and inferring various electronic structure properties such as geometry, symmetry, energy, conformation, natural bonding (NBO), frontier molecular orbitals (FMO’s), molecular electrostatics (MEP), charge, and additional associated molecular quantum chemical properties. The pure organic ligand L1 and its metal complex such as ZnL1 and CdL1 were examined using density functional theory (DFT). The conformational generation was performed using semiempirical level theory, namely, Austin Model 1 (AM1). For other electronic structure properties, L1 was treated with B3LYP/6-31+G(d) basis set. The metal complex was treated based on effective core potential (ECP) technique. In ZnL1 and CdL1 metal complex system, a dual basis set practice was incorporated simultaneously on both ligand and metal in a fashion like B3LYP/lanl2dz basis on Zn and Cd metal atoms, whereas for atoms of ligand B3LYP/6-31G(d) was applied.All the computations were performed using Gaussian 09W [12] theoretical code. The NBO enquiries were made by NBO 7.0 code [13].


## 2.1. Synthesis of Ligand (L1) and Metal Complexes (ZnL1 and CdL1)

The synthesis of 3-(2-hydroxyphenyl)-2-iminothiazolidin-4-one named L1 had been reported in our earlier work. The chemical structure of L1 was confirmed by various spectral characterizations. The L1 has been synthesized under double stage synthesis and its synthetic scheme is shown in Figure1. The synthesis of Zn and Cd metal complexes of L1, namely, ZnL1 and CdL1, was reported in our prior work, where L1 was reported. The structure of ZnL1 and CdL1 was confirmed using elemental analysis, chloride test, UV-Vis, conductometric analysis, FTIR, and NMR spectral techniques [9].Figure 1
The synthetic scheme of L1.


## 2.2. Antimicrobial Sensitivity

The antibacterial sensitivity of the synthesized L1 and its ZnL1 and CdL1 complexes was tested in vitro using the paper disc diffusion method [10]. Antibacterial tests were performed on three important bacteria: Escherichia coli (Gram-negative), Staphylococcus aureus (Gram-positive), and Salmonella typhi (Gram-negative), as well as two fungi, Fusarium oxysporum and Aspergillus niger, which were tested using nutrient agar medium, with chloramphenicol and Bavistin standard antibiotic drugs serving as controls in antibactericidal and fungicidal studies, respectively. The diameter of the inhibition zones was measured, and the effectiveness of the synthesized compounds was assessed.


### 2.2.1. Preparation of Media and Sample Solution

Escherichia coli, Staphylococcus aureus, and Salmonella typhi bacteria were transferred from the culture and streaked for 24 hours at 37°C on Mueller-Hinton agar (MHA) plates. The bacteria were then transferred to autoclaved MHA that had been cooled to 45 degrees Celsius in a water bath and mixed vigorously by swirling the flasks. After that, the medium was poured into sterilized Petri dishes, solidified, and used. From stock cultures, mycelia plugs were transferred to PDA and incubated for 6 days. The fungi spores were then transferred to a 50 mL autoclaved PDA that had been cooled in a water bath to about 45°C. Finally, the spore suspension-containing media was poured into sterilized plates, solidified, and used for biotesting. The ligand and complex solutions were prepared by dissolving their 10 mg samples in 1 ml DMSO, and 10 μl and 20 μl aliquots were used for biotest.


### 2.2.2. Antimicrobial Sensitivity Testing Procedure

The antibacterial sensitivity includes the following procedure: The Whatman no.1 filter paper was punctured with office puncture to obtain 6 mm diameter paper discs. The discs were sterilized in an oven at 180°C for 1 hour. Then, in two replications, 10μl and 20 μl of compound solution were pipetted to the discs. The sample-impregnated paper discs were transferred with sterile forceps to a nutrient agar plate seeded with bacteria and incubated at 37°C for 24 hours. In antifungal sensitivity examination, similar procedures were followed excluding that paper discs impregnated with samples were transferred with sterile forceps to PDA seeded with spore suspensions of Aspergillus niger and Rhizoctonia bataticola at room temperature for 3 days [11].


## 2.2.1. Preparation of Media and Sample Solution

Escherichia coli, Staphylococcus aureus, and Salmonella typhi bacteria were transferred from the culture and streaked for 24 hours at 37°C on Mueller-Hinton agar (MHA) plates. The bacteria were then transferred to autoclaved MHA that had been cooled to 45 degrees Celsius in a water bath and mixed vigorously by swirling the flasks. After that, the medium was poured into sterilized Petri dishes, solidified, and used. From stock cultures, mycelia plugs were transferred to PDA and incubated for 6 days. The fungi spores were then transferred to a 50 mL autoclaved PDA that had been cooled in a water bath to about 45°C. Finally, the spore suspension-containing media was poured into sterilized plates, solidified, and used for biotesting. The ligand and complex solutions were prepared by dissolving their 10 mg samples in 1 ml DMSO, and 10 μl and 20 μl aliquots were used for biotest.


## 2.2.2. Antimicrobial Sensitivity Testing Procedure

The antibacterial sensitivity includes the following procedure: The Whatman no.1 filter paper was punctured with office puncture to obtain 6 mm diameter paper discs. The discs were sterilized in an oven at 180°C for 1 hour. Then, in two replications, 10μl and 20 μl of compound solution were pipetted to the discs. The sample-impregnated paper discs were transferred with sterile forceps to a nutrient agar plate seeded with bacteria and incubated at 37°C for 24 hours. In antifungal sensitivity examination, similar procedures were followed excluding that paper discs impregnated with samples were transferred with sterile forceps to PDA seeded with spore suspensions of Aspergillus niger and Rhizoctonia bataticola at room temperature for 3 days [11].


## 2.3. Computation Profile

In general, the theoretical and computational investigations on molecular systems could help one to gain quantum chemical insight on the molecular electronic structure properties. The present work has been focused on computing, calculating, and inferring various electronic structure properties such as geometry, symmetry, energy, conformation, natural bonding (NBO), frontier molecular orbitals (FMO’s), molecular electrostatics (MEP), charge, and additional associated molecular quantum chemical properties. The pure organic ligand L1 and its metal complex such as ZnL1 and CdL1 were examined using density functional theory (DFT). The conformational generation was performed using semiempirical level theory, namely, Austin Model 1 (AM1). For other electronic structure properties, L1 was treated with B3LYP/6-31+G(d) basis set. The metal complex was treated based on effective core potential (ECP) technique. In ZnL1 and CdL1 metal complex system, a dual basis set practice was incorporated simultaneously on both ligand and metal in a fashion like B3LYP/lanl2dz basis on Zn and Cd metal atoms, whereas for atoms of ligand B3LYP/6-31G(d) was applied.All the computations were performed using Gaussian 09W [12] theoretical code. The NBO enquiries were made by NBO 7.0 code [13].


## 3. Result and Discussion

### 3.1. Inferences from Antimicrobial Studies

Compounds L1, ZnL1, and CdL1 were screened for their antibacterial and antifungal activities in vitro following the procedure described elsewhere [10, 14] against Escherichia coli (Gram-negative), Staphylococcus aureus (Gram-positive), and Salmonella typhi (Gram-negative) bacteria and Fusarium oxysporum and Aspergillus niger fungi (1 : 1 v/v) using chloramphenicol (standard antibiotic drug) and Bavistin (standard antifungal drug) as references, respectively, and inhibition zone diameters of the respective compounds were measured as indicated in Table 1.Table 1
Bacterial and fungal growth inhibition zone (mm).
CompoundsInhibition zone (mm)Escherichia coliStaphylococcus aureusSalmonella typhiFusarium oxysporumAspergillus niger10μL20μL10μL20μL10μL20μL10μL20μL10μL20μLL110121314151711141314ZnL111141617191014161416CdL110131719212211121011Chloramphenicol242723242325————Bavistin——————25252728DMSO——————————Note: the values of inhibition zones are average of triplications.The antibacterial and antifungal activities of the synthesized complexes were lower than those of the reference drugs. Compounds L1, ZnL1, and CdL1 are active against all microbes tested. As a result, higher sensitivity has been observed in complexes than in free ligands, owing to chelation theory [1, 10]. The synthesized complexes inhibited all of the pathogens. The polarities of the metal ions are reduced during coordination due to ligand orbital overlap and partial sharing of the positive charge of the metal ions with the ligand donor atoms. This may increase the lipophilic nature of the metal complexes, allowing them to permeate the lipid membrane and thus be active in some bacteria and fungi while causing minor inhibition in the ligand. While chelation is not the only criterion for antimicrobial sensitivity, it may be a complex combination of several factors, including the nature of the metal ion and the ligand, the geometry of the metal complex, lipophilicity, and steric and pharmacokinetic factors. However, one must be cautious to examine the degree of toxicity of these metal complexes against biological array to proceed further since metal complexes have heavy metals.


### 3.2. Dry Lab Investigations

#### 3.2.1. Conformational Analysis

The conformational analysis helps the system to identify the ground state conformer. The presence of rotatable single bond, bond angle, and dihedral bond could result in producing various conformers with different structural orientation with corresponding energy. In the present L1 system, a rigorous 3D conformational search has been executed under AM1 semiempirical level theory [15, 16]. In a 3D scan, one dimension represents energy coordinate and the other two orientations represent two dihedral scan coordinates. The pictorial projection is given in Figure 2. Scan coordinate-1 (SC-1) was taken from C13-N18-C4-C3 and the SC-2 was taken from H12-O11-C5-C6 dihedral coordinate due to the presence of single bond connectivity which obviously could produce large number of conformers from set of rotational instructions. The connecting junction of five and six membered rings, namely, N18-C4, and another bonding coordinate O11-C5 would be static on the scan coordinate. However, other moieties connected with either side of the terminal of these said bonds in the dihedral will rotate 360 degrees by 10 degrees of increment up to 36 steps. This rotational instruction would produce 1369 conformers with various energy levels as shown in Figure 2. The change in the energy level is shown in the color graph ranging from red (high energy) to purple (low energy). The high energy conformer has been identified in one location when SC-1 = 28.9553/SC-2 = 22.0012 in 3D scan map as mentioned at the apex position in the 3D color graph. The energy of this conformer was found to be 0.015627 hartree. Stereochemically as expected, it shows planner structure and the figure has been shown here. The steric and noncovalent van der Waals interaction could be responsible for this energy hike when five and six membered rings are in planar geometry. The ground state minimum energy conformers were marked and shown in the figure. Large numbers of stable conformers were observed in this scan coordinate out of 1369 conformers in which all of them exhibit the same structural orientation. As expected, the five and six membered rings were perpendicular to each other and eventually had less steric and noncovalent van der Waals interaction which results in minimization of energy. The energy of stable conformer was found to be −0.014669 hartree and its projection is shown in the figure. The SC-1 and SC-2 orientations of ground state conformer appeared at −71.0446 and −177.9987 degrees, respectively. The relative energy was found to be 0.030296 hartree.Figure 2
3D scan coordinates on SC1 and SC2 with respect to energy using AM1 level.


#### 3.2.2. Optimized Geometry

The ground state electronic structure properties of the title molecules were extracted from optimized ground state molecular geometry. Optimized geometrical parameters include spatial vectors such as bond length, bond angle, and dihedral angle of a given system. The geometrical parameters of L1 are given in Table2. The parameters of ZnL1 and CdL1 are given in Supplementary Material S1. The projections of their geometry are shown in Figures 3–5, respectively. The six membered benzenoid aromatic system with conjugation and the five membered heterocyclic system which has nonaromatic character are reflected in their bond order and bond length. Any aromatic system could have C-C bond length ranging from 1.390 to 1.410 Å. In benzene, it is found to be 1.39 Å exactly. In L1, the fused benzene moiety has 1.399 to 1.401 Å of aromatic C-C length. The trend between bond length and bond order could be reciprocally related. The same has been observed here. The aromatic C-C bond includes both end-end and side-side overlap of valence “p” orbital of carbon which resulted in formation of “σ” and “π” of bonds, respectively. These two types of overlap eventually reduce the bond length and increase the bond order with increased bond dissociation energy in comparison to nonaromatic C-C bond which has pure “σ” bond character. This trend has been observed in five membered heterocyclic moiety of L1 which has C13-C15 “σ” bond nature with 1.524 Å bond length and 0.995 and 1.023 fuzzy and Laplacian bond orders, respectively [17].Table 2
Optimized geometrical parameters and bond order of L1.
Bond length (Ǻ)FuzzyLaplacianBond angle (°)Dihedral angle (°)C1-C21.3991.4441.538C1-C6-C5120.81C5-C4-N18-C14−56.72C1-C61.3921.4811.566C5-O11-H12107.28C4-C5-C6-C1−0.85C2-C31.3921.4721.557C15-C13-N18112.16O11-C5-C6-C1−179.69C3-C41.4001.3661.505C15-C13-O20122.65N18-C13-C15-S190.15C4-C51.4091.3031.494N18-C13-O20125.19O20-C13-C15-S19179.60C4-N181.4461.0630.688N18-C14-S19111.59C15-C13-N18-C4175.17C5-C61.4011.3521.549N18-C14-N21121.83C15-C13-N18-C14−2.87C5-O111.3621.3500.535S19-C14-N21126.56O20-C13-N18-C4−4.27O11-H120.9870.7120.432C13-C15-S19107.62O20-C13-N18-C14177.69C13-C151.5240.9951.023C4-N18-C13120.42S19-C14-N18-C4−173.67C13-N181.4011.1940.924C4-N18-C14123.21S19-C14-N18-C134.31C13-O201.2122.0031.216C13-N18-C14116.34N21-C14-N18-C47.94C14-N181.3981.1710.940C14-S19-C1592.14N21-C14-N18-C13−174.08C14-S191.7871.1760.825C14-N21-H22112.83N18-C14-S19-C15−3.44C14-N211.2781.8281.646Dihedral angle (°)N21-C14-S19-C15174.85C15-S191.8261.1760.633C6-C1-C2-C31.36N18-C14-N21-H22−179.83N21-H221.0190.8520.698C2-C1-C6-C5−1.00S19-C14-N21-H222.03Bond angle (°)C1-C2-C3-C40.14C13-C15-S19-C141.82C2-C1-C6120.20C2-C3-C4-C5−2.01C1-C2-C3119.51C2-C3-C4-N18175.10C2-C3-C4120.57C3-C4-C5-C62.34C3-C4-C5120.05C3-C4-C5-O11−178.88C3-C4-N18118.16N18-C4-C5-C6−174.65C5-C4-N18121.73N18-C4-C5-O114.13C4-C5-C6118.82C3-C4-N18-C13−51.67C4-C5-O11122.94C3-C4-N18-C14126.23C6-C5-O11118.24C5-C4-N18-C13125.38Figure 3
Optimized structure, FMOs, surfaces, and ELF plots of L1.Figure 4
Optimized structure, FMOs, surfaces, and ELF plots of ZnL1.Figure 5
Optimized structure, FMOs, surfaces, and ELF plots of CdL1.The ECP technique has been implemented to optimize the metal complex. This metal complex numerical optimization was tedious; henceforth we usedTd constrained, symmetry-off, very tight Berny algorithm to get the ground state stationary point. The ground state was verified by existence of positive frequencies at potential energy surface. In accordance with the experimental evidences, all the four ligands were coordinated with the metal (Zn, Cd) under Td symmetry. In ZnL1 system, the central Zn atom has tetrahedral arrangement and all the four lobes are connected with four different oxygen atoms of four hydroxyl groups of phenyl moiety, respectively. The bond length of Zn1-O2 and Zn1-O23 was found to be 1.991 Ǻ, whereas that of Zn1-O44 and Zn1-O65 was observed as 1.989 Ǻ. The fuzzy bond order was found to be 1.013 and 1.026 (fuzzy) and Laplacian values were observed as 0.217 and 0.219, respectively. These theoretical values help us to understand the strength of the metal-ligand bonds and their nature. Similarly, in CdL1, the Cd has Td arrangement surrounded by four ligands. The bond length among Cd1-O2, Cd1-O23, Cd1-O44, and Cd1-O65 was found to be 2.191, 2.188, 2.191, and 2.192 Ǻ, respectively. The calculated fuzzy bond order was observed as 1.036, 1.034, 1.093, and 1.103 respectively. The Laplacian scale bond order was found to be 0.207, 0.209, 0.209, and 0.221 respectively. Hence, these results conclude that the strength of both Zn-O and Cd-O could be equally comparable except bond length.


#### 3.2.3. Fragmented FMO Analysis

Frontier molecular orbital analysis is a traditional technique to understand how electrons could be interacting between bonding and antibonding molecular orbitals. Chemical and electronic properties such as hardness, softness, reactivity, and charge transport depend on the FMO gap. The FMO gap values among HOMO-1, HOMO, LUMO, and LUMO+1 are tabulated in Table3 and the surface projections are given in Figures 3–5. The atomic contributions to FMOs are listed Table 4. ∆EL-H of L1 was found to be 5.06 eV. In ZnL1 and CdL1, these values were 0.5023 eV and 0.4624 eV, respectively. A more significant dropping has been observed in metal complex compared to pure L1. The atomic contribution on FMO formation for L1 largely comes from atom “C” with 80% on HOMO and 52% on LUMO. Atom “O and N” contributes second and third, respectively. In the case of ZnL1 and CdL1, the HOMO and LUMO were highly contributed by “C” as in L1. But more contributions were observed by “O” in ZnL1 and CdL1 compared to pure L1. Central metals “Zn and Cd” have 0% and 1% contribution in HOMO and LUMO formation. The “H” atom has no contribution in all the three systems. The position of lobes in L1 at HOMO was localized around six membered ring and LUMO was around five membered ring. Since the lobes of the orbitals are perpendicular to plane of the molecular symmetry, they must be π ⟶ π∗ transition [18–20]. The same type of transition is observed in ZnL1 and CdL1 transitions.Table 3
Other electronic structure properties of L1, ZnL1, and CdL1.
PropertiesL1ZnL1CdL1Energy−1005.944951 hartree−4086.75259 hartree−4069.258684 hartreeDipole moment3.2612 Debye3.7202 Debye2.8688 DebyePolarizability144.2924 au508.9803 au584.1757 auHyperpolarizability341.6341 au5058.6180 au3966.6924 auLUMO+1−1.0270 eV−0.8602 eV−0.8302 eVLUMO−1.3755 eV−4.8039 eV−4.8239 eVHOMO−6.4355 eV−5.3063 eV−5.2863 eVHOMO-1−7.0029 eV−5.5721 eV−5.5221 eV∆EL-H5.0599 eV0.5023 eV0.4624 eVIonization potential (IP)6.4355 eV5.3063 eV5.2863 eVElectron affinity (A)1.3755 eV4.8039 eV4.8201 eVGlobal hardness (η)2.53000.25120.2331Global softness (ν)0.19763.98084.2900Electronegativity (χ)3.90555.05514.7881Chemical potential (µ)−3.9055−5.0551−4.7881Global electrophilicity (ω)3.014450.863949.1761Table 4
Percentage fragmentation contributions in FMO.
FMO of L1 systemsAtoms/FMOCNOSHL+12450715L52201855H8011900H-18510410FMO of ZnL1 systemsAtoms/FMOCNOSHZnL+19014211L75124000H75124000H-175122001FMO of CdL1 systemsAtoms/FMOCNOSHCdL+18138430L72126001H73124001H-174224001


#### 3.2.4. MEP and Atomic Charge Analysis

The MEP and atomic charge analysis has been carried out for L1, ZnL1, and CdL1. The MEP surface of L1 is shown in Figure3 and the computed atomic charges are listed in Table 5. The MEP of ZnL1 and CdL1 is shown in Figures 4 and 5, respectively. The calculated charges are listed in Supplementary Material 2. Various atomic charge schemes such as Mulliken, atomic tensor polar (ATP), Hirshfeld, and natural population analysis (NPA) were computed for all the three systems. The mathematical formulation of MEP and various atomic changes is as follows:(1)Vr=ZARA−r−∫ρr′r′−rd3r′.Table 5
Various theoretical atomic charges on L1.
AtomMullikenAPTHirshfeldNPAC1−0.15750.0588−0.0349−0.2161C2−0.3308−0.1279−0.0509−0.2676C30.22990.0248−0.0414−0.2060C40.16520.17660.02180.0700C5−0.39250.46590.07240.3322C6−0.0108−0.1133−0.0514−0.2754H70.18230.02850.04820.2474H80.18220.02760.04610.2471H90.19150.04630.04720.2496H100.19830.04690.05160.2583O11−0.6771−0.7401−0.2281−0.6878H120.51660.39660.11950.5068C130.51921.02800.19430.6962C14−0.12321.04030.13720.2708C15−0.83490.0239−0.0266−0.6971H160.28260.03010.06370.2940H170.27870.02390.06210.2949N180.0675−0.8775−0.0422−0.5345S190.4487−0.2268−0.0074−0.2792O20−0.4159−0.7463−0.2682−0.5524N21−0.6904−0.7737−0.2289−0.6999H220.37050.18740.11600.3902The notations in the equation can be given as follows:ZA represents the charge of the nucleus “A” located at RA, ρ(r′) specifies the electronic density of the system, and r′ represents the trivial integral variable. Generally, the MEP color surface ranging from red to blue indicates the more electron populated region (electrophilic site) to lesser electron population region (nucleophilic site). In L1, the electropositive region was observed at five membered ring and electronegative region was observed in six membered ring. Around O11 and O20, the surface is rich in red and at N18, N21, and S19 it became blue. This trend is reflected in point change analysis as well and discussed hereunder. Similarly, in ZnL1 and Cd L1, the position around oxygen atoms exhibits red surface and nitrogen and sulfur region shows blue. This imprint could help one to understand the nature reactive in these systems when introduced to a Lewis acid and base. The total electron density map (TED) could project the size occupied as a whole system in space; eventually molecular electron density volume related attributes could be derived.Furthermore, the theoretical foundation of Mulliken point charge could be given as(2)qA=ZA−∑ini,A=ZA−∑iηi∑a∈AΘi,a,where η denotes orbital occupation number and ni,A states the contribution from orbital “i.” It is highly basis set dependent.The ATP model could be provided as follows:(3)qi=13∂μx∂xi+∂μy∂yi+∂μz∂zi,where “µ” is the dipole moment of the given system and xi, yi, and zi denote vectors of “ith” atom.Hirshfeld would be represented by(4)qA=−∫wAHirshrρdefrdr.For NPA, it can be given as follows:(5)qAN=∑iqiN,where qAN denotes natural electron population on overlap free natural atomic orbital [21–24].Though the Mulliken population analysis is a traditional method to calculate point charges, it is highly basis set dependent. Since the L1 was an organic system which was treated with B3LYP/6-31+G(d), a promising level basis set, the results were comparable with other methods except in atoms such as C3, C5, C14, and S19 where a negative reciprocal charge magnitude has been observed. However, the rest of the atoms are in good agreement with other point charge theories. In accordance with electronegativity, the excess electron population is expected in heteroatoms such as O11, N18, S19, O20, and N21. The same was observed in all the atomic charge theories with significant increased electron population as mentioned in Table5.In ZnL1 and CdL1 complexes, the L1 is arranged in aTd arrangement with 1 : 4 metal cum ligand stoichiometry. The Zn and Cd metal atoms nearly have more than a unity positive charge except Hirshfeld method. In ZnL1, more electron population has been observed in all heteroatoms of four ligands. But, in CdL1, less electron population trend has been observed in heteroatoms in all the theories except in few atoms in comparison with ZnL1. Electron localization function (ELF) is a method to calibrate electron at the neighboring space with reference to electron localized at a given point with the same spin. The ELF values in pi delocalized region fall around less than 0.65 and in sigma bond region they were noticed to be greater than 0.70 to 0.99.


#### 3.2.5. NBO Analysis

The natural bond orbital analysis method is an efficient technique to gain detailed chemical insight on chemical bonding, point charges, and second-order perturbed stabilization interactions. The stabilization interaction chemistry between Lewis donor orbitals and non-Lewis acceptor orbitals could help one to understand how a molecule could attain stabilized electronic stationary point structurally. The present study provides detailed NBO information on both ligand L1 and its metal complexes, namely, ZnL1 and CdL1, respectively. The figure incorporated first five strong stabilization interactions of L1, ZnL1, and CdL1, shown in Tables6–8, respectively.Table 6
NBO profile of L1.
S. no.DonorAcceptorStabilization01LP (2) O11/ED (i): 1.86916eπ∗C4- C5/ED (j): 0.40876eE(2) kJ mol−1 : 35.62OE (εiL): -0.32938 a.uOE (εjNL): 0.01441 a.uE(j)-E(i): 0.34 a.u%ED P: -/NLMOD: 1.18D%ED P: 43.15C4-56.85C5F(i,j): 0.099 a.u02LP (1) N 18/ED (i): 1.68286eπ∗C13-O 20/ED (j): 0.20748eE(2) kJ mol−1 : 34.32OE (εiL): -0.31154 a.uOE (εjNL): 0.01337 a.uE(j)-E(i): 0.32 a.u%ED P: -/NLMOD: 1.63D%ED P: 68.17C13-31.83O20F(i,j): 0.094 a.u03LP (2) O 20/ED (i): 1.84296eσ∗C13- N 18/ED (j): 0.10575eE(2) kJ mol−1 : 31.99OE (εiL): −0.28193 a.uOE (εjNL): 0.32151 a.uE(j)-E(i): 0.60 a.u%ED P: -/NLMOD: 1.31D%ED P: 63.64C13-36.36N18F(i,j): 0.124 a.u04LP (1) N 18/ED (i): 1.68286eπ∗C14- N 21/ED (j): 0.24930eE(2) kJ mol−1: 31.35OE (εiL): −0.31154 a.uOE (εjNL): −0.01791 a.uE(j)-E(i): 0.29 a.u%ED P: -/NLMOD: 1.63D%ED P: 60.08C14-39.92N21F(i,j): 0.086 a.u054LP (2) S 19/ED (i): 1.84334eπ∗C14- N 21/ED (j): 0.24930eE(2) kJ mol−1 : 26.18OE (εiL): −0.27665 a.uOE (εjNL): −0.01791 a.uE(j)-E(i): 0.26 a.u%ED P: -/NLMOD: 1.33D%ED P: 60.08C14-39.92N21F(i,j): 0.073 a.uTable 7
NBO profile of ZnL1.
S. no.DonorAcceptorStabilization01LP (1) C5/ED (i): 0.9890eπ∗O2-C3/ED (j): 0.5776eE(2) kJ mol−1 : 201.42OE (εiL): −0.1148 a.uOE (εjNL): −0.0255 a.uE(j)-E(i): 0.09 a.u%ED P: -/NLMOD: 0.00D%ED P: 21.94O2-78.06C3F(i,j): 0.120 a.u02LP(1) C47/ED (i): 0.9916eπ∗O44-C45/ED (j): 0.5326eE(2) kJ mol−1 : 179.82OE (εiL): −0.1142 a.uOE (εjNL): −0.0184 a.uE(j)-E(i): 0.10 a.u%ED P: -/NLMOD: 0.00D%ED P: 23.27O44-76.73C45F(i,j): 0.117 a.u03LP (1) C5/ED (i): 0.9890eπ∗C8-C9/ED (j): 0.26324eE(2) kJ mol−1 : 101.35OE (εiL): −0.1148 a.uOE (εjNL): 0.0243 a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 0.00D%ED P: 50.87C8-49.13C9F(i,j): 0.106 a.u04LP(1) C47/ED (i): 0.9916eπ∗C50-C51/ED (j): 0.2728eE(2) kJ mol−1:101.10OE (εiL): −0.1142 a.uOE (εjNL): 0.0245a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 0.00D%ED P: 49.84C50-50.16C51F(i,j): 0.106 a.u05LP(1)C37/ED (i): 0.9858eπ∗C32-C34/ED (j): 0.3123eE(2) kJ mol−1 : 96.16OE (εiL): −0.1090a.uOE (εjNL): 0.0378 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 19.44D%ED P: 46.79C32-53.21C34F(i,j): 0.106 a.uTable 8
NBO profile of CdL1.
S. NoDonorAcceptorStabilization01LP(1)C9/ED (i): 0.9988eπ∗ C4-C6/ED (j): 0.3416eE(2) kJ mol−1 : 104.04OE (εiL): −0.1181 a.uOE (εjNL): 0.0166 a.uE(j)-E(i): 0.13 a.u%ED P: -/NLMOD: 0.00D%ED P: 46.29C4- 53.71C6F(i,j): 0.106 a.u02LP(1)C37/ED (i): 0.9780eπ∗C32-C34/ED (j): 0.3103eE(2) kJ mol−1 : 96.58OE (εiL): −0.1138 a.uOE (εjNL): 0.0332 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 28.94D%ED P: 47.06C32- 52.94C34F(i,j): 0.106 a.u03LP(1)C51/ED (i): 0.9811eπ∗C46-C48/ED (j): 0.3047eE(2) kJ mol−1 : 95.58OE (εiL): −0.1159 a.uOE (εjNL): 0.0278 a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 26.71D%ED P: 46.24C46-53.76C48F(i,j): 0.105 a.u04LP(1)C51/ED (i): 0.9811eπ∗C47-C50/ED (j): 0.2860eE(2) kJ mol−1 : 91.93OE (εiL): −0.1159 a.uOE (εjNL): 0.0315 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 26.71D%ED P: 49.03C47-50.97C50F(i,j): 0.104 a.u05LP(1)C9/ED (i): 0.9988eπ∗C5-C8/ED (j): 0.2866eE(2) kJ mol−1 : 91.76OE (εiL): −0.1181 a.uOE (εjNL): 0.0312 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 0.00D%ED P: 49.31C5-50.69C8F(i,j): 0.105 a.uThe mathematical background of NBO interaction could be given as follows:(6)ΔEij2=−qiFij2εjNL−εiL,where ΔEij2 denotes stabilization energy of the corresponding contacts, qi specifies the population of the Lewis orbital, and Fij denotes Fock matrix which comes from the result of Lewis and non-Lewis mixing in delocalization. εiL,εjNL describe the orbital energy of donor and acceptor fragments. The stabilization energy is directly accompanied with the energy gap of Lewis and non-Lewis moieties projection [25–27].In L1 system, highest five stabilizations were observed due to lone pair (LP) ⟶π∗ interactions. The LP was contributed from O11, N18, O20, and S19 atomic Lewis moieties. The first interaction was stabilized by 35.62 kJ/mole, where the donor has 1.86916e population 0.34 au energy difference. Since the donation comes from LP, the %ED partition is zero; but, in acceptor, C5 has more electron density distribution than C4. The natural localized molecular orbital dipole (NLMOD) was found to be 1.18 Debye on the Lewis. The second stabilization energy was observed by 34.32 kJ/mole and the difference with the first one was found to be 1.3 kJ/mole. Large stabilization energy differences were observed between second and third interactions (2.33 kJ/mole) and between fourth and fifth interactions (5.17 kJ/mole), respectively.Similarly, in ZnL1, the following Lewis donor was observed such as C5, C47, and C37 atoms. The apex stabilization was attained by LP(C5) ⟶π∗(O2-C3) interaction. The electron density partition in non-Lewis acceptor was found to be 78.06% in C3 and 21.94% in O2. The stabilization energy difference between first and second interactions was found to be 21.6 kJ/mole. Likewise, the stabilization difference between the second and third interactions was found to be 78.47 kJ/mole. However, differences between third and fourth interactions and between fourth and fifth interactions were significantly less. The first and third Lewis donors are identical to each other, yet their corresponding non-Lewis acceptors are different. The same is true in the case of second and fourth Lewis donors.In the case of CdL1, the donor Lewis moieties were found to be C9, C37, and C51 with more than 0.9e population. The highest stabilization interaction was found to be 104.04 kJ/mole, which is very less in comparison with ZnL1. The second stabilization energy was found to be 96.58 due to LP(1)C37 ⟶π∗(C32-C34). Around 7.46 kJ/mole stabilization energy difference was observed in first and second donor acceptor interaction. However, there was no significant difference observed between second and third interactions and between fourth and fifth interactions. The first and fifth Lewis donor moieties and third and fourth donor moieties have similar second-order perturbation properties. But all the non-Lewis acceptor moieties have exclusively different constitution. Even though L1 and its nature of coordination with Zn and Cd were same, their stabilization trends were drastically different; and this was clarified in this rigorous NBO analysis [28, 29].


#### 3.2.6. Other Electronic Structure Properties

Other quantum chemical attributes such as ground state energy, dipole moment, polarizability, hyperpolarizability,EHOMO-1, EHOMO, ELUMO, ELUMO+1, and ∆EL-H, that is, energy gap between HOMO and LUMO, electronically calculated chemical potential (µ), chemical hardness (ɳ), electron affinity (EA), ionization potential (IP), and global electrophilicity index (ω) are tabulated in Table 3 [30, 31]. These calculated quantum chemical descriptors could assist one to gain intuition on fundamental electronic structure properties of L1, ZnL1, and CdL1 systems. The theoretical basis for µ and ɳ was initiated from hard soft acid base (HSAB) principle and based on first and second partial derivatives of stationary state molecular energy “E” against the number of electrons at constant marginal potential ν.(7)μ=∂E∂Nνr,η=12∂2E∂N2νr.The ground state parabola model [b] of these equations can be given by (8)μ=−I+A2,η=I−A2,where I and A denote vertical ionization potential (IP) and electron affinity (EA), respectively. The global electrophilicity index (ω) [c] can be given by (9)ω=χ22η=EHOMO2+2EHOMOELUMO+EHOMO24ELUMO−EHOMO,where χ denotes Mulliken electronegativity and is correlated as µ = −χ.The ground state energy revels the ZnL1 and CdL1 their stability and complexation energies, respectively. In ZnL1 system, the complexation energy was found to be 4.51 a.u, and, in CdL1, the complexation energy was 4.49 a.u. Hence, the coordination of L1 with Zn has been more largely stabilized than the Cd metal. On considering FMOs, the pure L1 has large ∆EL-H (5.06 eV) in comparison with ZnL1 (0.5023 eV) and CdL1 (0.4624 eV) which eventually results in absorption of visible light to give complimentary color. The dipole moment of L1 and ZnL1 has relatively same magnitude, whereas CdL1 has less dipole moment than the other two. The polarizability values are increasing pure L1 to ZnL1 and CdL1 complexes. The ZnL1 has more NLO property compared to CdL1 due to increased hyperpolarizability. The FMO related properties such as IP, A, η, ν, χ, µ, and ω have relative trend as shown in Table 3. Both metal complexes have lower hardness and higher softness, yet the reciprocal has been observed in L1. The negative magnitude of electronegativity could be chemical potential as mentioned above. The high “ω” value for metal complexes indicates a high molecular toxicity compared to pure organic system L1 [32–34].


## 3.1. Inferences from Antimicrobial Studies

Compounds L1, ZnL1, and CdL1 were screened for their antibacterial and antifungal activities in vitro following the procedure described elsewhere [10, 14] against Escherichia coli (Gram-negative), Staphylococcus aureus (Gram-positive), and Salmonella typhi (Gram-negative) bacteria and Fusarium oxysporum and Aspergillus niger fungi (1 : 1 v/v) using chloramphenicol (standard antibiotic drug) and Bavistin (standard antifungal drug) as references, respectively, and inhibition zone diameters of the respective compounds were measured as indicated in Table 1.Table 1
Bacterial and fungal growth inhibition zone (mm).
CompoundsInhibition zone (mm)Escherichia coliStaphylococcus aureusSalmonella typhiFusarium oxysporumAspergillus niger10μL20μL10μL20μL10μL20μL10μL20μL10μL20μLL110121314151711141314ZnL111141617191014161416CdL110131719212211121011Chloramphenicol242723242325————Bavistin——————25252728DMSO——————————Note: the values of inhibition zones are average of triplications.The antibacterial and antifungal activities of the synthesized complexes were lower than those of the reference drugs. Compounds L1, ZnL1, and CdL1 are active against all microbes tested. As a result, higher sensitivity has been observed in complexes than in free ligands, owing to chelation theory [1, 10]. The synthesized complexes inhibited all of the pathogens. The polarities of the metal ions are reduced during coordination due to ligand orbital overlap and partial sharing of the positive charge of the metal ions with the ligand donor atoms. This may increase the lipophilic nature of the metal complexes, allowing them to permeate the lipid membrane and thus be active in some bacteria and fungi while causing minor inhibition in the ligand. While chelation is not the only criterion for antimicrobial sensitivity, it may be a complex combination of several factors, including the nature of the metal ion and the ligand, the geometry of the metal complex, lipophilicity, and steric and pharmacokinetic factors. However, one must be cautious to examine the degree of toxicity of these metal complexes against biological array to proceed further since metal complexes have heavy metals.


## 3.2. Dry Lab Investigations

### 3.2.1. Conformational Analysis

The conformational analysis helps the system to identify the ground state conformer. The presence of rotatable single bond, bond angle, and dihedral bond could result in producing various conformers with different structural orientation with corresponding energy. In the present L1 system, a rigorous 3D conformational search has been executed under AM1 semiempirical level theory [15, 16]. In a 3D scan, one dimension represents energy coordinate and the other two orientations represent two dihedral scan coordinates. The pictorial projection is given in Figure 2. Scan coordinate-1 (SC-1) was taken from C13-N18-C4-C3 and the SC-2 was taken from H12-O11-C5-C6 dihedral coordinate due to the presence of single bond connectivity which obviously could produce large number of conformers from set of rotational instructions. The connecting junction of five and six membered rings, namely, N18-C4, and another bonding coordinate O11-C5 would be static on the scan coordinate. However, other moieties connected with either side of the terminal of these said bonds in the dihedral will rotate 360 degrees by 10 degrees of increment up to 36 steps. This rotational instruction would produce 1369 conformers with various energy levels as shown in Figure 2. The change in the energy level is shown in the color graph ranging from red (high energy) to purple (low energy). The high energy conformer has been identified in one location when SC-1 = 28.9553/SC-2 = 22.0012 in 3D scan map as mentioned at the apex position in the 3D color graph. The energy of this conformer was found to be 0.015627 hartree. Stereochemically as expected, it shows planner structure and the figure has been shown here. The steric and noncovalent van der Waals interaction could be responsible for this energy hike when five and six membered rings are in planar geometry. The ground state minimum energy conformers were marked and shown in the figure. Large numbers of stable conformers were observed in this scan coordinate out of 1369 conformers in which all of them exhibit the same structural orientation. As expected, the five and six membered rings were perpendicular to each other and eventually had less steric and noncovalent van der Waals interaction which results in minimization of energy. The energy of stable conformer was found to be −0.014669 hartree and its projection is shown in the figure. The SC-1 and SC-2 orientations of ground state conformer appeared at −71.0446 and −177.9987 degrees, respectively. The relative energy was found to be 0.030296 hartree.Figure 2
3D scan coordinates on SC1 and SC2 with respect to energy using AM1 level.


### 3.2.2. Optimized Geometry

The ground state electronic structure properties of the title molecules were extracted from optimized ground state molecular geometry. Optimized geometrical parameters include spatial vectors such as bond length, bond angle, and dihedral angle of a given system. The geometrical parameters of L1 are given in Table2. The parameters of ZnL1 and CdL1 are given in Supplementary Material S1. The projections of their geometry are shown in Figures 3–5, respectively. The six membered benzenoid aromatic system with conjugation and the five membered heterocyclic system which has nonaromatic character are reflected in their bond order and bond length. Any aromatic system could have C-C bond length ranging from 1.390 to 1.410 Å. In benzene, it is found to be 1.39 Å exactly. In L1, the fused benzene moiety has 1.399 to 1.401 Å of aromatic C-C length. The trend between bond length and bond order could be reciprocally related. The same has been observed here. The aromatic C-C bond includes both end-end and side-side overlap of valence “p” orbital of carbon which resulted in formation of “σ” and “π” of bonds, respectively. These two types of overlap eventually reduce the bond length and increase the bond order with increased bond dissociation energy in comparison to nonaromatic C-C bond which has pure “σ” bond character. This trend has been observed in five membered heterocyclic moiety of L1 which has C13-C15 “σ” bond nature with 1.524 Å bond length and 0.995 and 1.023 fuzzy and Laplacian bond orders, respectively [17].Table 2
Optimized geometrical parameters and bond order of L1.
Bond length (Ǻ)FuzzyLaplacianBond angle (°)Dihedral angle (°)C1-C21.3991.4441.538C1-C6-C5120.81C5-C4-N18-C14−56.72C1-C61.3921.4811.566C5-O11-H12107.28C4-C5-C6-C1−0.85C2-C31.3921.4721.557C15-C13-N18112.16O11-C5-C6-C1−179.69C3-C41.4001.3661.505C15-C13-O20122.65N18-C13-C15-S190.15C4-C51.4091.3031.494N18-C13-O20125.19O20-C13-C15-S19179.60C4-N181.4461.0630.688N18-C14-S19111.59C15-C13-N18-C4175.17C5-C61.4011.3521.549N18-C14-N21121.83C15-C13-N18-C14−2.87C5-O111.3621.3500.535S19-C14-N21126.56O20-C13-N18-C4−4.27O11-H120.9870.7120.432C13-C15-S19107.62O20-C13-N18-C14177.69C13-C151.5240.9951.023C4-N18-C13120.42S19-C14-N18-C4−173.67C13-N181.4011.1940.924C4-N18-C14123.21S19-C14-N18-C134.31C13-O201.2122.0031.216C13-N18-C14116.34N21-C14-N18-C47.94C14-N181.3981.1710.940C14-S19-C1592.14N21-C14-N18-C13−174.08C14-S191.7871.1760.825C14-N21-H22112.83N18-C14-S19-C15−3.44C14-N211.2781.8281.646Dihedral angle (°)N21-C14-S19-C15174.85C15-S191.8261.1760.633C6-C1-C2-C31.36N18-C14-N21-H22−179.83N21-H221.0190.8520.698C2-C1-C6-C5−1.00S19-C14-N21-H222.03Bond angle (°)C1-C2-C3-C40.14C13-C15-S19-C141.82C2-C1-C6120.20C2-C3-C4-C5−2.01C1-C2-C3119.51C2-C3-C4-N18175.10C2-C3-C4120.57C3-C4-C5-C62.34C3-C4-C5120.05C3-C4-C5-O11−178.88C3-C4-N18118.16N18-C4-C5-C6−174.65C5-C4-N18121.73N18-C4-C5-O114.13C4-C5-C6118.82C3-C4-N18-C13−51.67C4-C5-O11122.94C3-C4-N18-C14126.23C6-C5-O11118.24C5-C4-N18-C13125.38Figure 3
Optimized structure, FMOs, surfaces, and ELF plots of L1.Figure 4
Optimized structure, FMOs, surfaces, and ELF plots of ZnL1.Figure 5
Optimized structure, FMOs, surfaces, and ELF plots of CdL1.The ECP technique has been implemented to optimize the metal complex. This metal complex numerical optimization was tedious; henceforth we usedTd constrained, symmetry-off, very tight Berny algorithm to get the ground state stationary point. The ground state was verified by existence of positive frequencies at potential energy surface. In accordance with the experimental evidences, all the four ligands were coordinated with the metal (Zn, Cd) under Td symmetry. In ZnL1 system, the central Zn atom has tetrahedral arrangement and all the four lobes are connected with four different oxygen atoms of four hydroxyl groups of phenyl moiety, respectively. The bond length of Zn1-O2 and Zn1-O23 was found to be 1.991 Ǻ, whereas that of Zn1-O44 and Zn1-O65 was observed as 1.989 Ǻ. The fuzzy bond order was found to be 1.013 and 1.026 (fuzzy) and Laplacian values were observed as 0.217 and 0.219, respectively. These theoretical values help us to understand the strength of the metal-ligand bonds and their nature. Similarly, in CdL1, the Cd has Td arrangement surrounded by four ligands. The bond length among Cd1-O2, Cd1-O23, Cd1-O44, and Cd1-O65 was found to be 2.191, 2.188, 2.191, and 2.192 Ǻ, respectively. The calculated fuzzy bond order was observed as 1.036, 1.034, 1.093, and 1.103 respectively. The Laplacian scale bond order was found to be 0.207, 0.209, 0.209, and 0.221 respectively. Hence, these results conclude that the strength of both Zn-O and Cd-O could be equally comparable except bond length.


### 3.2.3. Fragmented FMO Analysis

Frontier molecular orbital analysis is a traditional technique to understand how electrons could be interacting between bonding and antibonding molecular orbitals. Chemical and electronic properties such as hardness, softness, reactivity, and charge transport depend on the FMO gap. The FMO gap values among HOMO-1, HOMO, LUMO, and LUMO+1 are tabulated in Table3 and the surface projections are given in Figures 3–5. The atomic contributions to FMOs are listed Table 4. ∆EL-H of L1 was found to be 5.06 eV. In ZnL1 and CdL1, these values were 0.5023 eV and 0.4624 eV, respectively. A more significant dropping has been observed in metal complex compared to pure L1. The atomic contribution on FMO formation for L1 largely comes from atom “C” with 80% on HOMO and 52% on LUMO. Atom “O and N” contributes second and third, respectively. In the case of ZnL1 and CdL1, the HOMO and LUMO were highly contributed by “C” as in L1. But more contributions were observed by “O” in ZnL1 and CdL1 compared to pure L1. Central metals “Zn and Cd” have 0% and 1% contribution in HOMO and LUMO formation. The “H” atom has no contribution in all the three systems. The position of lobes in L1 at HOMO was localized around six membered ring and LUMO was around five membered ring. Since the lobes of the orbitals are perpendicular to plane of the molecular symmetry, they must be π ⟶ π∗ transition [18–20]. The same type of transition is observed in ZnL1 and CdL1 transitions.Table 3
Other electronic structure properties of L1, ZnL1, and CdL1.
PropertiesL1ZnL1CdL1Energy−1005.944951 hartree−4086.75259 hartree−4069.258684 hartreeDipole moment3.2612 Debye3.7202 Debye2.8688 DebyePolarizability144.2924 au508.9803 au584.1757 auHyperpolarizability341.6341 au5058.6180 au3966.6924 auLUMO+1−1.0270 eV−0.8602 eV−0.8302 eVLUMO−1.3755 eV−4.8039 eV−4.8239 eVHOMO−6.4355 eV−5.3063 eV−5.2863 eVHOMO-1−7.0029 eV−5.5721 eV−5.5221 eV∆EL-H5.0599 eV0.5023 eV0.4624 eVIonization potential (IP)6.4355 eV5.3063 eV5.2863 eVElectron affinity (A)1.3755 eV4.8039 eV4.8201 eVGlobal hardness (η)2.53000.25120.2331Global softness (ν)0.19763.98084.2900Electronegativity (χ)3.90555.05514.7881Chemical potential (µ)−3.9055−5.0551−4.7881Global electrophilicity (ω)3.014450.863949.1761Table 4
Percentage fragmentation contributions in FMO.
FMO of L1 systemsAtoms/FMOCNOSHL+12450715L52201855H8011900H-18510410FMO of ZnL1 systemsAtoms/FMOCNOSHZnL+19014211L75124000H75124000H-175122001FMO of CdL1 systemsAtoms/FMOCNOSHCdL+18138430L72126001H73124001H-174224001


### 3.2.4. MEP and Atomic Charge Analysis

The MEP and atomic charge analysis has been carried out for L1, ZnL1, and CdL1. The MEP surface of L1 is shown in Figure3 and the computed atomic charges are listed in Table 5. The MEP of ZnL1 and CdL1 is shown in Figures 4 and 5, respectively. The calculated charges are listed in Supplementary Material 2. Various atomic charge schemes such as Mulliken, atomic tensor polar (ATP), Hirshfeld, and natural population analysis (NPA) were computed for all the three systems. The mathematical formulation of MEP and various atomic changes is as follows:(1)Vr=ZARA−r−∫ρr′r′−rd3r′.Table 5
Various theoretical atomic charges on L1.
AtomMullikenAPTHirshfeldNPAC1−0.15750.0588−0.0349−0.2161C2−0.3308−0.1279−0.0509−0.2676C30.22990.0248−0.0414−0.2060C40.16520.17660.02180.0700C5−0.39250.46590.07240.3322C6−0.0108−0.1133−0.0514−0.2754H70.18230.02850.04820.2474H80.18220.02760.04610.2471H90.19150.04630.04720.2496H100.19830.04690.05160.2583O11−0.6771−0.7401−0.2281−0.6878H120.51660.39660.11950.5068C130.51921.02800.19430.6962C14−0.12321.04030.13720.2708C15−0.83490.0239−0.0266−0.6971H160.28260.03010.06370.2940H170.27870.02390.06210.2949N180.0675−0.8775−0.0422−0.5345S190.4487−0.2268−0.0074−0.2792O20−0.4159−0.7463−0.2682−0.5524N21−0.6904−0.7737−0.2289−0.6999H220.37050.18740.11600.3902The notations in the equation can be given as follows:ZA represents the charge of the nucleus “A” located at RA, ρ(r′) specifies the electronic density of the system, and r′ represents the trivial integral variable. Generally, the MEP color surface ranging from red to blue indicates the more electron populated region (electrophilic site) to lesser electron population region (nucleophilic site). In L1, the electropositive region was observed at five membered ring and electronegative region was observed in six membered ring. Around O11 and O20, the surface is rich in red and at N18, N21, and S19 it became blue. This trend is reflected in point change analysis as well and discussed hereunder. Similarly, in ZnL1 and Cd L1, the position around oxygen atoms exhibits red surface and nitrogen and sulfur region shows blue. This imprint could help one to understand the nature reactive in these systems when introduced to a Lewis acid and base. The total electron density map (TED) could project the size occupied as a whole system in space; eventually molecular electron density volume related attributes could be derived.Furthermore, the theoretical foundation of Mulliken point charge could be given as(2)qA=ZA−∑ini,A=ZA−∑iηi∑a∈AΘi,a,where η denotes orbital occupation number and ni,A states the contribution from orbital “i.” It is highly basis set dependent.The ATP model could be provided as follows:(3)qi=13∂μx∂xi+∂μy∂yi+∂μz∂zi,where “µ” is the dipole moment of the given system and xi, yi, and zi denote vectors of “ith” atom.Hirshfeld would be represented by(4)qA=−∫wAHirshrρdefrdr.For NPA, it can be given as follows:(5)qAN=∑iqiN,where qAN denotes natural electron population on overlap free natural atomic orbital [21–24].Though the Mulliken population analysis is a traditional method to calculate point charges, it is highly basis set dependent. Since the L1 was an organic system which was treated with B3LYP/6-31+G(d), a promising level basis set, the results were comparable with other methods except in atoms such as C3, C5, C14, and S19 where a negative reciprocal charge magnitude has been observed. However, the rest of the atoms are in good agreement with other point charge theories. In accordance with electronegativity, the excess electron population is expected in heteroatoms such as O11, N18, S19, O20, and N21. The same was observed in all the atomic charge theories with significant increased electron population as mentioned in Table5.In ZnL1 and CdL1 complexes, the L1 is arranged in aTd arrangement with 1 : 4 metal cum ligand stoichiometry. The Zn and Cd metal atoms nearly have more than a unity positive charge except Hirshfeld method. In ZnL1, more electron population has been observed in all heteroatoms of four ligands. But, in CdL1, less electron population trend has been observed in heteroatoms in all the theories except in few atoms in comparison with ZnL1. Electron localization function (ELF) is a method to calibrate electron at the neighboring space with reference to electron localized at a given point with the same spin. The ELF values in pi delocalized region fall around less than 0.65 and in sigma bond region they were noticed to be greater than 0.70 to 0.99.


### 3.2.5. NBO Analysis

The natural bond orbital analysis method is an efficient technique to gain detailed chemical insight on chemical bonding, point charges, and second-order perturbed stabilization interactions. The stabilization interaction chemistry between Lewis donor orbitals and non-Lewis acceptor orbitals could help one to understand how a molecule could attain stabilized electronic stationary point structurally. The present study provides detailed NBO information on both ligand L1 and its metal complexes, namely, ZnL1 and CdL1, respectively. The figure incorporated first five strong stabilization interactions of L1, ZnL1, and CdL1, shown in Tables6–8, respectively.Table 6
NBO profile of L1.
S. no.DonorAcceptorStabilization01LP (2) O11/ED (i): 1.86916eπ∗C4- C5/ED (j): 0.40876eE(2) kJ mol−1 : 35.62OE (εiL): -0.32938 a.uOE (εjNL): 0.01441 a.uE(j)-E(i): 0.34 a.u%ED P: -/NLMOD: 1.18D%ED P: 43.15C4-56.85C5F(i,j): 0.099 a.u02LP (1) N 18/ED (i): 1.68286eπ∗C13-O 20/ED (j): 0.20748eE(2) kJ mol−1 : 34.32OE (εiL): -0.31154 a.uOE (εjNL): 0.01337 a.uE(j)-E(i): 0.32 a.u%ED P: -/NLMOD: 1.63D%ED P: 68.17C13-31.83O20F(i,j): 0.094 a.u03LP (2) O 20/ED (i): 1.84296eσ∗C13- N 18/ED (j): 0.10575eE(2) kJ mol−1 : 31.99OE (εiL): −0.28193 a.uOE (εjNL): 0.32151 a.uE(j)-E(i): 0.60 a.u%ED P: -/NLMOD: 1.31D%ED P: 63.64C13-36.36N18F(i,j): 0.124 a.u04LP (1) N 18/ED (i): 1.68286eπ∗C14- N 21/ED (j): 0.24930eE(2) kJ mol−1: 31.35OE (εiL): −0.31154 a.uOE (εjNL): −0.01791 a.uE(j)-E(i): 0.29 a.u%ED P: -/NLMOD: 1.63D%ED P: 60.08C14-39.92N21F(i,j): 0.086 a.u054LP (2) S 19/ED (i): 1.84334eπ∗C14- N 21/ED (j): 0.24930eE(2) kJ mol−1 : 26.18OE (εiL): −0.27665 a.uOE (εjNL): −0.01791 a.uE(j)-E(i): 0.26 a.u%ED P: -/NLMOD: 1.33D%ED P: 60.08C14-39.92N21F(i,j): 0.073 a.uTable 7
NBO profile of ZnL1.
S. no.DonorAcceptorStabilization01LP (1) C5/ED (i): 0.9890eπ∗O2-C3/ED (j): 0.5776eE(2) kJ mol−1 : 201.42OE (εiL): −0.1148 a.uOE (εjNL): −0.0255 a.uE(j)-E(i): 0.09 a.u%ED P: -/NLMOD: 0.00D%ED P: 21.94O2-78.06C3F(i,j): 0.120 a.u02LP(1) C47/ED (i): 0.9916eπ∗O44-C45/ED (j): 0.5326eE(2) kJ mol−1 : 179.82OE (εiL): −0.1142 a.uOE (εjNL): −0.0184 a.uE(j)-E(i): 0.10 a.u%ED P: -/NLMOD: 0.00D%ED P: 23.27O44-76.73C45F(i,j): 0.117 a.u03LP (1) C5/ED (i): 0.9890eπ∗C8-C9/ED (j): 0.26324eE(2) kJ mol−1 : 101.35OE (εiL): −0.1148 a.uOE (εjNL): 0.0243 a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 0.00D%ED P: 50.87C8-49.13C9F(i,j): 0.106 a.u04LP(1) C47/ED (i): 0.9916eπ∗C50-C51/ED (j): 0.2728eE(2) kJ mol−1:101.10OE (εiL): −0.1142 a.uOE (εjNL): 0.0245a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 0.00D%ED P: 49.84C50-50.16C51F(i,j): 0.106 a.u05LP(1)C37/ED (i): 0.9858eπ∗C32-C34/ED (j): 0.3123eE(2) kJ mol−1 : 96.16OE (εiL): −0.1090a.uOE (εjNL): 0.0378 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 19.44D%ED P: 46.79C32-53.21C34F(i,j): 0.106 a.uTable 8
NBO profile of CdL1.
S. NoDonorAcceptorStabilization01LP(1)C9/ED (i): 0.9988eπ∗ C4-C6/ED (j): 0.3416eE(2) kJ mol−1 : 104.04OE (εiL): −0.1181 a.uOE (εjNL): 0.0166 a.uE(j)-E(i): 0.13 a.u%ED P: -/NLMOD: 0.00D%ED P: 46.29C4- 53.71C6F(i,j): 0.106 a.u02LP(1)C37/ED (i): 0.9780eπ∗C32-C34/ED (j): 0.3103eE(2) kJ mol−1 : 96.58OE (εiL): −0.1138 a.uOE (εjNL): 0.0332 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 28.94D%ED P: 47.06C32- 52.94C34F(i,j): 0.106 a.u03LP(1)C51/ED (i): 0.9811eπ∗C46-C48/ED (j): 0.3047eE(2) kJ mol−1 : 95.58OE (εiL): −0.1159 a.uOE (εjNL): 0.0278 a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 26.71D%ED P: 46.24C46-53.76C48F(i,j): 0.105 a.u04LP(1)C51/ED (i): 0.9811eπ∗C47-C50/ED (j): 0.2860eE(2) kJ mol−1 : 91.93OE (εiL): −0.1159 a.uOE (εjNL): 0.0315 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 26.71D%ED P: 49.03C47-50.97C50F(i,j): 0.104 a.u05LP(1)C9/ED (i): 0.9988eπ∗C5-C8/ED (j): 0.2866eE(2) kJ mol−1 : 91.76OE (εiL): −0.1181 a.uOE (εjNL): 0.0312 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 0.00D%ED P: 49.31C5-50.69C8F(i,j): 0.105 a.uThe mathematical background of NBO interaction could be given as follows:(6)ΔEij2=−qiFij2εjNL−εiL,where ΔEij2 denotes stabilization energy of the corresponding contacts, qi specifies the population of the Lewis orbital, and Fij denotes Fock matrix which comes from the result of Lewis and non-Lewis mixing in delocalization. εiL,εjNL describe the orbital energy of donor and acceptor fragments. The stabilization energy is directly accompanied with the energy gap of Lewis and non-Lewis moieties projection [25–27].In L1 system, highest five stabilizations were observed due to lone pair (LP) ⟶π∗ interactions. The LP was contributed from O11, N18, O20, and S19 atomic Lewis moieties. The first interaction was stabilized by 35.62 kJ/mole, where the donor has 1.86916e population 0.34 au energy difference. Since the donation comes from LP, the %ED partition is zero; but, in acceptor, C5 has more electron density distribution than C4. The natural localized molecular orbital dipole (NLMOD) was found to be 1.18 Debye on the Lewis. The second stabilization energy was observed by 34.32 kJ/mole and the difference with the first one was found to be 1.3 kJ/mole. Large stabilization energy differences were observed between second and third interactions (2.33 kJ/mole) and between fourth and fifth interactions (5.17 kJ/mole), respectively.Similarly, in ZnL1, the following Lewis donor was observed such as C5, C47, and C37 atoms. The apex stabilization was attained by LP(C5) ⟶π∗(O2-C3) interaction. The electron density partition in non-Lewis acceptor was found to be 78.06% in C3 and 21.94% in O2. The stabilization energy difference between first and second interactions was found to be 21.6 kJ/mole. Likewise, the stabilization difference between the second and third interactions was found to be 78.47 kJ/mole. However, differences between third and fourth interactions and between fourth and fifth interactions were significantly less. The first and third Lewis donors are identical to each other, yet their corresponding non-Lewis acceptors are different. The same is true in the case of second and fourth Lewis donors.In the case of CdL1, the donor Lewis moieties were found to be C9, C37, and C51 with more than 0.9e population. The highest stabilization interaction was found to be 104.04 kJ/mole, which is very less in comparison with ZnL1. The second stabilization energy was found to be 96.58 due to LP(1)C37 ⟶π∗(C32-C34). Around 7.46 kJ/mole stabilization energy difference was observed in first and second donor acceptor interaction. However, there was no significant difference observed between second and third interactions and between fourth and fifth interactions. The first and fifth Lewis donor moieties and third and fourth donor moieties have similar second-order perturbation properties. But all the non-Lewis acceptor moieties have exclusively different constitution. Even though L1 and its nature of coordination with Zn and Cd were same, their stabilization trends were drastically different; and this was clarified in this rigorous NBO analysis [28, 29].


### 3.2.6. Other Electronic Structure Properties

Other quantum chemical attributes such as ground state energy, dipole moment, polarizability, hyperpolarizability,EHOMO-1, EHOMO, ELUMO, ELUMO+1, and ∆EL-H, that is, energy gap between HOMO and LUMO, electronically calculated chemical potential (µ), chemical hardness (ɳ), electron affinity (EA), ionization potential (IP), and global electrophilicity index (ω) are tabulated in Table 3 [30, 31]. These calculated quantum chemical descriptors could assist one to gain intuition on fundamental electronic structure properties of L1, ZnL1, and CdL1 systems. The theoretical basis for µ and ɳ was initiated from hard soft acid base (HSAB) principle and based on first and second partial derivatives of stationary state molecular energy “E” against the number of electrons at constant marginal potential ν.(7)μ=∂E∂Nνr,η=12∂2E∂N2νr.The ground state parabola model [b] of these equations can be given by (8)μ=−I+A2,η=I−A2,where I and A denote vertical ionization potential (IP) and electron affinity (EA), respectively. The global electrophilicity index (ω) [c] can be given by (9)ω=χ22η=EHOMO2+2EHOMOELUMO+EHOMO24ELUMO−EHOMO,where χ denotes Mulliken electronegativity and is correlated as µ = −χ.The ground state energy revels the ZnL1 and CdL1 their stability and complexation energies, respectively. In ZnL1 system, the complexation energy was found to be 4.51 a.u, and, in CdL1, the complexation energy was 4.49 a.u. Hence, the coordination of L1 with Zn has been more largely stabilized than the Cd metal. On considering FMOs, the pure L1 has large ∆EL-H (5.06 eV) in comparison with ZnL1 (0.5023 eV) and CdL1 (0.4624 eV) which eventually results in absorption of visible light to give complimentary color. The dipole moment of L1 and ZnL1 has relatively same magnitude, whereas CdL1 has less dipole moment than the other two. The polarizability values are increasing pure L1 to ZnL1 and CdL1 complexes. The ZnL1 has more NLO property compared to CdL1 due to increased hyperpolarizability. The FMO related properties such as IP, A, η, ν, χ, µ, and ω have relative trend as shown in Table 3. Both metal complexes have lower hardness and higher softness, yet the reciprocal has been observed in L1. The negative magnitude of electronegativity could be chemical potential as mentioned above. The high “ω” value for metal complexes indicates a high molecular toxicity compared to pure organic system L1 [32–34].


## 3.2.1. Conformational Analysis

The conformational analysis helps the system to identify the ground state conformer. The presence of rotatable single bond, bond angle, and dihedral bond could result in producing various conformers with different structural orientation with corresponding energy. In the present L1 system, a rigorous 3D conformational search has been executed under AM1 semiempirical level theory [15, 16]. In a 3D scan, one dimension represents energy coordinate and the other two orientations represent two dihedral scan coordinates. The pictorial projection is given in Figure 2. Scan coordinate-1 (SC-1) was taken from C13-N18-C4-C3 and the SC-2 was taken from H12-O11-C5-C6 dihedral coordinate due to the presence of single bond connectivity which obviously could produce large number of conformers from set of rotational instructions. The connecting junction of five and six membered rings, namely, N18-C4, and another bonding coordinate O11-C5 would be static on the scan coordinate. However, other moieties connected with either side of the terminal of these said bonds in the dihedral will rotate 360 degrees by 10 degrees of increment up to 36 steps. This rotational instruction would produce 1369 conformers with various energy levels as shown in Figure 2. The change in the energy level is shown in the color graph ranging from red (high energy) to purple (low energy). The high energy conformer has been identified in one location when SC-1 = 28.9553/SC-2 = 22.0012 in 3D scan map as mentioned at the apex position in the 3D color graph. The energy of this conformer was found to be 0.015627 hartree. Stereochemically as expected, it shows planner structure and the figure has been shown here. The steric and noncovalent van der Waals interaction could be responsible for this energy hike when five and six membered rings are in planar geometry. The ground state minimum energy conformers were marked and shown in the figure. Large numbers of stable conformers were observed in this scan coordinate out of 1369 conformers in which all of them exhibit the same structural orientation. As expected, the five and six membered rings were perpendicular to each other and eventually had less steric and noncovalent van der Waals interaction which results in minimization of energy. The energy of stable conformer was found to be −0.014669 hartree and its projection is shown in the figure. The SC-1 and SC-2 orientations of ground state conformer appeared at −71.0446 and −177.9987 degrees, respectively. The relative energy was found to be 0.030296 hartree.Figure 2
3D scan coordinates on SC1 and SC2 with respect to energy using AM1 level.


## 3.2.2. Optimized Geometry

The ground state electronic structure properties of the title molecules were extracted from optimized ground state molecular geometry. Optimized geometrical parameters include spatial vectors such as bond length, bond angle, and dihedral angle of a given system. The geometrical parameters of L1 are given in Table2. The parameters of ZnL1 and CdL1 are given in Supplementary Material S1. The projections of their geometry are shown in Figures 3–5, respectively. The six membered benzenoid aromatic system with conjugation and the five membered heterocyclic system which has nonaromatic character are reflected in their bond order and bond length. Any aromatic system could have C-C bond length ranging from 1.390 to 1.410 Å. In benzene, it is found to be 1.39 Å exactly. In L1, the fused benzene moiety has 1.399 to 1.401 Å of aromatic C-C length. The trend between bond length and bond order could be reciprocally related. The same has been observed here. The aromatic C-C bond includes both end-end and side-side overlap of valence “p” orbital of carbon which resulted in formation of “σ” and “π” of bonds, respectively. These two types of overlap eventually reduce the bond length and increase the bond order with increased bond dissociation energy in comparison to nonaromatic C-C bond which has pure “σ” bond character. This trend has been observed in five membered heterocyclic moiety of L1 which has C13-C15 “σ” bond nature with 1.524 Å bond length and 0.995 and 1.023 fuzzy and Laplacian bond orders, respectively [17].Table 2
Optimized geometrical parameters and bond order of L1.
Bond length (Ǻ)FuzzyLaplacianBond angle (°)Dihedral angle (°)C1-C21.3991.4441.538C1-C6-C5120.81C5-C4-N18-C14−56.72C1-C61.3921.4811.566C5-O11-H12107.28C4-C5-C6-C1−0.85C2-C31.3921.4721.557C15-C13-N18112.16O11-C5-C6-C1−179.69C3-C41.4001.3661.505C15-C13-O20122.65N18-C13-C15-S190.15C4-C51.4091.3031.494N18-C13-O20125.19O20-C13-C15-S19179.60C4-N181.4461.0630.688N18-C14-S19111.59C15-C13-N18-C4175.17C5-C61.4011.3521.549N18-C14-N21121.83C15-C13-N18-C14−2.87C5-O111.3621.3500.535S19-C14-N21126.56O20-C13-N18-C4−4.27O11-H120.9870.7120.432C13-C15-S19107.62O20-C13-N18-C14177.69C13-C151.5240.9951.023C4-N18-C13120.42S19-C14-N18-C4−173.67C13-N181.4011.1940.924C4-N18-C14123.21S19-C14-N18-C134.31C13-O201.2122.0031.216C13-N18-C14116.34N21-C14-N18-C47.94C14-N181.3981.1710.940C14-S19-C1592.14N21-C14-N18-C13−174.08C14-S191.7871.1760.825C14-N21-H22112.83N18-C14-S19-C15−3.44C14-N211.2781.8281.646Dihedral angle (°)N21-C14-S19-C15174.85C15-S191.8261.1760.633C6-C1-C2-C31.36N18-C14-N21-H22−179.83N21-H221.0190.8520.698C2-C1-C6-C5−1.00S19-C14-N21-H222.03Bond angle (°)C1-C2-C3-C40.14C13-C15-S19-C141.82C2-C1-C6120.20C2-C3-C4-C5−2.01C1-C2-C3119.51C2-C3-C4-N18175.10C2-C3-C4120.57C3-C4-C5-C62.34C3-C4-C5120.05C3-C4-C5-O11−178.88C3-C4-N18118.16N18-C4-C5-C6−174.65C5-C4-N18121.73N18-C4-C5-O114.13C4-C5-C6118.82C3-C4-N18-C13−51.67C4-C5-O11122.94C3-C4-N18-C14126.23C6-C5-O11118.24C5-C4-N18-C13125.38Figure 3
Optimized structure, FMOs, surfaces, and ELF plots of L1.Figure 4
Optimized structure, FMOs, surfaces, and ELF plots of ZnL1.Figure 5
Optimized structure, FMOs, surfaces, and ELF plots of CdL1.The ECP technique has been implemented to optimize the metal complex. This metal complex numerical optimization was tedious; henceforth we usedTd constrained, symmetry-off, very tight Berny algorithm to get the ground state stationary point. The ground state was verified by existence of positive frequencies at potential energy surface. In accordance with the experimental evidences, all the four ligands were coordinated with the metal (Zn, Cd) under Td symmetry. In ZnL1 system, the central Zn atom has tetrahedral arrangement and all the four lobes are connected with four different oxygen atoms of four hydroxyl groups of phenyl moiety, respectively. The bond length of Zn1-O2 and Zn1-O23 was found to be 1.991 Ǻ, whereas that of Zn1-O44 and Zn1-O65 was observed as 1.989 Ǻ. The fuzzy bond order was found to be 1.013 and 1.026 (fuzzy) and Laplacian values were observed as 0.217 and 0.219, respectively. These theoretical values help us to understand the strength of the metal-ligand bonds and their nature. Similarly, in CdL1, the Cd has Td arrangement surrounded by four ligands. The bond length among Cd1-O2, Cd1-O23, Cd1-O44, and Cd1-O65 was found to be 2.191, 2.188, 2.191, and 2.192 Ǻ, respectively. The calculated fuzzy bond order was observed as 1.036, 1.034, 1.093, and 1.103 respectively. The Laplacian scale bond order was found to be 0.207, 0.209, 0.209, and 0.221 respectively. Hence, these results conclude that the strength of both Zn-O and Cd-O could be equally comparable except bond length.


## 3.2.3. Fragmented FMO Analysis

Frontier molecular orbital analysis is a traditional technique to understand how electrons could be interacting between bonding and antibonding molecular orbitals. Chemical and electronic properties such as hardness, softness, reactivity, and charge transport depend on the FMO gap. The FMO gap values among HOMO-1, HOMO, LUMO, and LUMO+1 are tabulated in Table3 and the surface projections are given in Figures 3–5. The atomic contributions to FMOs are listed Table 4. ∆EL-H of L1 was found to be 5.06 eV. In ZnL1 and CdL1, these values were 0.5023 eV and 0.4624 eV, respectively. A more significant dropping has been observed in metal complex compared to pure L1. The atomic contribution on FMO formation for L1 largely comes from atom “C” with 80% on HOMO and 52% on LUMO. Atom “O and N” contributes second and third, respectively. In the case of ZnL1 and CdL1, the HOMO and LUMO were highly contributed by “C” as in L1. But more contributions were observed by “O” in ZnL1 and CdL1 compared to pure L1. Central metals “Zn and Cd” have 0% and 1% contribution in HOMO and LUMO formation. The “H” atom has no contribution in all the three systems. The position of lobes in L1 at HOMO was localized around six membered ring and LUMO was around five membered ring. Since the lobes of the orbitals are perpendicular to plane of the molecular symmetry, they must be π ⟶ π∗ transition [18–20]. The same type of transition is observed in ZnL1 and CdL1 transitions.Table 3
Other electronic structure properties of L1, ZnL1, and CdL1.
PropertiesL1ZnL1CdL1Energy−1005.944951 hartree−4086.75259 hartree−4069.258684 hartreeDipole moment3.2612 Debye3.7202 Debye2.8688 DebyePolarizability144.2924 au508.9803 au584.1757 auHyperpolarizability341.6341 au5058.6180 au3966.6924 auLUMO+1−1.0270 eV−0.8602 eV−0.8302 eVLUMO−1.3755 eV−4.8039 eV−4.8239 eVHOMO−6.4355 eV−5.3063 eV−5.2863 eVHOMO-1−7.0029 eV−5.5721 eV−5.5221 eV∆EL-H5.0599 eV0.5023 eV0.4624 eVIonization potential (IP)6.4355 eV5.3063 eV5.2863 eVElectron affinity (A)1.3755 eV4.8039 eV4.8201 eVGlobal hardness (η)2.53000.25120.2331Global softness (ν)0.19763.98084.2900Electronegativity (χ)3.90555.05514.7881Chemical potential (µ)−3.9055−5.0551−4.7881Global electrophilicity (ω)3.014450.863949.1761Table 4
Percentage fragmentation contributions in FMO.
FMO of L1 systemsAtoms/FMOCNOSHL+12450715L52201855H8011900H-18510410FMO of ZnL1 systemsAtoms/FMOCNOSHZnL+19014211L75124000H75124000H-175122001FMO of CdL1 systemsAtoms/FMOCNOSHCdL+18138430L72126001H73124001H-174224001


## 3.2.4. MEP and Atomic Charge Analysis

The MEP and atomic charge analysis has been carried out for L1, ZnL1, and CdL1. The MEP surface of L1 is shown in Figure3 and the computed atomic charges are listed in Table 5. The MEP of ZnL1 and CdL1 is shown in Figures 4 and 5, respectively. The calculated charges are listed in Supplementary Material 2. Various atomic charge schemes such as Mulliken, atomic tensor polar (ATP), Hirshfeld, and natural population analysis (NPA) were computed for all the three systems. The mathematical formulation of MEP and various atomic changes is as follows:(1)Vr=ZARA−r−∫ρr′r′−rd3r′.Table 5
Various theoretical atomic charges on L1.
AtomMullikenAPTHirshfeldNPAC1−0.15750.0588−0.0349−0.2161C2−0.3308−0.1279−0.0509−0.2676C30.22990.0248−0.0414−0.2060C40.16520.17660.02180.0700C5−0.39250.46590.07240.3322C6−0.0108−0.1133−0.0514−0.2754H70.18230.02850.04820.2474H80.18220.02760.04610.2471H90.19150.04630.04720.2496H100.19830.04690.05160.2583O11−0.6771−0.7401−0.2281−0.6878H120.51660.39660.11950.5068C130.51921.02800.19430.6962C14−0.12321.04030.13720.2708C15−0.83490.0239−0.0266−0.6971H160.28260.03010.06370.2940H170.27870.02390.06210.2949N180.0675−0.8775−0.0422−0.5345S190.4487−0.2268−0.0074−0.2792O20−0.4159−0.7463−0.2682−0.5524N21−0.6904−0.7737−0.2289−0.6999H220.37050.18740.11600.3902The notations in the equation can be given as follows:ZA represents the charge of the nucleus “A” located at RA, ρ(r′) specifies the electronic density of the system, and r′ represents the trivial integral variable. Generally, the MEP color surface ranging from red to blue indicates the more electron populated region (electrophilic site) to lesser electron population region (nucleophilic site). In L1, the electropositive region was observed at five membered ring and electronegative region was observed in six membered ring. Around O11 and O20, the surface is rich in red and at N18, N21, and S19 it became blue. This trend is reflected in point change analysis as well and discussed hereunder. Similarly, in ZnL1 and Cd L1, the position around oxygen atoms exhibits red surface and nitrogen and sulfur region shows blue. This imprint could help one to understand the nature reactive in these systems when introduced to a Lewis acid and base. The total electron density map (TED) could project the size occupied as a whole system in space; eventually molecular electron density volume related attributes could be derived.Furthermore, the theoretical foundation of Mulliken point charge could be given as(2)qA=ZA−∑ini,A=ZA−∑iηi∑a∈AΘi,a,where η denotes orbital occupation number and ni,A states the contribution from orbital “i.” It is highly basis set dependent.The ATP model could be provided as follows:(3)qi=13∂μx∂xi+∂μy∂yi+∂μz∂zi,where “µ” is the dipole moment of the given system and xi, yi, and zi denote vectors of “ith” atom.Hirshfeld would be represented by(4)qA=−∫wAHirshrρdefrdr.For NPA, it can be given as follows:(5)qAN=∑iqiN,where qAN denotes natural electron population on overlap free natural atomic orbital [21–24].Though the Mulliken population analysis is a traditional method to calculate point charges, it is highly basis set dependent. Since the L1 was an organic system which was treated with B3LYP/6-31+G(d), a promising level basis set, the results were comparable with other methods except in atoms such as C3, C5, C14, and S19 where a negative reciprocal charge magnitude has been observed. However, the rest of the atoms are in good agreement with other point charge theories. In accordance with electronegativity, the excess electron population is expected in heteroatoms such as O11, N18, S19, O20, and N21. The same was observed in all the atomic charge theories with significant increased electron population as mentioned in Table5.In ZnL1 and CdL1 complexes, the L1 is arranged in aTd arrangement with 1 : 4 metal cum ligand stoichiometry. The Zn and Cd metal atoms nearly have more than a unity positive charge except Hirshfeld method. In ZnL1, more electron population has been observed in all heteroatoms of four ligands. But, in CdL1, less electron population trend has been observed in heteroatoms in all the theories except in few atoms in comparison with ZnL1. Electron localization function (ELF) is a method to calibrate electron at the neighboring space with reference to electron localized at a given point with the same spin. The ELF values in pi delocalized region fall around less than 0.65 and in sigma bond region they were noticed to be greater than 0.70 to 0.99.


## 3.2.5. NBO Analysis

The natural bond orbital analysis method is an efficient technique to gain detailed chemical insight on chemical bonding, point charges, and second-order perturbed stabilization interactions. The stabilization interaction chemistry between Lewis donor orbitals and non-Lewis acceptor orbitals could help one to understand how a molecule could attain stabilized electronic stationary point structurally. The present study provides detailed NBO information on both ligand L1 and its metal complexes, namely, ZnL1 and CdL1, respectively. The figure incorporated first five strong stabilization interactions of L1, ZnL1, and CdL1, shown in Tables6–8, respectively.Table 6
NBO profile of L1.
S. no.DonorAcceptorStabilization01LP (2) O11/ED (i): 1.86916eπ∗C4- C5/ED (j): 0.40876eE(2) kJ mol−1 : 35.62OE (εiL): -0.32938 a.uOE (εjNL): 0.01441 a.uE(j)-E(i): 0.34 a.u%ED P: -/NLMOD: 1.18D%ED P: 43.15C4-56.85C5F(i,j): 0.099 a.u02LP (1) N 18/ED (i): 1.68286eπ∗C13-O 20/ED (j): 0.20748eE(2) kJ mol−1 : 34.32OE (εiL): -0.31154 a.uOE (εjNL): 0.01337 a.uE(j)-E(i): 0.32 a.u%ED P: -/NLMOD: 1.63D%ED P: 68.17C13-31.83O20F(i,j): 0.094 a.u03LP (2) O 20/ED (i): 1.84296eσ∗C13- N 18/ED (j): 0.10575eE(2) kJ mol−1 : 31.99OE (εiL): −0.28193 a.uOE (εjNL): 0.32151 a.uE(j)-E(i): 0.60 a.u%ED P: -/NLMOD: 1.31D%ED P: 63.64C13-36.36N18F(i,j): 0.124 a.u04LP (1) N 18/ED (i): 1.68286eπ∗C14- N 21/ED (j): 0.24930eE(2) kJ mol−1: 31.35OE (εiL): −0.31154 a.uOE (εjNL): −0.01791 a.uE(j)-E(i): 0.29 a.u%ED P: -/NLMOD: 1.63D%ED P: 60.08C14-39.92N21F(i,j): 0.086 a.u054LP (2) S 19/ED (i): 1.84334eπ∗C14- N 21/ED (j): 0.24930eE(2) kJ mol−1 : 26.18OE (εiL): −0.27665 a.uOE (εjNL): −0.01791 a.uE(j)-E(i): 0.26 a.u%ED P: -/NLMOD: 1.33D%ED P: 60.08C14-39.92N21F(i,j): 0.073 a.uTable 7
NBO profile of ZnL1.
S. no.DonorAcceptorStabilization01LP (1) C5/ED (i): 0.9890eπ∗O2-C3/ED (j): 0.5776eE(2) kJ mol−1 : 201.42OE (εiL): −0.1148 a.uOE (εjNL): −0.0255 a.uE(j)-E(i): 0.09 a.u%ED P: -/NLMOD: 0.00D%ED P: 21.94O2-78.06C3F(i,j): 0.120 a.u02LP(1) C47/ED (i): 0.9916eπ∗O44-C45/ED (j): 0.5326eE(2) kJ mol−1 : 179.82OE (εiL): −0.1142 a.uOE (εjNL): −0.0184 a.uE(j)-E(i): 0.10 a.u%ED P: -/NLMOD: 0.00D%ED P: 23.27O44-76.73C45F(i,j): 0.117 a.u03LP (1) C5/ED (i): 0.9890eπ∗C8-C9/ED (j): 0.26324eE(2) kJ mol−1 : 101.35OE (εiL): −0.1148 a.uOE (εjNL): 0.0243 a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 0.00D%ED P: 50.87C8-49.13C9F(i,j): 0.106 a.u04LP(1) C47/ED (i): 0.9916eπ∗C50-C51/ED (j): 0.2728eE(2) kJ mol−1:101.10OE (εiL): −0.1142 a.uOE (εjNL): 0.0245a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 0.00D%ED P: 49.84C50-50.16C51F(i,j): 0.106 a.u05LP(1)C37/ED (i): 0.9858eπ∗C32-C34/ED (j): 0.3123eE(2) kJ mol−1 : 96.16OE (εiL): −0.1090a.uOE (εjNL): 0.0378 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 19.44D%ED P: 46.79C32-53.21C34F(i,j): 0.106 a.uTable 8
NBO profile of CdL1.
S. NoDonorAcceptorStabilization01LP(1)C9/ED (i): 0.9988eπ∗ C4-C6/ED (j): 0.3416eE(2) kJ mol−1 : 104.04OE (εiL): −0.1181 a.uOE (εjNL): 0.0166 a.uE(j)-E(i): 0.13 a.u%ED P: -/NLMOD: 0.00D%ED P: 46.29C4- 53.71C6F(i,j): 0.106 a.u02LP(1)C37/ED (i): 0.9780eπ∗C32-C34/ED (j): 0.3103eE(2) kJ mol−1 : 96.58OE (εiL): −0.1138 a.uOE (εjNL): 0.0332 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 28.94D%ED P: 47.06C32- 52.94C34F(i,j): 0.106 a.u03LP(1)C51/ED (i): 0.9811eπ∗C46-C48/ED (j): 0.3047eE(2) kJ mol−1 : 95.58OE (εiL): −0.1159 a.uOE (εjNL): 0.0278 a.uE(j)-E(i): 0.14 a.u%ED P: -/NLMOD: 26.71D%ED P: 46.24C46-53.76C48F(i,j): 0.105 a.u04LP(1)C51/ED (i): 0.9811eπ∗C47-C50/ED (j): 0.2860eE(2) kJ mol−1 : 91.93OE (εiL): −0.1159 a.uOE (εjNL): 0.0315 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 26.71D%ED P: 49.03C47-50.97C50F(i,j): 0.104 a.u05LP(1)C9/ED (i): 0.9988eπ∗C5-C8/ED (j): 0.2866eE(2) kJ mol−1 : 91.76OE (εiL): −0.1181 a.uOE (εjNL): 0.0312 a.uE(j)-E(i): 0.15 a.u%ED P: -/NLMOD: 0.00D%ED P: 49.31C5-50.69C8F(i,j): 0.105 a.uThe mathematical background of NBO interaction could be given as follows:(6)ΔEij2=−qiFij2εjNL−εiL,where ΔEij2 denotes stabilization energy of the corresponding contacts, qi specifies the population of the Lewis orbital, and Fij denotes Fock matrix which comes from the result of Lewis and non-Lewis mixing in delocalization. εiL,εjNL describe the orbital energy of donor and acceptor fragments. The stabilization energy is directly accompanied with the energy gap of Lewis and non-Lewis moieties projection [25–27].In L1 system, highest five stabilizations were observed due to lone pair (LP) ⟶π∗ interactions. The LP was contributed from O11, N18, O20, and S19 atomic Lewis moieties. The first interaction was stabilized by 35.62 kJ/mole, where the donor has 1.86916e population 0.34 au energy difference. Since the donation comes from LP, the %ED partition is zero; but, in acceptor, C5 has more electron density distribution than C4. The natural localized molecular orbital dipole (NLMOD) was found to be 1.18 Debye on the Lewis. The second stabilization energy was observed by 34.32 kJ/mole and the difference with the first one was found to be 1.3 kJ/mole. Large stabilization energy differences were observed between second and third interactions (2.33 kJ/mole) and between fourth and fifth interactions (5.17 kJ/mole), respectively.Similarly, in ZnL1, the following Lewis donor was observed such as C5, C47, and C37 atoms. The apex stabilization was attained by LP(C5) ⟶π∗(O2-C3) interaction. The electron density partition in non-Lewis acceptor was found to be 78.06% in C3 and 21.94% in O2. The stabilization energy difference between first and second interactions was found to be 21.6 kJ/mole. Likewise, the stabilization difference between the second and third interactions was found to be 78.47 kJ/mole. However, differences between third and fourth interactions and between fourth and fifth interactions were significantly less. The first and third Lewis donors are identical to each other, yet their corresponding non-Lewis acceptors are different. The same is true in the case of second and fourth Lewis donors.In the case of CdL1, the donor Lewis moieties were found to be C9, C37, and C51 with more than 0.9e population. The highest stabilization interaction was found to be 104.04 kJ/mole, which is very less in comparison with ZnL1. The second stabilization energy was found to be 96.58 due to LP(1)C37 ⟶π∗(C32-C34). Around 7.46 kJ/mole stabilization energy difference was observed in first and second donor acceptor interaction. However, there was no significant difference observed between second and third interactions and between fourth and fifth interactions. The first and fifth Lewis donor moieties and third and fourth donor moieties have similar second-order perturbation properties. But all the non-Lewis acceptor moieties have exclusively different constitution. Even though L1 and its nature of coordination with Zn and Cd were same, their stabilization trends were drastically different; and this was clarified in this rigorous NBO analysis [28, 29].


## 3.2.6. Other Electronic Structure Properties

Other quantum chemical attributes such as ground state energy, dipole moment, polarizability, hyperpolarizability,EHOMO-1, EHOMO, ELUMO, ELUMO+1, and ∆EL-H, that is, energy gap between HOMO and LUMO, electronically calculated chemical potential (µ), chemical hardness (ɳ), electron affinity (EA), ionization potential (IP), and global electrophilicity index (ω) are tabulated in Table 3 [30, 31]. These calculated quantum chemical descriptors could assist one to gain intuition on fundamental electronic structure properties of L1, ZnL1, and CdL1 systems. The theoretical basis for µ and ɳ was initiated from hard soft acid base (HSAB) principle and based on first and second partial derivatives of stationary state molecular energy “E” against the number of electrons at constant marginal potential ν.(7)μ=∂E∂Nνr,η=12∂2E∂N2νr.The ground state parabola model [b] of these equations can be given by (8)μ=−I+A2,η=I−A2,where I and A denote vertical ionization potential (IP) and electron affinity (EA), respectively. The global electrophilicity index (ω) [c] can be given by (9)ω=χ22η=EHOMO2+2EHOMOELUMO+EHOMO24ELUMO−EHOMO,where χ denotes Mulliken electronegativity and is correlated as µ = −χ.The ground state energy revels the ZnL1 and CdL1 their stability and complexation energies, respectively. In ZnL1 system, the complexation energy was found to be 4.51 a.u, and, in CdL1, the complexation energy was 4.49 a.u. Hence, the coordination of L1 with Zn has been more largely stabilized than the Cd metal. On considering FMOs, the pure L1 has large ∆EL-H (5.06 eV) in comparison with ZnL1 (0.5023 eV) and CdL1 (0.4624 eV) which eventually results in absorption of visible light to give complimentary color. The dipole moment of L1 and ZnL1 has relatively same magnitude, whereas CdL1 has less dipole moment than the other two. The polarizability values are increasing pure L1 to ZnL1 and CdL1 complexes. The ZnL1 has more NLO property compared to CdL1 due to increased hyperpolarizability. The FMO related properties such as IP, A, η, ν, χ, µ, and ω have relative trend as shown in Table 3. Both metal complexes have lower hardness and higher softness, yet the reciprocal has been observed in L1. The negative magnitude of electronegativity could be chemical potential as mentioned above. The high “ω” value for metal complexes indicates a high molecular toxicity compared to pure organic system L1 [32–34].


## 4. Conclusion

In our earlier work, we reported the synthesis of L1 and its metal complexes with Zn and Cd metal. Spectroscopic and thermodynamic attributes were derived, and their structural features were confirmed earlier. The present work was extended to probe the biological sensitivity and theoretical investigations of both pure ligand and metal complexes. The biological evaluation of complexes against various pathogenic bacterial and fungal strains revealed that metal complexes had higher antimicrobial sensitivity than free ligand, but they were lower than standard drugs. However, the toxicity analysis has not been carried out and investigated. Theoretical and computational studies provide significant findings on structural features and electronic structure properties of target systems. The global minimum stationary point was derived from 3D PES scan surface analysis and further ground state properties were derived from that stationary point. The MEP and charge analysis on L1 and its metal complexes provides various point charge distributions and their reactive site profiles. Entire “O” atoms exhibit electrophilic nature and “N and S” atoms show nucleophilic nature on their potential surface. The highest molecular stabilization was satisfied by LP⟶π∗ interaction in both pure L1 and its metal complexes. Additional electronic structure properties which are completely based on FMO gaps provide details on global harness, softness, ionization potential, electron affinity, and electrophilicity index. This thorough probe on the ground of biological and theoretical electronic structure provides deep understanding on 3-(2-hydroxyphenyl)-2-iminothiazolidin-4-one ligand and its Zn2+ and Cd2+ metal complexes.



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