Investigation of the structural properties of hexadeca-substituted phthalocyanines by X-ray crystallography and NMR spectroscopy

Porphyrins, porphyrazines and phthalocyanines are a group of tetrapyrrole derivatives which are one of the class of compounds for intensive research on both basic and applied sciences in recent years. They have found applications as dyes and pigments due to their intense color. They are also used in energy conversion, optical data storage, gas sensor and liquid crystal application and photodynamic therapy against tumors. Unsubstituted phthalocyanine, 18-π electon aromatic system, has rigid planar structure and has low solubility in any solvent. To overcome this low solubility, phthalocyanines can be substituted from peripheral and non-peripheral positions such as alkyl and alkoxy groups. Overall phthalocyanine molecule can be fully substituted from sixteen positions. This type of substitution, hexadeca substituted phthalocyanines, are relatively less studied when compared to -tetra or -octa substituted counterparts; therefore, synthesis and studies of structural properties of hexadeca substituted phthalocyanine complexes are important. Today, one of the application areas of these phthalocyanines is photosensitizers in photodynamic therapy (PDT). They are considered as the second generation PDT agents. The compounds to be used in PDT should be water soluble and should have high singlet oxygen generation quantum yields. Water solubility can be achieved by substituting the macrocycle with cationic, anionic or noninonic groups. One of the disadvantages of a phthalocyanine PDT agent is aggregation tendency of these complexes in aqueous media. For this purpose, fully substituted phthalocyanines are expected to show low aggregation tendency due to sterical congestion around phthalocyanine macrocycle. In this work, synthesis of hexadeca substituted metal-free and metallo phthalocyanines carrying hydrophobic alkoxy groups on non-peripheral positions and quaternizable 3-(diethylamino)phenoxy hydrophilic groups on peripheral positions have been given. Their properties and structural features are investigated by spectroscopic methods. Quaternization of diethyl amino substituents yields water soluble derivatives of the complexes for potential PDT agents. The synthesis of phthalonitrile derivatives for target phthalocyanine complexes was achieved in three steps starting from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. In the first step, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone reduced to 4,5-dichloro-3,6-dihydroxyphthalonitrile, and then the subsequent alkylation of the OH groups with n-alkyl iodide (n-iodohexane, n-iodobutan and iodoetan) yielded 4,5-dichloro-3,6-dialkoxyphthalonitrile derivatives. In the last step, the displacement of one or two chloro groups of 4,5-dichloro-3,6-dialkoxyphthalonitrile with the OH function of 3-(diethylamino)phenol or 3-(dimethylamino)phenol by nucleophilic aromatic substitution reaction gave the desired phthalonitrile derivatives. When this reaction was carried out at room temperature, one of the chloro groups of 4,5-dichloro-3,6-dialkoxyphthalonitrile displaced with the OH function of 3-(diethylamino)phenol and compounds 6 and 7 were obtained. When the reaction was heated at 110 oC the main product was doubly displaced phthalontirile derivatives 8, 9 and 10. The structure of phthalonitrile compounds were characterized by FT-IR, EI-MS, MALDI-TOF MS, 1H and 13C NMR spectroscopic methods. Compounds 8 and 9 were also characterized by single crystal X-ray diffraction. The synthesis of zinc phthalocyanine derivatives of phthalonitrile compounds 6, 7, 8 and 10 has been achieved by microwave irradiation in n-pentanol in the presence of catalytic amount of DBU and zinc acetate as metal salt. The synthesis of 9H2 metal free phthalocyanine has been achieved by Linstead method starting with 9 phthalonitrile derivative in n-butanol and lithium metal followed by the demetallation of lithium with acetic acid. When this reaction is carried out in n-pentanol and lithium metal, in-situ generated lithium pentoxide gives transetherification reaction with the butoxy group on nonperipheral positions of the phthalocyanine, so the obtained phthalocyanine products are mixtures of compounds which carry butoxy or pentoxy groups on non-peripheral positions. Synthesis of metallo phthalocyanine derivatives 9Zn, 9Ni, 9Co, 9Cu, 9Mn and 9Mg have been achieved by refluxing metal-free derivative 9H2 in DMF with corresponding metal salts (Zn(OAc)2, NiCl2, CoCl2, CuCl2, MnCl2 and MgCl2). The diethylamino groups of 9H2, 9Zn, 9Ni and 10Zn have been quaternized with methyl iodide to give water-soluble octa-cationic derivatives 9H2Q, 9ZnQ, 9NiQ and 10ZnQ. Zinc derivatives are especially important for potential PDT agents. Due to high substitution the synthesized phthalocyanine complexes are very soluble in common organic solvents. All of the synthesized phthalocyanine complexes have been characterized by FT-IR, UV-Vis, MALDI-TOF, 1H and 13C NMR spectroscopic methods. In MALDI-TOF spectra, they showed corresponding molecular ion peaks for the phthalocyanine complexes. UV-Vis spectroscopy of the metallo phthalocyanine complexes in chloroform showed Q band absorption around 740 nm except manganese phthalocyanine which showed Q band at 823 nm. In the case of 9H2, metal-free phthalocyanine, the splitting of Q band absorption was not observed. The absorption maxima of 9H2 was observed at 765 nm with an accompanying shoulder at 740 nm. All of the synthesized zinc phthalocyanine complexes 6Zn, 7Zn, 8Zn, 9Zn, 10Zn and magnesium 9Mg have shown high proton affinity. In UV-Vis spectroscopy of chloroform or dichloromethane solution, additional red shifted band relative to Q band around 800 nm was observed due to acidic impurities in these solvents. This is attributed to protonation of meso nitrogens of phthalocyanine macrocycle. This behavior was not observed in case of nickel, cobalt, manganese and copper phthalocyanine derivatives. To understand the effect of coordinated metal on proton affinity of phthalocyanine derivatives, thermodynamic calculations have been performed with Density Functional Theory (DFT) computational chemistry methods. Unsubstituted copper(II), zinc(II), nickel(II) and magnesium(II) phthalocyanines have been modelled for this purpose. The calculations are performed using B3LYP functional and on Def2-TZVP level of theory. The obtained results showed that the protonation of the ring is favored in case of zinc(II) and magnesium(II) phthalocyanine, but it is not favored in case of nickel and copper. Overall the theoretical results are in harmony with the experimental observations. Furthermore, protonated form of 9Zn showed a signal at 15 ppm in 1H NMR spectrum, and methylene protons of n-butoxy chain on nonperipheral position of the phthalocyanine molecule was observed as diastereotopic. This implies that the two faces of the phthalocyanine molecule are not identical, and one negatively charged ion is coordinated to zinc center from the axial position. It can be concluded that the zinc complexes synthesized in this work function as proton sensor in solution. 1H and 13C NMR studies of diamagnetic phthalocyanines synthesized in this work showed the expected signals. Among the synthesized complexes, 6Zn and 7Zn were obtained as a mixture of four constitutional isomers; hence, their NMR spectra were more complex compared to symmetric 9Zn and 10Zn derivatives. Metal-free phthalocyanine inner N-H protons were normally observed in negative chemical shift region as broad signals. N-H protons of 9H2 complex were observed at 0.4 ppm in 1H NMR spectra. This is because of the reduction of the aromaticity of the phthalocyanine molecule due to highly substitution. When we look at the 13C NMR spectra, 9Zn and 9Mg complexes have shown very similar spectra. 9Ni and 9H2 complexes differ from these two in several ways. The closest carbon atoms to the phthalocyanine center in 13C NMR of 9H2 is not observed at room temperature due to N-H tautomerization. However, when the spectra is acquired at 55 oC, it is observed as a broad signal at 149 ppm. 13C NMR spectra of 9Ni complex 7 ppm upfield shift is observed for the closest carbon atom to the metal center with respect to 9Zn and 9Mg derivatives. From NMR point of view, this implies that the coordination character of Ni metal is different from that of Zn and Mg. For paramagnetic molecules, the nature of the detectability of the NMR signals and their shifts depend on the electron relaxation times of the paramagnetic center and the spin delocalization pathways from metal center to the nuclei in question. Among paramagnetic metal containing 9 phthalocyanine derivatives, 9Co complex has small magnetic anisotropy and cobalt center has fast electron relaxation time (10-11 s), the structure is symmetrically substituted and has low aggregation tendency. All this features of the complex make it suitable candidate for liquid state high resolution NMR research. Experimentally all of the proton NMR signals are observed in NMR spectra of 9Co. In 13C NMR spectra of 9Co only the signal of the closest carbon atom to the metal center is not observed at room temperature. This is probably due to the fast relaxation of this carbon atom. The closest proton is seven bonds away from the metal center, so the observed hyperfine chemical shifts can be considered as pseudocontact chemical shifts. The pseudocontact chemical shift arises from the dipolar interactions between the nuclei and the paramagnetic center, so it depends on the distance between the cobalt center and the nuclei in question. All of the proton signals showed positive paramagnetic chemical shifts with respect to diamagnetic zinc derivative 9Zn. For example, the observed paramagnetic chemical shifts for nonperipheral substituent n-butoxy chain are 4.39, 2.25, 1.38 and 0.65 ppm respectively from O-CH2 protons to CH3 protons. Qualitatively, this is in agreement with the distances of the protons with respect to the metal center. All proton chemical shifts of the 9Co were towards the diamagnetic positions with the addition of pyridine to NMR solution of 9Co in CDCl3. In addition, the linewidths of the signals increased. On the other hand, with the addition of pyridine to the NMR solution additional signals were observed except from paramagnetic complex. The observed signals probably belong to the different species and diamagnetic. This solution was kept in aerobic conditions for two weeks and its NMR spectra were acquired. The spectrum showed that while the intensity of the signals from paramagnetic species decreased, the intensity of the signals from diamagnetic species increased. This implies that the cobalt center was chemically oxidized from cobalt(II) to cobalt(III) in basic media. Quaternized water soluble derivatives, 9H2Q, 9ZnQ, 9NiQ and 10ZnQ, have shown sharp Q band in water similar to DMSO or DMF solutions. This implies that the low aggregation tendency of these complexes, and this makes them possible candidate for PDT applications. The singlet oxygen generation capability of quaternized water soluble phthalocyanine derivatices was detected qualitatively by monitoring the disappearance of the 415 nm absorbance of 1,3-diphenylisobenzofuran (DPBF). UV–Vis spectra of a solution containing DPBF and the phthalocyanine derivative (10ZnQ or 9ZnQ) were recorded in 5 s intervals while the sample was being irradiated at 650 nm. During this process the phthalocyanine absorption did not change, while the absorption of DPBF at 415 nm decreased, which confirms that 10ZnQ is an efficient singlet oxygen generator. Suitable single crystals of 9H2, 9Ni, 9Zn and 8Zn are obtained and the structures are characterized with X-Ray diffraction. All the complexes were crystallized in tricilinic unit cell and in P_1 space group. Only 9Zn complex has two molecules in unit cell and one of these molecules corresponds to asymmetric unit. The other complexes contain only one molecule in unit cell and asymmetric unit is half of the molecule. While 8Zn complex has two THF molecules coordinated to zinc metal and its coordination geometry is octahedral, 9Zn complexes have one pyridine molecule coordinated to zinc center and its coordination geometry is square pyramidal. 9Zn complex is highly disordered on alkyl chains but the phthalocyanine core structure is very well defined and the zinc metal is 0.45 Å above the plane of eight nitrogens of phthalocyanine macrocycle. 9H2 and 9Ni crystallize in very similar unit cell and they only differ in the conformations of the substituents. The structures are fully substituted; therefore, due to steric congestion around phthalocyanine macrocycle, distortion of planar core is expected in these types of phthalocyanine molecules. The analysis of solid state structures indicates that phthalocyanine macrocycle distortion dictated by the conformation of substituents on benzo units is observed as tilt or twist of benzo units with respect to the plane of eight phthalocyanine nitrogens. Furthermore, due to full substitution, phthalocyanine-phthalocyanine distances in solid state are larger; hence, π-π interactions are diminished. For example, the closest distance in between phthalocyanine-phthalocyanine pi-pi centers is 6.89 Å for 9H2. This also agrees with the low aggregation tendency of these complexes in liquid state.