4-(triflorometoksi)fenoksi grupları içeren ftalosiyaninlerin sentezi, tıpta, biyolojide ve ileri teknolojide kullanılabilirliklerinin araştırılması
Synthesis of phthalocyanines containing 4- (trifluorometoxy) phenoxy groups and investigation of their usability in medicine, biology, and advanced technology
Yazar: NAZLI FARAJZADEH
Danışman: PROF. DR. MAKBULE KOÇAK
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Doktora, 2021
Konu: Kimya = Chemistry
Dizin: Ftalosiyaninler = Phthalocyanines

Özet:
Ftalosiyaninler (Pcs) ve onların metalli türevleri benzersiz optik, elektronik, katalitik ve yapısal özelliklerinden dolayı son yıllarda büyük ilgi çekmektedir. Geleneksel olarak, ftalosiyaninler boya ve pigment olarak kullanılmıştır, fakat son zamanlarda kataliz, sıvı kristaller, kimyasal sensörler, fotodinamik tedavi, güneş enerjisi dönüşümü, optik veri depolama, yarı iletkenler ve nonlineer optik gibi farklı bilimsel ve teknolojik alanlarda geniş uygulama alanı bulmuşlardır. Ayrıca, metal ftalosiyaninler, elektrokatalitik, elektrokromik ekranlar ve sensör uygulamaları gibi çeşitli elektrokimyasal teknolojilerde işlevsel malzemeler olarak yaygın bir şekilde kullanılmaktadır. Metal ftalosiyaninlerin redox zenginliği, bu uygulamalardaki işlevsellikleri için anahtar faktördür ve bu özellikler, metal merkezler ve sübstitüentler değiştirilerek kolayca uyarlanabilir. Son yıllarda, araştırmacılar Pc moleküllerinin antioksidan, antimikrobiyal ve enzim inhibisyon aktivitelerini de incelemiştir. Reaktif oksijen türleri (ROS), canlı organizmaların metabolizmalarında üretilir ve bu ROS, hücresel biyomoleküllerin çoğu ile kolayca reaksiyona girerek bir organizmanın normal savunma mekanizmalarını azaltır. Çoklu ilaç direnci ile sonuçlanan ticari antibiyotik ilaçların yaygın kullanımı nedeniyle, antimikrobiyal aktiviteye sahip yeni Pc'lerin sentezi önemli hale gelmiştir.
Düzlemsel makrosiklikler arasındaki π istiflenme (kümelenme) nedeniyle, sübstitüe edilmemiş ftalosiyaninler, organik çözücülerde ve suda çözünmez veya az çözünür, bu durum onların uygulamalarını sınırlandırmıştır. Makrosikliklerin periferal veya eksenel olarak sübstitüe edilmesi, 18π - elektron konjüge sistemleri arasındaki mesafeyi arttırır, kümelenmeyi azaltır böylece çeşitli çözücülerde çözünürlüklerini arttırır ve optik özelliklerini geliştirir. Flor atomları, yüksek oranda elektron çekme özelliğine sahiptir ve florlu Pc'ler için olağanüstü elektron geçişi, manyetik ve ışığa duyarlılık özellikleri sunar. Ayrıca, multi-floro-sübstitüe ftalosiyaninler mükemmel termal stabilite, kimyasal direnç ve polar/apolar çözünürlük gibi benzersiz özellikler gösterdiklerinden yeni malzemeleri üretmek için flor içeren Pc'lerin geliştirilmesine odaklanan çalışmaların sayısında son zamanlarda büyük bir artış vardır. 
Bu tez kapsamında fotodinamik terapide, biyolojide ve yüksek teknolojide kullanılabilme potansiyellerini araştırmak amacıyla, ikisi asimetrik ve 26 sı yeni olmak üzere 27 adet ftalosiyanin bileşiği sentezlendi. Bu amaçla tezin birinci aşamasında 4-nitroftalonitril veya 3-nitroftalonitril ile 4-(triflorometoksi)fenol kuru dimetil formamid (DMF) içerisinde, potasyum karbonat varlığında, azot atmosferi altında, 45 oC de reaksiyona sokularak, sırasyla 4-(4-(triflorometoksi) fenoksi) ftalonitril (1) ve 3-(4-(triflorometoksi) fenoksi) ftalonitril (2) bileşikleri sentezlendi. 4,5 dikloroftalonitril ile 4-(triflorometoksi)fenol kuru dimetil sülfoksit (DMSO) içerisinde, potasyum karbonat varlığında, azot atmosferi altında, 80 oC de reaksiyona sokularak 4,5-bis(4-(triflorometoksi)fenoksi) ftalonitril (3) bileşiği hazırlandı. Elde edilen 1, 2 ve 3 nolu ftalonitrillerin ilgili metal tuzları (metalsiz ftalosiyain için metal tuzu kullanılmadan) ile uygun çözücülerde (pentanol katalitik miktarda DBU, dimetilaminoetanol ve kinolin) azot atmosferi altında ve uygun sıcaklıklarda (135 oC, 165 oC, 170 oC) siklotetramerizasyon reaksiyonları sonucu hedeflenen simetrik mono metalli (1-Zn, 2-Zn, 3-Zn, 1-Co, 2-Co, 3-Co, 1-Cu, 2-Cu, 3-Cu, 1-Pd, 3-Pd, 1-Ga, 2-Ga, 3-Ga, 1-In, 2-In, 3-In, 1-Lu, 2-Lu, 3-Lu), metalsiz (1-H2, 2-H2), ftalosyaninler ve sandviç tipi lutesyum ftalosiyaninler (1'-Lu, 2'-Lu, 3'-Lu) sentezlendi. Yine bu aşamada elektron itici gruplar içeren 4-(triflorometoksi)fenoksi)ftalonitril (1), 4,5-bis(4 triflorometoksi)fenoksi)ftalonitril ligantları (3) ve elektron çekici 4-((4-nitrofenil)etinil)ftalonitril ligantı (4) ile istatiksel kondenzasyon yöntemi kullanılarak A3B tipi halka dışı üçlü bağlar içeren push-pull yeni asimetrik çinko ftalosiyaninler sentezlendi. Reaksiyon 135 oC de azot altında DMAE içinde gerçekleştirildi. Sentezlenen bütün moleküllerin saflıkları ince tabaka kromatorafisi ile takip edilip, yapıları Ft-ır, 1H NMR (paramamanyetik ftalosiyaninler hariç), 13C NMR (paramamanyetik ftalosiyaninler hariç), kütle spektroskopisi ve UV-vis gibi spektral teknikler kullanılarak aydınlatıldı. Sandviç tipi lutesym ftalosiyaninlerin (1'Lu-3'Lu) yapılarını aydınlatmak için elektro spin resonas ölçümleri (ESR) de kullanıldı.
Sentezlenen ftalosiyaninlerin elektronik spektrumları, farklı çözücülerde ve farklı derişimlerde UV-vis spektrometresi aracılığıyla ölçülerek çözücünün cinsinin ve derişiminin spektoskopik ve agregasyon (kümeleşme) özellikleri üzerindeki etkisi araştırıldı. 
Tezin ikinci aşamasında sentezlenen ftalosiyaninlerin biyolojide kullanılabilme potansiyellerini araştırmak amacıyla 1, 1-H2, 1-Cu, 1-Pd bileşiklerinin antioksidan aktiviteleri ve tirozinaz inhibisyon özellikleri, 3, 3-Zn, 3-Cu, 3-Co bileşiklerinin antimikrobiyal ve antioksidan aktiviteleri incelendi. Ayrıca 4 veya 3 konumlarında 4-(triflorometoksi)fenoksi (1,2) veya 4-(triflorometoksi)tiyofenoksi gruplarını (1S, 2S) içeren ftalonitrillerden hazırlanan metalsiz ve bakır ftalosiyaninlerin (1-H2, 1-Cu, 2-H2, 2-Cu, 1S-H2 , 1S-Cu, 2S-H2, 2S-Cu) bağlayıcı atomun cinsinin ve konumunun bu bileşiklerin biyolojik özelliklerinin üzerindeki etkisini incelemek için antioksidan ve tirozinaz inhibisyon aktiviteleri araştırıldı. 
Tezin üçüncü aşamasında, fotodinamik terapide kullanılabilme potansiyellerini araştırmak amacıyla, 1-Zn, 1-InCl, 1-Ga, 1-Lu, 2-Zn, 2-InCl, 2-Ga, 2-Lu, 3-Ga, 3- Lu bileşiklerinin, UV-vis ve floresans spekroskopisi kullanılarak, floresans kuantum verimleri, singlet oksijen kuantum verimleri ve fotobozunma kuantum verimleri hesaplandı. Ayrıca bu tez kapsamında, ilk defa, mono lutesyum ftalosianinlerin (1-Lu, 2- Lu, 3- Lu) SPDT'de kullanılabilme potansiyellerini araştırmak amacıyla, fotofiziksel ve fotokimyasal özellikleri incelendi.
Tezin dördüncü aşamasında sentezlenen ftalosiyaninlerin elektrokataliz, elektroalgılayıcı, görüntüleme ve optoelektronik alanlarında kullanılabilme potansiyellerini araştırmak amacıyla 1-Zn, 1-Co, 1-In, 2-Zn, 2-Co, 2-In, 3-Zn, 3-Co, 3-In bileşiklerinin elektrokimyasal ve in-situ spektroelektrokimyasal özellikleri incelendi. 
Tezin son aşamasında ise 1 ve 3 nolu ftalonitrillerden hazıralana simetrik ve A3B tipi asimetrik çinko ftalosiyaninlerin (1-Zn, 3-Zn, 1-AZn, 3-AZn) non lineer optik malzemeler olarak kullanılabilme potansiellerini arştırmak amacıyla NLO ve optik sınırlama özellikleri açık yarık Z-tarama yöntemi kullanılarak incelendi.

Abstract:
Phthalocyanines (Pcs) and their metal derivatives include a planar 18π-electron system and exhibit high electron transfers. They have attracted great attention in recent years owing to their unique optical, electronic, and catalytic properties that result from their highly conjugated structure. Albeit phthalocyanines have been used as dyes and pigments for many years, recently they have found wide application in different scientific and technological fields such as catalysis, liquid crystals, chemical sensors, photodynamic therapy, solar energy conversion, optical data storage, semiconductors, and nonlinear optics. Also, metal phthalocyanines are widely used as functional materials in various electrochemical technologies such as electrocatalytic, electrochromic screens, and sensor applications. The redox richness of metal phthalocyanines is a key factor for their functionality in these applications and these properties can be easily altered by changing the metal center and substituents. In recent years, researchers have also examined the antioxidant, antimicrobial, and enzyme inhibition activities of Pc molecules. Reactive oxygen species (ROS) are produced in the metabolism of living organisms, and these ROS readily react with most cellular biomolecules and reduce an organism's normal defense mechanisms. Due to the widespread use of commercial antibiotic drugs resulting in multi-drug resistance, the synthesis of new Pcs with antimicrobial activity has become important. As known, all of these applications require materials that show good solubility in a wide range of different solvents. But π-stacking (clustering) between planar rings of unsubstituted phthalocyanines leads to low insolubility or poor solubility of these compounds in organic solvents and water that in turn limits their applications. Alteration of phthalocyanine periphery can significantly overcome this problem. Generally, there are mainly two approaches: 1) Peripherally or non-peripherally addition of long and bulky substituents into phthalocyanine ring; 2) Insertion of metal ions. In addition to peripheral or non-peripheral substituents, the presence of axial group on metal ion also increases the distance between the 18π-electron conjugated systems, reduces aggregation, thus increases their solubility in various solvents. Besides, the chemical, physical, and optical properties of phthalocyanines can be improved using different metal cations or substituents. These changes are usually followed by the study of their spectral properties especially the UV-vis spectra. The presence of axial ligand on the metal center shifts the Q-band to the red region and makes the phthalocyanines useful for IR or near-IR applications. Compared to the electron-withdrawing substituents, the electron-donating groups leads to the red-shift of the Q-band. Also, the Q-bands of the non-peripherally substituted phthalocyanines show up more red-shift in comparison to their peripherally substituted analogs. Besides, temperature, concentration, and solvent nature can affect the Uv-vis spectra. For the instance, an increase in the refractive index of the solvent is followed by the red-shift of the Q-band. 
The fluorine atom is a high electron-withdrawing atom and results in exceptional electron-transfer, magnetic, and photosensitivity properties of fluorinated Pc. Since fluorine-containing Pcs exhibit excellent thermal resistance, chemical stability, and good solubility, the study of their synthesis and characterization for development of the Pcs performance in the different applications.
Within the scope of this thesis, 27 symmetric and non-symmetric phthalocyanines were synthesized to investigate their potential as suitable materials for photodynamic therapy, biology, and high technology. For this purpose, 4- (4- (trifluoromethoxy) phenoxy) phthalonitrile (1) and 3- (4- (trifluoromethoxy) phenoxy) phthalonitrile (2) were synthesized by reaction of 4-nitrophthalonitrile or 3-nitrophthalonitrile and 4- (trifluoromethoxy)phenol in dry dimethylformamide (DMF) in the presence of potassium carbonate under nitrogen atmosphere at 45 oC. The pure products were obtained by crystallization from ethanol. Combination of 4,5 dichlorophthalonitrile and 4- (trifluoromethoxy) phenol in dry dimethyl sulfoxide (DMSO) in the presence of potassium carbonate under nitrogen atmosphere at 80 oC resulted in 4,5-bis (4- (trifluoromethoxy) phenoxy) phthalonitrile (3). The crude compound was purifıed by crystallization from ethanol. Cyclotetramerization of the obtained phthalonitriles (1-3) with the related metal salts (except for metal-free phthalocyanine) in suitable solvents (pentanol in the presence of catalytic amounts of DBU, dimethylaminoethanol, and quinoline) under a nitrogen atmosphere at suitable temperatures (135 oC, 165 oC, 170 oC) resulted in symmetrical mono-metal (1-Zn, 2-Zn, 3-Zn, 1-Co, 2-Co, 3-Co, 1-Cu, 2-Cu, 3-Cu, 1-Pd, 3-Pd, 1-Ga, 2-Ga, 3-Ga, 1-In, 2-In, 3-In, 1-Lu, 2-Lu, 3-Lu), metal-free (1-H2, 2-H2), phthalocyanines and sandwich-type lutetium phthalocyanines (1'-Lu, 2'-Lu, 3'-Lu). According to the statistical condensation method, 4- (trifluoromethoxy)phenoxy) phthalonitrile (1) or 4,5-bis (4 trifluoromethoxy) phenoxy) phthalonitrile (3) and electron-withdrawing 4 - ((4-nitrophenyl) ethynyl) phthalonitrile ligand (4) reacted in DMAE under nitrogen at 135 oC to synthesize new asymmetric push-pull zinc phthalocyanines (A3B type) including extra-ring triple bonds. All the macromolecules were purified by performing the column chromatographic technique on silica gel. For symmetrically substituted phthalocyanines DCM: THF or chloroform: THF mixture were used as the eluent. However, hexane: THF mixture was used as the mobile phase for the non-symmetrically substituted phthalocyanınes. The purities of all synthesized molecules were tested by applying thin layer chromatography, and their structures were elucidated using spectroscopic techniques such as Ft-ır, 1H NMR (except for paramagnetic phthalocyanines), 13C NMR (except for paramagnetic phthalocyanines), mass and UV-vis spectroscopy. Electron spin resonance measurements (ESR) were also performed to study the structures of sandwich-type lutetium phthalocyanines (1'Lu-3'Lu).
Electronic spectra of the synthesized phthalocyanines were recorded in different solvents and different concentrations at room temperature using a UV-vis spectrometer. The effect of the concentration and the effect of the solvent nature on the spectral and aggregation properties of the newly synthesized phthalocyanines were investigated, as well. 
Besides, the antioxidant activities and tyrosinase inhibition properties of compounds (1, 1-H2, 1-Cu, 1-Pd) were studied. Compared to the literature, all the compounds exhibited moderate antioxidant activity and 1-Cu had the highest tyrosinase inhibitory activity among the synthesized molecules. The antimicrobial and antioxidant activities of compounds (3, 3-Zn, 3-Cu, 3-Co) were investigated for evaluation of the biological utilization potential of the synthesized phthalocyanines. 3-Zn showed the highest antioxidant activity in both DPPH scavenging activity and reducing power experiments. The tested phthalocyanines demonstrated antimicrobial activity against gram (+) bacteria. In addition, peripheral/ non-peripheral tetra- substituted metal-free and copper phthalocyanines (1-H2, 1-Cu, 2-H2, 2-Cu) containing 4- (trifluoromethoxy) phenoxy or 4- (trifluoromethoxy) thiophenoxy groups (1S-H2, 1S-Cu, 1S-Cu, 2S-H2, 2S-Cu) were prepared and their antioxidant and tyrosinase inhibition activities were examined to study the effect of the type and position of the binding atom on the biological properties of these compounds. In comparison to the literature, they had moderate antioxidant activities and quite good tyrosinase enzyme inhibition activities.
Moreover, the fluorescence quantum yields, singlet oxygen quantum yields, and photodegradation quantum yields of compounds (1-Zn, 1-In, 1-Ga, 1-Lu, 2-Zn, 2-In, 2-Ga, 2-Lu, 3-Ga, 3-Lu) were measured using UV-vis and fluorescence spectroscopy. The highest fluorescent quantum yield (ΦF = 0.28 in DMSO) was obtained for the peripheral tetra-substituted gallium chloride complex. Compared to the literature, the newly synthesized complexes have higher singlet oxygen yields and higher stability against photodegradation. To conclude, all the examined phthalocyanines have the potential to be used as photosensitizers in PDT. For the first time, the photophysical and photochemical properties of mono lutetium phthalocyanines (1-Lu, 2- Lu, 3- Lu) were investigated to evaluate their potential as alternative materials for SPDT.
Electrochemical and in-situ spectroelectrochemical properties of compounds (1-Zn, 1-Co, 1-InCl, 2-Zn, 2-Co, 2-In, 3-Zn, 3-Co, 3-In) were examined for the study of their possible utility in the electrocatalysis, electro-sensing, visualization, and optoelectronics. The characteristic and spectral changes observed during spectroelectrochemical measurements confirmed that the complexes have the electro-optical activity required for various electrochemical and optical applications such as electrocatalytic and electrochromic fields. It was also found that nonperipheral tetra-substituted cobalt phthalocyanine (2-Co) redox processes have a multi-electron, reversible, and metal-based character that in turn increase the redox richness of the compound for technological applications.
To investigate the possibility of their use as non-linear optical materials, NLO and optical limitation features of symmetrical and A3B type asymmetric zinc phthalocyanines (1-Zn, 3-Zn, 1-AZn, 3-AZn) were examined by performing the open Z-scan method. The values of the second-order NLO-absorption coefficient (β) and the third-order susceptibility's imaginary component (Im [X(3)]) of symmetric and asymmetric phthalocyanines were calculated for investigation of the NLO properties. To examine OL performances, the threshold values were measured. The good NLO and optical limiting properties of all the examined compounds indicated that these compounds have the potential to be used as NLO materials. The highest value was obtained for 2 (3) - (4-Nitrophenyl) ethinyl] - (9 (10), 16 (17), 23 (24) -tris- (4- (trifluorometxy) phenoxy) -phthalocyaninato} zinc (II) (33.6 × 10-4 M).