Green Synthesis, SC-XRD, Non-Covalent Interactive Potential and Electronic Communication via DFT Exploration of Pyridine-Based Hydrazone

: Ultrasound-based synthesis at room temperature produces valuable compounds greener and safer than most other methods. This study presents the sonochemical fabrication and characterization of a pyridine-based halogenated hydrazone, (E)-2-((6-chloropyridin-2-yl)oxy)-N (cid:48) -(2-hydroxybenzylidene) acetohydrazide (HBPAH). The NMR spectroscopic technique was used to determine the structure, while SC-XRD conﬁrmed its crystalline nature. Our structural studies revealed that strong, inter-molecular attractive forces stabilize this crystalline organic compound. Moreover, the compound was optimized at the B3LYP / 6-311G(d,p) level using the Crystallographic Information File (CIF). Natural bonding orbital (NBO) and natural population analysis (NPA) were performed at the same level using optimized geometry. Time-dependent density functional theory (DFT) was performed at the B3LYP / 6-311G (d,p) method to calculate the frontier molecular orbitals (FMOs) and molecular electrostatic potential (MEP). The global reactivity descriptors were determined using HOMO and LUMO energy gaps. Theoretical calculations based on the Quantum Theory of Atoms in Molecules (QT-AIM) and Hirshfeld analyses identiﬁed the non-covalent and covalent interactions of the HBPAH compound. Consequently, QT-AIM and Hirshfeld analyses agree with experimental results.


Introduction
Humanity faces increasing health, shelter, and economic problems as we consume more resources to pollute, urbanize, and deforest our environment. Fatal diseases have not only taken many lives Studies show that microwave-assisted synthesis accelerates chemical synthesis with a better yield and higher purity in comparison to conventional methods [18,36,37]. Microwave (MW) radiations assist in non-thermal polarizing radiation, dipolar polarization, ionic conduction reactions [38]., This study reports the ultrasound-based synthesis, SC-XRD exploration, and density functional theory (DFT) analysis of the pyridine-based novel crystalline hydrazones, i.e., (E)-2-((6chloropyridin-2-yl)oxy)-N'-(2-hydroxybenzylidene) acetohydrazide.

General
Analytical grade solvents and pure reagents were used without any further purification. TLC (Thin layer chromatography) cards, coated with silica gel (0.25 mm thickness), were used to monitor the reaction progress. For the NMR spectra measurement, Bruker-Avance, A-V spectrometer, was used. For the single crystal analysis, Bruker Kappa APEX-II diffractometer was used where the data correction and data reduction were made by APEX-II and SAINT, respectively [39]. For the structure solution, SHELXS97 software [40,41] and for refinement, SHELXL2014/6 was used to minimize the structural errors [42]. For the graphical representation of the asymmetric unit, ORTEP was used while for the hydrogen bonding, PLATON was used [43].

General
Analytical grade solvents and pure reagents were used without any further purification. TLC (Thin layer chromatography) cards, coated with silica gel (0.25 mm thickness), were used to monitor the reaction progress. For the NMR spectra measurement, Bruker-Avance, A-V spectrometer, was used. For the single crystal analysis, Bruker Kappa APEX-II diffractometer was used where the data correction and data reduction were made by APEX-II and SAINT, respectively [39]. For the structure solution, SHELXS97 software [40,41] and for refinement, SHELXL2014/6 was used to minimize the structural errors [42]. For the graphical representation of the asymmetric unit, ORTEP was used while for the hydrogen bonding, PLATON was used [43].
Koopmans's theorem [73] was usually used to calculate the chemical potential (µ), electronegativity (x) and chemical hardness (η) and was equated as: Crystals 2020, 10, 778 4 of 20 The following equation was used for global softness (σ): The calculation of electrophilicity index (ω) was reported by Parr et al. as:

Results and Discussion
The hydrazone, (E)-2-((6-chloropyridin-2-yl)oxy)-N -(2-hydroxybenzylidene) acetohydrazide (HBPAH), was synthesized with a yield of 85% and its structures were determined by NMR spectroscopy and SC-XRD analysis. The 1 H-and 13 C-NMR of the title compound showed the presence of each signal in duplication that indicates that the title compound exists in two isomeric forms; a minor isomer A (E) that is 45.87% and a major isomer B (Z) that is 54.12% (Scheme 2). The ratio of the E and Z isomers was calculated from the 1 H-NMR analysis, where the methylenic signals of both isomers were integrated into the 1 H NMR spectra ( Figure S2 in Supplementary Materials).
The calculation of electrophilicity index (ω) was reported by Parr et al. as:
In both molecules within the lattice, the NH of acetohydrazide group interacts with the O-atom of 6-chloropyridin-2-ol moiety through intra N-H· · · O bonding to form S(5) loop, and the hydroxyl group of o-cresol moiety interacts with N-atom of acetohydrazide group through intra O-H· · · N bonding to form S(6) loop. The first molecule connects with the second molecule through N-H· · · O bonding, where NH is from acetohydrazide group E, and O-atom is from the acetohydrazide group B. Water molecule is engaged in two types of classical H-bonding named as O-H· · · O and N-H· · · O. Water acts as a donor in O-H· · · O (carbonyl O-atom of acetohydrazide group B) and O-H· · · O (carbonyl O-atom of acetohydrazide group E) to connect molecule of the first type with a molecule of the second type whereas it acts as an acceptor in N-H· · · O bonding where NH is from acetohydrazide group E. Water molecule is also engaged in one weak non-classical C-H· · · O (CH is from O-cresol moiety C) bonding with C-O distance of 3.271 Å and angle of 139.06 • [74,75]. R 1 2 (6) loop is formed through classical N-H· · · O and non-classical C-H· · · O bonding in which water acts as an acceptor. The carbonyl O-atom of acetohydrazide group E is also engaged in weak non-classical C-H· · · O(CH is from o-cresol moiety F) bonding to connect molecules of the second type with each other with a C-O distance of 3.433 Å and angle of 162.40 • [76].

Cg(e)-Cg(f) D ef DA ef D e (f) D f (e) Ring Off-Set
Cg (1)

Comparative Structural Study
The SC-XRD-based structure of HBPAH was used for geometry optimization in bond length and bond angle calculations. For HBPAH, an atom numbering scheme was presented in Figure S4 (Supplementary Information), and the aforementioned geometrical parameter results were shown in Table S1 (Supplementary Information). DFT-calculated and SC-XRD-driven parameters agree with each other with an overall variation of 0.039 ± 0.028 Å. Similarly, bond angles in HBPAH deviate around 3.0 ± 3.3 • .
Our HS analysis also reports secondary interactions between molecules [78,87,89], such as carbon atom attached with -NH of hydrazide part bonded with the hydrogen atom of the O=C-H In the curvedness diagram, the broader green areas separated by blue outlines show the stacking interactions. Figure 6 shows the shape index that explains the π-π stacking interactions with blue humps and red hollows.
We then used two-dimensional fingerprint plots to explain the intermolecular interactions within the molecular structure [86][87][88]. The strongest interaction among hydrogen atoms in the compound is 33.2%, as shown in Figure 7, alongside percentage contribution for all interatomic contacts. Figure S5 shows the two-dimensional fingerprint plots. The most dominant contributions within the crystal packing are as follows: H-H (33.20%), C-H (13.00%), O-H (17.20%), Cl-H (15.60%), C-C (7.50%) and C-N (2.70%). Our HS analysis shows that C-H· · · π interactions dominate the stability within the molecular structure of HBPAH.

shows the intermolecular hydrogen bonds (dashed green lines between the hydrazide -NH and the hydroxybenzylide O-H) and intermolecular hydrogen bond with the water molecule (solvent interaction).
HBPAH.   Our HS analysis also reports secondary interactions between molecules [78,87,89], such as carbon atom attached with -NH of hydrazide part bonded with the hydrogen atom of the O=C-H group [90]. Figure 8 shows the intermolecular hydrogen bonds (dashed green lines between the hydrazide -NH and the hydroxybenzylide O-H) and intermolecular hydrogen bond with the water molecule (solvent interaction).

shows the intermolecular hydrogen bonds (dashed green lines between the hydrazide -NH and the hydroxybenzylide O-H) and intermolecular hydrogen bond with the water molecule (solvent interaction).
HBPAH.

Natural Bonding Orbital (NBO) Analysis
We next used NBO analysis to interpret charge transformation, different types of HB (inter-and intra-molecular), and hyper conjugative interactions [95−97]. For all orbitals, second-order perturbation energy E (2) could be calculated from Equation (9).
qi is donor orbital occupancy, εj and εi are diagonal elements, and F(i,j) is off-diagonal NBO Fock matrix element. For HBPAH, all E (2) values are displayed in Table S3, while the imperative E (2) values are arranged in Table 5.   HBPAH shows two different sets of HBs, intramolecular and intermolecular, with the water molecule (solvent interaction). The intramolecular HB was displayed between oxygen next to pyridine moiety and the hydrazide hydrogen, with the O-H ρ value (O2-H8 = +0.0181 e/a 3 and O35-H41 = +0.0179 e/a 3 ). The solvent-based HBs measure weaker than the intramolecular HB with O-H ρ values at BCPs, H49-O67, H56-O67, and H41-O67 were +0.0062 e/a 3 , +0.0114 e/a 3 , and +0.0148 e/a 3 , respectively (Table 4 and Table S2).
For HBPAH, two additional interactions, i.e., LP1(N40)→π*(O36-C54) and LP1(N7)→π*(O3-C21) with respective high stabilization energy values of 62.83 and 56.48 kcal/mol, indicated the strong HB between lone-pair to anti-bonding orbitals in our HS and QT-AIM analyses. We conclude that these interactions directly stabilize HBPAH in its solid-state. Table 5. Natural bonding orbital (NBO) analysis for HBPAH using the B3LYP/6-311G(d,p) level.  (2) is the energy of hyper conjugative interaction (stabilization energy in kcal mol −1 ); b E(j)E(i) is the energy difference between donor and acceptor i and j NBO orbitals; c F(i;j) is the Fock matrix element between i and j NBO orbitals.

Natural Population Analysis (NPA)
For HBPAH, the natural population-based analysis on NBO was determined by B3LYP/6-311G(d,p) ( Figure S7). The phenomenon correlates to charge transformation, and the electronegativity equalization process occurs in reaction to access the electrostatic ability on the external surfaces of the structure [66,98,99]. The charges of atoms play a crucial role within the molecular conformation and bonding capability in HBPAH. The electronegative atoms such as Cl, O, and N made unequal redistribution of the electron density over the pyridine or aromatic rings. Atomic charge of oxygen atoms was O2 (−0.38655e) and O36 (−0.39665e), and for hydrogen atoms, charges were H8(0.28089e) and H38(0.281296e), respectively, due to the involvement of these atoms in the intermolecular hydrogen bonding interactions.

Frontier Molecular Orbital (FMO) Analysis
The FMOs evaluate chemical bond strength and molecule stability [100]. In HBPAH, the energy of HOMO, LUMO, and its two upper and lower orbitals (HOMO-1, HOMO-2, LUMO+1, LUMO+2) were calculated by the TD-DFT/B3LYP/6-311G (d, p) and displayed in Figure 10. The energy difference between HOMO-LUMO is assumed to be a significant key factor to illustrate the chemical reactivity, optical properties, kinetic stability, and electronic character of the compounds [101,102]. Table 6 shows the energy data with their energy gap (∆E) for six MO (molecular orbitals).   Figure 10 shows that HBPAH contained an energy gap of 3.634 eV, which exposed the effective intra-molecular charge transfer (ICT) within the compound. For HBPAH, the HOMO was populated on the first part of molecule (Z)-N'-(2-hydroxybenzylidene) acetohydrazide moiety and a small effect exists on the hydroxyl group. LUMO was populated on the second part of the molecule, i.e., (Z)-N'-(2-hydroxybenzylidene) propionohydrazide moiety ( Figure 10). HOMO and LUMO energy gap values for two antifungal 1,2,4-triazolo[4,3-a]pyridine derivatives were found to be 4.318 and 3.705 eV, where high energy gap was associated with the more potent antifungal compound [16].
HBPAH contained an IP value of 5.6 eV and an EA value of 1.966 eV. Its electron loss and the electron gain capacity were defined by the ionization potential and the electron affinity values, which correlate to the HOMO-LUMO energy difference. Consequently, the IP value shows a lower magnitude than the EA value, indicating that HBPAH contained excellent electron-donating capability. This supports the findings of global electrophilicity (ω) ( Table S4). In HBPAH, the calculated global softness (σ) values obtained were lower than the global hardness ( ) values, making HBPAH stable and relatively unreactive. Additionally, the chemical potential (μ) value (−3.783 (eV)) revealed that HBPAH was chemically hard with the affective electron-donating ability and highest kinetic stability (Table S4).

Molecular Electrostatic Potential (MEP)
The MEP significance shows the size and configuration of the molecule, along with neutral (white), negative (red), and positive (blue) electrostatic potential regions comparable to shading assessing scheme. MEP explores the connection between molecular structural insights and physicochemical properties [103]. We Analyzed HBPAH's MEP surface through the B3LYP/6-311G(d,p) level of theory, as shown in Figure 11. The negative red indicates the electrophilic sites at the oxygen atoms. Therefore, the oxygen atoms are the most effective target for nucleophilic attack, along with the most suitable sphere to attack the molecules' positive zones. The negative potential magnitude of HBPAH is −1.00 × 10 −2 to 1.00 × 10 −2 a.u. Green areas represent the region of zero potential. The blue areas of the HBPAH molecule situate over the hydrogen atoms. They show a combination of positive charges, demonstrating the nucleophilic localities.   Figure 10 shows that HBPAH contained an energy gap of 3.634 eV, which exposed the effective intra-molecular charge transfer (ICT) within the compound. For HBPAH, the HOMO was populated on the first part of molecule (Z)-N -(2-hydroxybenzylidene) acetohydrazide moiety and a small effect exists on the hydroxyl group. LUMO was populated on the second part of the molecule, i.e., (Z)-N -(2-hydroxybenzylidene) propionohydrazide moiety ( Figure 10). HOMO and LUMO energy gap values for two antifungal 1,2,4-triazolo[4,3-a]pyridine derivatives were found to be 4.318 and 3.705 eV, where high energy gap was associated with the more potent antifungal compound [16].
HBPAH contained an IP value of 5.6 eV and an EA value of 1.966 eV. Its electron loss and the electron gain capacity were defined by the ionization potential and the electron affinity values, which correlate to the HOMO-LUMO energy difference. Consequently, the IP value shows a lower magnitude than the EA value, indicating that HBPAH contained excellent electron-donating capability. This supports the findings of global electrophilicity (ω) ( Table S4). In HBPAH, the calculated global softness (σ) values obtained were lower than the global hardness (η) values, making HBPAH stable and relatively unreactive. Additionally, the chemical potential (µ) value (−3.783 (eV)) revealed that HBPAH was chemically hard with the affective electron-donating ability and highest kinetic stability (Table S4).

Molecular Electrostatic Potential (MEP)
The MEP significance shows the size and configuration of the molecule, along with neutral (white), negative (red), and positive (blue) electrostatic potential regions comparable to shading assessing scheme. MEP explores the connection between molecular structural insights and physicochemical properties [103]. We Analyzed HBPAH's MEP surface through the B3LYP/6-311G(d,p) level of theory, as shown in Figure 11. The negative red indicates the electrophilic sites at the oxygen atoms. Therefore, the oxygen atoms are the most effective target for nucleophilic attack, along with the most suitable sphere to attack the molecules' positive zones. The negative potential magnitude of HBPAH is −1.00 × 10 −2 to 1.00 × 10 −2 a.u. Green areas represent the region of zero potential. The blue areas of the HBPAH molecule situate over the hydrogen atoms. They show a combination of positive charges, demonstrating the nucleophilic localities.

Conclusions
In conclusion, we used a room-temperature sonochemical approach to synthesize crystalline (E)-2-((6-chloropyridin-2-yl)oxy)-N'-(2-hydroxybenzylidene)acetohydrazide. The SC-XRD study revealed the presence of attractive intermolecular forces for the structural stabilization in this Triclinic crystal system with P1 space group. The QT-AIM and Hirshfeld analysis revealed the presence of non-covalent interactions (NCIs); Scheme H5-N9, H38-N42, H16-O36, H8-O36, H19-O37, and H33-H53 that stabilize the structure of the compound. The NBO study showed that HBPAH has molecular stability of hyper-conjugation due to the intramolecular charge transfer (62.83, kcal/mol for LP1(N40) →π*(O36-C54)). The HOMO/LUMO energy band gap value describes the possible charge-transfer interactions, which occur inside the molecule. The calculated FMO energy bandgap of HBPAH is 3.634 eV, which illustrates it has intra-molecular charge-transferability and good NLO properties. The global reactivity descriptors calculation illustrates less reactivity and good stability. The MEP map displayed the negative red areas indicating the electrophilic sites at the oxygen atoms. All computational and experimental findings determined that HBPAH exists in stabilized crystal form because of non-covalent interactions (NCIs) and intra-and inter-molecular H-bonding interactions.

Conclusions
In conclusion, we used a room-temperature sonochemical approach to synthesize crystalline (E)-2-((6-chloropyridin-2-yl)oxy)-N -(2-hydroxybenzylidene)acetohydrazide. The SC-XRD study revealed the presence of attractive intermolecular forces for the structural stabilization in this Triclinic crystal system with P1 space group. The QT-AIM and Hirshfeld analysis revealed the presence of non-covalent interactions (NCIs); Scheme H5-N9, H38-N42, H16-O36, H8-O36, H19-O37, and H33-H53 that stabilize the structure of the compound. The NBO study showed that HBPAH has molecular stability of hyper-conjugation due to the intramolecular charge transfer (62.83, kcal/mol for LP1(N40) →π*(O36-C54)). The HOMO/LUMO energy band gap value describes the possible charge-transfer interactions, which occur inside the molecule. The calculated FMO energy bandgap of HBPAH is 3.634 eV, which illustrates it has intra-molecular charge-transferability and good NLO properties. The global reactivity descriptors calculation illustrates less reactivity and good stability. The MEP map displayed the negative red areas indicating the electrophilic sites at the oxygen atoms. All computational and experimental findings determined that HBPAH exists in stabilized crystal form because of non-covalent interactions (NCIs) and intra-and inter-molecular H-bonding interactions.