Synthesis, DFT Calculations, Photophysical, Photochemical Properties of Peripherally Metallophthalocyanines Bearing (2-(Benzo[d] [1,3] Dioxol-5-Ylmethoxy) Phenoxy) Substituents

Abstract 4-(2-(benzo[d] [1,3] dioxol-5-ylmethoxy) phenoxy) phthalonitrile was first prepared as a starting material. Then, this new phthalonitrile derivative was reacted with Zn and Co salts to obtain new phthalocyanine complexes. Phthalocyanine complexes were evaluated by fluorescence emission, extinction, and absorption measurements. Aggregation studies show compliance with the lambert-beer law in the concentration range studied for peripheral phthalocyanine compounds. The density functional theory calculations of the metallophthalocyanines compounds were performed using the B3LYP method- LanL2DZ basis set to derive structural optimization, HOMO-LUMO energy parameters, and nonlinear Optical properties. The calculated values of metallophthalocyanines with different center atoms were obtained close to each other. Molecular electronic surface maps of the studied compounds are mapped and discussed. The HOMO-LUMO energy gaps of our compounds studied are around 2.1 eV. The docking studies were performed with the phthalonitrile.


Introduction
Phthalocyanines have been a subject of interest for research for nearly a century. Promising results have been achieved in many areas. It is produced and used for fifty tons of paint industry worldwide. 1,2 Besides, it is used in many fields such as catalyst, 3 sensor, 4,5 liquid crystal, 6 optical data storage, 7,8 solar cells. 9 Photodynamic therapy, which is one of the cancer treatment methods, is being researched as the subject of intensive research. [10][11][12] As an alternative to chemotherapy and radio therapy, which are currently used in cancer, potodynamic therapy is preferred in terms of nontoxic and daylight application. The synthesis of phthalocyanine compounds capable of producing appropriate singlet oxygen excites researchers. For this purpose, many scientific articles on phthalocyanines are published annually. Obtaining new functional and soluble phthalocyanines from these publications is seen as an important objective. [13][14][15][16] Phthalocyanines are used to produce new and functional materials to meet today's needs. New substitute groups are formed by connecting to the peripheral and non-peripheral or axial positions of the phthalocyanines. 17 One of the main goals of phthalocyanine chemistry is to provide the use of this compound in photodynamic therapy for sensor and therapeutic purposes. 18 In addition to the research of the present compounds, there is a need for alternative studies with the synthesis of new phthalocyanine 4-(2-(Benzo[d] [1,3] dioxol-5-ylmethoxy) phenoxy) phthalonitrile (4) 2-nitrophenol 1 (0.402 g, 2.89 mmol) and 4-nitrophthalonitrile 2 (0.500 g, 2.89 mmol) in 25 mL dimethylformamide (DMF) was stirred at room temperature under nitrogen atmosphere. After stirring for 30 min, piperonyl alcohol 3 (0.439 g, 2.89 mmol) was added into the mixture. After stirring for 15 min, K 2 CO 3 (2.2 g, 16 mmol) was added into the mixture over a period of 2 h. The reaction mixture was further stirred for 42 h at room temperature. The reaction mixture was poured into cold water (ics) (150 mL) and stirred. The precipitate was filtered off, washed with water to neutralize it, the product was dried in a vacuum oven at 80 C.  [1,3] dioxol-5-ylmethoxy) phenoxy) phthalonitrile 4 (0.050 g, 0.135 mmol) and ZnCl 2 (0.015 g) mixture was powdered in a quartz crucible and heated in a sealed glass tube for 5 min 210 C in the presence of DBU (2 drops). After reaching room temperature, the product was washed with hot and cold water, ethanol, methanol. The product soluble in THF was collected and the solvent was removed to obtain a green solid. This compound is soluble in dichloromethane, CHCl 3 [1,3] dioxol-5-ylmethoxy) phenoxy) phthalocyaninato) cobalt(II) (6) A mixture of 4-(2-(benzo[d] [1,3] dioxol-5-ylmethoxy) phenoxy) phthalonitrile 3 (0.050 g, 0.135 mmol) and CoCl 2 (0.015 g) mixture was powdered in a quartz crucible and heated in a sealed glass tube for 5 min 210 C. After reaching room temperature, the product was washed with hot and cold water, ethanol, methanol. The product soluble in THF was collected and the solvent was removed to obtain a green solid. This compound is soluble in ethanol, THF, DMF, DMSO. MP >300 C. Yield: 0.035 g (67.37%
Vibration of aromatic (C-H) peak in the IR spectrum of compound number 4 is 3086 cm À1 , (CH 2 ) vibration 2926 cm À1 , (CN) vibration 2233 cm À1 , (Ar-O-Ar) vibration 1249 cm À1 , (C ¼ C) vibration peaks were observed at 1564 and 1500 cm À1 . The vibration peaks observed here are compatible with the expected structure. The most prominent change is observed in nitrile peaks after the conversion of this compound to zinc and cobalt phthalocyanine compounds. In the formation of phthalocyanine compounds that do not contain substituted nitrile groups, the nitrile peak present in the starting material completely disappears after the starting material is converted to phthalocyanine. 19 The nitrile peak observed in this study is also not seen in phthalocyanine compounds. Vibration peaks for phthalocyanine 5 were observed as aromatic (C-H) at 3084 cm À1 , (CH 2 ) at 2926 cm À1 , (C ¼ C) at 1598 cm À1, and (Ar-O-Ar) at 1234 cm À1 . Finally, the vibrations of phthalocyanine 6 were observed at aromatic (C-H) peak 3018 cm À1 , (CH 2 ) 2970 cm À1 , (C ¼ C) 1598 cm À1 , (Ar -O -Ar) peak at 1238 cm À1 peaks appear to be in good harmony.
As expected in the 1 H NMR spectrum of compound 4 in DMSO-d 6 , aromatic protons were observed as multiplets in the 8.18-6.93 ppm range. (CH 2 ) protons located between oxygen and oxygen among the aliphatic protons were observed at 6.01 ppm, while the (CH 2 ) peak bound to single oxygen was observed at 5.14 ppm. The 13 C NMR spectrum of the compound in DMSO-d 6 also gives the peaks of the expected aromatic and aliphatic carbon atoms of the compound. Here, the carbon peaks of (CN) were observed at 116.68-116.15 ppm, the aromatic carbon peaks at 162.09-106.50 ppm, the carbon peak of the (CH 2 ) atom between oxygen and oxygen at 101.59 ppm, and the carbon peak of single oxygen-bonded (CH 2 ) at 70.92 ppm. These observed peaks are in good agreement with the structure of the compound. 1  protons in DMSO-d 6 are observed as multiplets between 7.24-6.07 ppm, while aliphatic (CH 2 ) protons are observed at 6.00 ppm and 5.54 ppm. Due to its paramagnetic nature, 1 H NMR measurements of compound 6 were not made.  Another spectral instrument related to the structure of phthalocyanines is UV-Visible spectroscopy. It gives the absorbance value for the Q and B bands that are characteristic for phthalocyanines. 20 While the Q band of the phthalocyanine compound is observed as a single peak when metal is attached, it is observed as a cleavage in the Q band in metal-free phthalocyanine compounds. 21,22 For the phthalocyanines 5 and 6, the Q band absorption values in the THF solvent were measured as 676 and 668 nm, respectively. The B band of compound 5 was found to be 348 nm. These values are consistent with the tetra peripheral substitute structure. The absorption values of these compounds measured at different concentrations in THF are given in Figures 4 and 5. In addition, the electronic absorption of phthalocyanine 5 and 6 complexes in different solvents such as CH 2 Cl 2 , CHCl 3 , THF, DMF, and DMSO is shown in Figures S1 and S2. As can be seen from these diagrams, these phthalocyanine compounds exist as monomers in the measured concentration range. This shows that it may be useful for some areas that wish to be nonaggregated (such as photodynamic therapy).
One of the foremost applications of phthalocyanine compounds is their use as a sensor agent in photodynamic therapy. For this application, the compound should exhibit fluorescence. The data obtained from fluorescence absorption, excitation, and emission spectra reveal fluorescence properties. Fluorescence absorption, excitation, and emission spectra of the zinc phthalocyanine compound observed is shown in Figure 6. Stokes shifts are within the expected range for the phthalocyanine compound. The Stokes shift detected in tetrahydrofuran for this phthalocyanine is 10 nm. The fluorescence emission was measured at 694 nm, while the excitation value was 682. The quantum yield of this compound (U F ) was calculated as 0.30. This value is higher than the unsubstituted zinc phthalocyanine value. 23 These spectral values are consistent with the studies given in the literature. 24,25 These data strengthen the possibility that the compound can be used as a sensor. . Aggregation of compound 5 in 6.46 Â 10 À6 , 5.17 Â 10 À6 , 4.14 Â 10 À6 , 3.31 Â 10 À6 , 2.65 Â 10 À6 , 2.12 Â 10 À6 , 1.69 Â 10 À6 concentrations.  In addition to the fluorescence properties and fluorescence quantum efficiencies of the photosensors considered for photodynamic therapy, they can show an effective photosensor effect with their ability to produce singlet oxygen. In this study, a chemical method was used for the singlet oxygen production test to determine the photosensory ability of the zinc phthalocyanine compound. The singlet oxygen quantum yield (U D ) of phthalocyanines 5 was determined in DMSO by using 1,3-diphenylisobenzofuran (DPBF) as a singlet oxygen quencher. During the measurements, the Q bands of phthalocyanine compound 5 did not change, while a decrease in DPBF absorbance was observed due to the reaction of singlet oxygen with DPBF (at 417 nm) (Figure 7). The U D value of compound 5 (U D ¼ 0.57) was found to be lower than Std-ZnPc. 26 Here, one of the factors that can affect singlet oxygen production is substituted (2-(benzo [d] [1,3] dioxol-5ylmethoxy) phenoxy) groups. The other is the electronic structure of the selected metal atom.

Quantum chemical calculation instructions
DFT calculations 27,28 used in phthalocyanine compounds were carried out using the method coded B3LYP/LanL2DZ basis set of this method in the Gaussian 09 program. 29 Within the scope of this study, optimization of metallo phthalocyanines in the gas phase and ground state was performed. Molecular orbital energies were calculated especially in phthalocyanine minimum energy optimization. The log and chk extension files obtained from the program were visualized with the program named Gauss View 6 and numerical data were transferred to tables.

Structure details and analysis
The molecular structure optimized by the method of the phthalocyanines 5,6 compound is shown in Figure 8, together with the bond length values. The optimized structural parameters calculated with the DFT/B3LYP -LanL2DZ basis set are determined. Here the planar structure of the nucleus of the phthalocyanine compound is obtained. The bond lengths and angles between the optimized molecular atoms were compared for MPcs given in Table 1. When comparing the two MPcs, the bond lengths of the M-N atoms in phthalocyanine nuclei were calculated as 2.02 Å in Zn-N24 and 1.95 Å in Co-N24 with B3LYP/LanL2DZ, respectively. In the phthalocyanines 6, bond lengths were shorter. The small differences between them are due to the sensitivity of the methods and the metal atoms' radii. In the optimization, the phthalocyanine nucleus has a planar structure and the metal atom is positioned at an angle of about 90. Dihedral angles of

HOMO and LUMO analysis
Quantum chemical calculations are widely used to calculate basic electronic parameters related to orbitals in the molecule. As frontier orbital molecules, the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) are important. 31 However, by using these values, the activity parameters and energy deficit of the molecule are calculated and the chemical character of the molecule is determined. Perturbation MO theory is based on the energy difference between HOMO and LUMO. [32][33][34] The closer the energy levels of the interacting molecular orbitals to each other, the stronger the interaction. That is, the smaller the HOMO -LUMO energy difference, the stronger the interaction of the reactants and the easier the reaction. 35 The calculated results and their comparison for the MPcs are presented in Table 2. Figures 9 and 10 is the density orbital representation of the HOMO and LUMO of the compounds 5-6 in both methods. LUMO þ 1 and HOMO-1 graphs of the compound were also taken. Frontiers orbitals of the compound 5, HOMO À4.96 eV LUMO À2.82 eV value and for compound 6, HOMO À4.96 eV LUMO À2.77 eV values at DFT/B3LYP/LanL2DZ level were calculated. The HOMO and LUMO, frontiers orbitals also help determine the degree of activity and interaction of the molecule with other species. 36-38 HOMO, LUMO, and the chemical reactivity descriptors of the compounds 5-6 calculated in the DFT method were correlated and shown in Figure 11. In the comparison of band gap and other orbital energies, it was slightly higher in phthalocyanine with cobalt atoms.

Nonlinear optics analysis
The dipole moment, which is the specialty of energy, is applied intramolecular. [39][40][41] The dipole moment consists of Van der Waals-type intermolecular interactions and intermolecular attraction is strong. The electronic dipole moment and total dipole moment are listed in Table 3.
The dipole moment, molecular polarization and hyperpolarization values should be calculated to determine nonlinear optical properties. 33,[42][43][44] In the compound 5, the parameters are respectively l ¼ 8.4 D, a ¼ 598.6 au, b ¼ 5.13 Â 10 À31 esu. Also, in the compound 6 the parameters are respectively l ¼ 8.4 D, a ¼ 593.5 au, b ¼ 5.08 Â 10 À31 esu. Compound 5 was higher than compound 6 due to the difference in the central atom, dipole moment and other related parameters. According to these values, the molecule has parametric quantities that can be considered as nonlinear optics materials.

Molecular electrostatic potential
Molecular electrostatic potential (MEP) maps provide information about the electronic charge distribution of a molecule. The density of the electron distribution on the molecule is useful for illuminating bonds with descriptors such as polarity, electronegativity. The electronic structure and molecular reactivity of complex molecules can exhibit rich topographic properties. 32,42,[44][45][46] In this study, electrophilic potential (MEP) maps of three phthalocyanine molecules were obtained. As shown in Figure 7 they are visualized with MEP maps at the DFT/B3LYP method with LanL2DZ basis set using the GaussView 6.0 software. The MEP maps show that the region characterized by the blue color around the Zn and Co atoms has positive values. The red regions on the map indicate the region rich in electrons. The aromatic ring region shows an almost neutral potential, most of which is represented by a yellow-green color. Contour maps of phthalocyanines confirm negative and positive potential parameters in accordance with the electrostatic potential map (ESP). The phthalocyanine nucleus in the structures shows the delocalized structure and high stabilization with green-yellow colors in color. Moreover, in the MEP maps, the negative potentials are mainly found in, for example, O-107 and O-118, while the potential occurring around the H-147 atom is the most positive. In terms of electronegativity, oxygen atoms can be interpreted higher than other atoms.

Molecular docking analysis
The protein crystal structure of different enzymes was selected for the compound 4 in the Protein Data Bank (http://www.rcsb.org). From these complexes, PDB codes were selected and retrieved from the Protein Data Bank. As protein receptors, human carbonic anhydrase isozyme II (PDB ID: 6R6F), acetylcholinesterase (PDB ID: 4RVK), and butyrylcholinesterase (PDB ID: 6SAM) enzymes were used. The Docking studies were performed using the commercial software Schrodinger suite Maestro version 10.2. 47 Ligand preparation and protein preparation via LigPrep, and Protein preparation modules were used in accordance with the previous studies. [48][49][50] In addition, enzyme inhibition in-silico study compound 4 was conducted in this study. Enzyme binding affinity was found as À5.24 and 7.67 kcal/mol and gave well results. The best docking poses were selected for analysis of interactions, and protein-ligand interaction was presented with Discovery Studio Client 2017 software.
Computational ADME modeling is a very mature but still-developing field. In silico ADME tools are routinely applied to drug design. 51 The synthesized compound 4 also complied with the drug similarity rules and displayed acceptable predicted ADME properties. In the analysis made on SwissADME: Drug similarity was evaluated a free web tool to evaluate. In this analysis, it was found to be compatible compared to the Lipinski (Pfizer) filter. The online servers SwissADME  (http://www.swissadme.ch/index.php) were employed to check the chemo-informatics and biological properties of this ligand molecule.
The compound 4 with (6SAM BChE) had the most effective coupling score (-7.69 kcal/mol) and good binding affinity was obtained ( Figure 12). Here, when the ligand interactions with protein residues are evaluated, the strongest bindings were line up as TRP82 3.09 Å conventional Figure 11. The correlation graphs of chemical reactivity descriptors between phthalocyanines 5-6 with DFT/LanL2DZ.     Finally, in another docking with receptor 4RVK AChE, a docking score of À5.24 kcal/mol was obtained. This docking complex, respectively ASP148 exhibited interactions with 4.84 Å pi-anion, GLU91 4.47 Å pi-anion, VAL23 4.30 Å pi-alkyl, LEU137 5.26 Å and 5.37 Å pi-alkyl, LEU15 4.05 Å pi-alkyl, and TYR86 3.08 Å conventional hydrogen bonds ( Figure 13). Here, it was determined that the phthalonitrile compound on the three enzyme proteins exhibited good performance in enzyme inhibition. The ligand-receptor binding score in the docking study also correlated well with the published data. 53,54 Conclusion In this study, 4-(2-(benzo[d] [1,3]dioxol-5-ylmethoxy)phenoxy)phthalonitrile (4) was synthesized as a starting material. From the reaction of this starting material with zinc and cobalt salts, zinc(II) and cobalt(II) phthalocyanine complexes (5-6) were synthesized. Compounds (4-6) were characterized by IR, UV, NMR and mass spectroscopy methods. Non-agglomeration properties of phthalocyanine compounds and fluorescent emission properties of zinc phthalocyanine compounds and its ability to produce singlet oxygen were investigated. Quantum chemical calculations show that both phthalocyanine complexes have very similar structures in the gas phase. We used the DFT/B3LYP method with the LanL2DZ basis set to determine and analyze the geometric optimization of MPcs. The dipole moments of compounds 5-6 were calculated as 8.00 and 8.38 Debye, respectively. This value gives the potential to be used as nonlinear material. In addition, the starting material phthalonitrile molecule was also docking studied in terms of compliance with drug similarity rules and it was observed that it exhibited acceptable predicted ADME properties.