Synthesis and development of new fluorenyl substituted phthalocyanines for biological applications

Abstract

Phthalocyanines (Pc) are macrocyclic compounds. They belong to the porphyrinoid family and have close structural similarity to important biological molecules such as heme, vitamin B12, and chlorophyll. Even though they are structurally similar to natural porphyrins, Pc's are recognized by the existence of an additional benzene ring. The ring is attached to each of the four pyrrole units. This property helps electron delocalization, and it also increases the absorption. The basic form of Pcs includes four isoindole subunits connected by nitrogen bridges, helping to form a macrocyclic framework. This arrangement helps Pcs coordinate multiple metal ions in their core and makes them adaptable for many uses. The added benzene rings to the Pc structure also improve the π-conjugation system. It causes strong absorption and promotes efficient electron transmission. These features make phthalocyanines useful in many fields, such as photonics, optoelectronics, and molecular electronics. Their potential to absorb and transmit electrons has attracted researchers toward their applications in advanced technology. Since their accidental discovery in 1928, phthalocyanines (Pcs) have gained economic significance, especially as blue and green pigments with excellent optical properties. These macrocyclic compounds are used in many industrial and pharmaceutical fields because of their vital light-absorbing and emission characteristics, in addition to their role as colorants. Phthalocyanines and their metal derivatives (MPCs) have gained interest as dyes and pigments, as well as basic components in molecular materials for electrical and optoelectronic applications. Their exceptional electrical instability increases their useful properties in various scientific and technical areas. Phthalocyanines have excellent photostability and absorbance in the red spectral range (about 680–700 nm), corresponding to the "therapeutic window" of photodynamic therapy (PDT). Their significant absorption in the far-infrared and near-infrared spectrum (600–850 nm), due to increased tissue penetration and singlet oxygen production, improves their performance as second-generation photosensitizers for photodynamic therapy. Phthalocyanines show an important quantum yield for singlet oxygen generation. This property enables them to easily cause cell death by necrosis and apoptosis when exposed to light. This feature makes them appealing candidates for medical uses, particularly in cancer therapy and antimicrobial medications. Phthalocyanines, due to their complex electrical properties, can exhibit unpredictable spectral patterns depending on the environment in which they are present. Molecular aggregation, electron transfer, and acid-base balance affect their optical properties. At higher concentrations, aggregation causes significant spectral changes, while at lower concentrations, interactions with small impurities can produce protonated, oxidized, or demetallated species. Because of their high molar extinction coefficients (about 105 M⁻¹ cm⁻¹), precise concentration control is necessary for continuous spectral investigations. xxiv A major challenge in the application of phthalocyanines is their restricted solubility in common organic solvents. This restriction can be avoided by the addition of appropriate substituents into the ring structure. With the use of appropriate substituents in Pcs, solubility in common organic solvents or water can be achieved and the aggregation problem can be eliminated. In addition, by inserting different metal ions to the Pc ring cavity, both the solubility problem can be improved and the spectral properties can be changed according to the purpose of use. The functionality and flexibility of Pcs in this way enable them to be continuously researched for new applications and technological developments. Fluorene is an aromatic compound characterized by two peripheral phenyl rings fused to a core five-membered carbon ring. This chemical structure offers several unique features, including exceptional thermal stability, efficient charge transport ability, broad band gaps, and significant fluorescence quantum yield. A notable feature of fluorene's chemistry is the acidic nature of the proton at the sp³-hybridized carbon in the C9 position. The strong acidity makes the molecule particularly reactive in basic conditions. It facilitates specific changes at this location. These changes can improve solubility and processing efficiency, hence facilitating their application in the production of fluorescent compounds. Due to all these properties, fluorene-based materials and polyfluorenes are generally used as fluorescent chromophores, photocatalyst, and recently they have also been used in organic light-emitting diodes and organic photovoltaics. Although there are many studies in the literature on porphyrins bearing fluorene groups, only a limited number of studies have been conducted on phthalocyanines. Based on these observations, in the present thesis, a novel phthalonitrile compound 4-((9,9-bis(5-hydroxypentyl)-9H-fluoren-2-yl)ethynyl)phthalonitrile (4) was successfully synthesized. This molecule features dialkyl-substituted fluorene moieties connected to the periphery of tetra-substituted zinc (ZnPc (5)) and indium (InPc (6)) phthalocyanines through an ethynyl linker. The synthesized new ligand (4) and phthalocyanines (5, 6) were characterized by spectroscopic methods. The resulting phthalocyanine complexes, designated as zinc (5) and indium (6), were evaluated for their photophysical and photochemical characteristics, including fluorescence behavior and the ability to produce singlet oxygen. Additionally, this study represents the first exploration of the biological activity of phthalocyanines incorporating bis(hydroxypentyl)-functionalized fluorene units. In the first part of the thesis, 4-((9,9-bis(5-hydroxypentyl)-9H-fluoren-2-yl)ethynyl)phthalonitrile (4) was synthesized from 2-bromofluorene in 4 steps with 74% yield. Then, ZnPc (5) and InPc (6) were obtained from the reaction of phthalonitrile compound (4) with zinc and indium salts (Zn(CH3COO)2 and InCl3) in the presence of DBU in n-pentanol. Phthalocyanines 5 and 6 are a mixture of isomers due to the fact that the starting phthalonitrile (4) carries a single substituent at the 4-position. Characterization results of the synthesized new compounds confirmed their structures. In the second part of the thesis, photochemical and photophysical measurements of the synthesized phthalocyanines (5, 6) were made using fluorescence and UV-Vis devices. By taking the fluorescence spectra of phthalocyanines (5, 6), fluorescence quantum yields (ΦF), fluorescence (τF) and radioactive (τ0) lifetimes and Stokes shifts were calculated. Additionally, singlet oxygen and photodegradation quantum yields were calculated using UV-Vis measurements. xxv In the last part of the thesis, studies were carried out to determine the biological activities of zinc (5) and indium phthalocyanines (6). Both ZnPc (5) and InPc (6) demonstrated promising results, showing significant antioxidant effects, as well as efficient DNA cleavage performance. Considering their singlet oxygen production, spectral results and biological activities, the Pcs (5, 6) obtained in the thesis are potential candidates for application in photodynamic therapy.