Sitozin türevi içeren yeni tip ftalosiyaninlerin sentezi ve karakterizasyonu = Synthesis and characterization of new types of phthalocyanines containing cytosine deriveatives

Abstract

Ftalosiyaninler, delokalize 18 π elektron sistemi içeren çok önemli aromatik makrosiklik bileşiklerdir. Benzersiz elektronik, optik ve yapısal özellikleri vardır. Periyodik tablodaki birçok metal ile kompleks oluşturabildikleri gibi, halka pozisyonlarına farklı fonksiyonel gruplar takılabildiği için birçok alanda kullanılabilmektedirler. Bu çalışmada, başlangıç materyali olarak yeni 3-(4- aminopirimidin-2-iltiyo) ftalonitril (1) sentezlenmiş ve moleküler yapısı tek kristal X- ışını kırınımı (XRD) deneyi ile doğrulanmıştır. Sonrasında sitozin türevi içeren bu başlangıç maddesi kullanılarak periferik olmayan (non-periferol) pozisyonlarından kükürt köprüleriyle bağlı tetra sübstitüye bakır ve kobalt metalli ftalosiyaninleri (2,3) ve onun metillenmiş türevleri (2a,3a) sentezlenmiştir. Sentezlenen bütün bileşikler sıcak ve soğuk organik / inorganik çözücülerle yıkama ve kolon kromotografisi gibi yöntemlerle saflaştırılmıştır. Sentezlenen bütün bileşiklerin yapıları elementel analiz, UV-Vis, FT-IR, 1H- ve 13C-NMR ve Maldi TOF yardımıyla doğrulanmıştır.

Phthalocyanines are important aromatic macrocyclic compounds with a delocalized 18 π-electron system. Phthalocyanines exhibit many unique properties that attract great interest in different scientific and technological fields such as antioxidant, antibacterial and photodynamic therapy (PDT), etc. They possess unique electronic, optical, and structural properties. Due to their ability to form complexes with various metals in the periodic table and the ability to attach different functional groups to their ring positions, they can be used in a wide range of applications. In order for phthalocyanines to be used easily in biological applications, it is preferred that they have water solubility. Phthalocyanines differ in both their solubility and applicability, depending on the property of their functional group such as carboxylates, sulfonates, phosphonates, and quaternarized amino groups. This can be achieved by attaching at the peripheral, non-peripheral and axial positions of the Pc ring and/or by inserting different central metal ions into the inner core of phthalocyanines. Such phthalocyanines are highly likely to be useful in biological applications. At the beginning of this study, a new starting material called 3-(4-aminopyrimidin-2- ylthio) phthalonitrile (1) was synthesized and its molecular structure was confirmed by single crystal X-ray diffraction (XRD) experiment. To summarize briefly, 3-(4- aminopyrimidin-2-ylthio) phthalonitrile (1) was synthesized first as a starting material by reacting 2-thiocytosine/4-Amino-2-thiopyrimidine and 3-nitrophthalonitrile in the solvent of dry DMF containing anhydrous K2CO3 at room temperature under nitrogen atmosphere for about 2 days. After some purification procedures such as column chromatography, it was crystallized in methanol-acetone (1/1 (v/v)) to remove impurities, allowing it to crystallize out of the solution, and isolating it by filtration, giving a pure crystal product. Then, its molecular structure was verified by the experiment of single crystal X-ray diffraction. A colourless and plate type single crystal specimen with a dimension of 0.29 × 0.16 × 0.12 mm has been used in the experiment. The XRD data has been collected at room conditions (296 K) by using a Bruker APEX II QUAZAR three-circle diffractometer. Besides, the crystal stabilization dynamics and Hirshfeld surfaces have been investigated by analysing the obtained crystallographic information file (cif, CCDC No: 2068429) using PLATON and Crystalexplorer softwares, respectively. The XRD experiment shows that an orthorhombic (Pca1) unitcell has formed for the investigated single crystal. Where, the unitcell dimensions are a = 23.702 Å, b = 3.910 Å, c = 12.693 Å and,  =  =  = 90°. In the unitcell, there are four C12H7N5S molecules. In the FT-IR spectrum of 3-(4-aminopyrimidin-2-ylthio) phthalonitrile (1), the -NH2 group in 3-(4-aminopyrimidin-2-ylthio) phthalonitrile (1) was observed at 3426 cm-1 (asymmetric N-H stretch), at 3332 cm-1 (symmetric N-H stretch) and at 3205 cm-1 (N- H bend overtone) as well as the strong peaks such as NH2 scissors at 1638 cm-1 and out-of-plane bend at 717 cm-1 . In the 1H-NMR and 13C-NMR ([d6]-DMSO) spectra of xxii the starting material (1), the proton signal of the –NH2 group was observed at 7.15 ppm as a singlet. The carbon signals (ppm) of (1) appeared at 167.88, 164.11, 155.89, 141.69, 136.48, 134.88, 134.81, 122.07, 116.87, 116.47, 115.45, 103.35. In MALDI- TOF MS (Dithranol, m/z), the obtained results that is consistent with the targeted structures confirmed the structures of all compounds used in this study. The protonated ion peak of the starting material (1) was observed at high intensity as 253.742 [M]+ . Subsequently, using this starting material containing cytosine derivatives, non- peripherally substituted tetra-substituted copper and cobalt metallophthalocyanines (2,3) and their methylated derivatives (2a,3a) were synthesized, where sulfur bridges were attached from the non-peripheral positions. The phthalocyanines (2,3) were synthesized by using this starting material "3-(4-aminopyrimidin-2-ylthio) phthalonitrile (1)" and anhydrous metal salt (copper (II) chloride/cobalt (II) chloride) in the solvent of dry N,N-dimethylaminoethanol (DMAE) (2 mL) containing a catalytic amount of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) at reflux temperature with stirring for 8 hours. Finally, quaternization process was used to give phthalocyanines (2,3) water solubility. Therefore, the synthesis of the methylated derivatives (2a,3a) was carried out with the help of dimethyl sulfate (DMS), quaternizing agent in DMF solvent at 120 °C. Both compounds (2a,3a) are well soluble in water as well as solvents such as DMSO and DMF. All synthesized compounds were purified by using methods such as washing with hot and cold organic/inorganic solvents and column chromatography. All the compounds used were characterized with various spectroscopic methods such as UV-Vis, FT-IR, 1H-NMR, 13C-NMR and MALDI-TOF MS by obtaining highly satisfactory results. All chemicals were purchased from commercial suppliers and used without purification. FT-IR spectra were recorded on a Shimadzu IR-Prestige-2 spectrophotometer. 1H- NMR and 13C-NMR spectra were recorded on a Bruker 300 MHz spectrometer. Routine. UV-Vis spectra were recorded on an Agilent Model 8453 diode array spectrophotometer. Mass spectras (MS) were analyzed by Bruker microflex LT MALDI-TOF MS. In UV-Vis spectroscopy, phthalocyanine compounds give two important strong absorption peaks called Q band and Soret band (B). UV-Vis spectra of the synthesized phthalocyanines (2,3) were investigated in DMSO solvent and according to the results obtained, the Q band absorptions were observed as a single like typical metallophthalocyanines at 698 nm and at 685 nm, respectively. The Soret (B) band absorptions, another important peak indicating the formation of phthalocyanines (2,3), were also observed at 359 nm and 349 nm, respectively. When the starting material (1) was converted to phthalocyanine, the disappearance of CN stretching vibration at 2233 cm-1 belong to 3-(4-aminopyrimidin-2-ylthio) phthalonitrile (1) supported the formation of phthalocyanines (2,3). Except for minor shifts, all the phthalocyanines obtained gave results similar to the starting material (1). Following the reaction with DMS, the methylated derivatives (2a,3a) gave some specific vibrations at 1375-1365 (S=O (strong) asymmetric stretching), 1205-1200 (S=O (strong) symmetric stretching), 750-740 (C-S stretching) and 560-530 (S-O stretching) as an indication that the quaternization of the related phthalocyanines (2,3) carried out in accordance with the literature. The protonated ion peaks of the synthesized phthalocyanines (2,3) were obtained at 1077.830 [M+H]+ and 1073.672 [M+H]+ , respectively. The methylated derivatives (2a,3a) gave satisfactory results which are 1330.943 [M+2H]+ , 1132.432 [M-2SO4-4H]+ for (2a) and 1228.187 [M-SO4] + , 1129.567 [M-2SO4-3H]+ for (3a), respectively. xxiii Aggregation, one of the most striking properties of phthalocyanines, occurs when the two or more extended π-system of phthalocyanines are stacked on top of each other or side by side due to intermolecular attraction forces. Depending on the inserted metal atom in the inner core, nature of the substituents, the concentration, the solvent used, and temperature, these clusters formed by the combination of molecules or atoms with these interactions are called aggregates. In this study, whether the phthalocyanines (2,3) were aggregated or not at different concentrations was investigated in DMSO solvent by dilution studies. When the phthalocyanine concentration was increased, the increase in Q band absorption and no additional band formation in the spectrum supported the absence of aggregation in accordance with Lambert-Beer law for the concentrations between roughly 8.0 × 106- M and 0,5 × 106- M. The methylated derivatives (2a,3a) gave typical absorption spectra for aggregated phthalocyanines in water due to the observation of a new blue-shifted band that is an indication that there is an H-type aggregation (facial aggregation) in the solvent of water. After the addition of a surfactant (triton x-100) to the water solutions of the methylated derivatives (2a,3a), the metallophthalocyanine (3a) containing cobalt in the inner core prevented the formation of aggregation while no change was observed for the metallophthalocyanine (2a) containing copper in the inner core. This supported that the existing aggregation was broken with the addition of triton x-100 for (3a).