Nonperiferal terminalalkin sübstitüe ftalosiyaninlerin sentezi, karakterizasyonu ve klik kimyası kullanılarak glukokonjugasyonu
Synthesis and characterization of nonperipheral terminalalkynyl substituted phthalocyanines and their glucoconjugation via click chemistry
Yazar: ZELİHA KANAT
Danışman: DOÇ. DR. HATİCE DİNÇER
İstanbul Teknik Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı
Derece: Yüksek Lisans, 2015
Konu: Kimya = Chemistry

Özet:
Ftalosiyaninler tesadüfen yan ürün olarak elde edilmelerinden bu yana, çeşitli moleküler materyal ve teknolojik ürünler elde etmek amacıyla uygun yapı değişiklikleri ile ilgili birçok çalışmaya konu olmuştur. Son zamanlarda ftalosiyaninler sensör, nonlineer optik, boya duyarlı güneş pilleri, OLED, moleküler elektronikler, sıvı kristaller, yarı iletken, katalizör ve kanser tedavisinde fotodinamik reaktif olarak kullanılmaktadır. 
Ftalosiyaninlerin özellikleri metale ve sübstitüentin yapısı, sayısı ve pozisyonuna bağlı olarak değişmektedir. Nonperiferal sübstitüe ftalosiyaninler periferal sübstitüe ftalosiyaninlere göre Q bandını kırmızıya kaydırır, daha iyi çözünür ve agregasyonu engellerler. Aynı zamanda nonperiferal sübstitüe bileşikler kolay kristallenebildikleri için X-ray kristalografi cihazında yapıları rahatlıkla belirlenebilir. Nonperiferal sübstitüe okta ve tetra alkil, alkiloksi ve alkiltiyo ftalosiyaninler literatürde yer almıştır. Ancak nonperiferal Pc türevleri özellikle tetra sübstitüe örnekleri sınırlıdır. 
Leznoff ve arkadaşları tarafından 1998 yılında sentezlenen 1,8,15,22-tetrakis (propargiloksi) çinko(II) ftalosiyanin, nonperiferal terminal alkin sübstitüe ftalosiyaninleri içeren ilk ve tek örnektir. Ayrıca şimdiye kadar nonperiferal terminal alkin sübstitüe ftalosiyaninlerin klik reaksiyonu ile türevlendirilmiş hiçbir örneği bulunmamaktadır.
İlk karbonhidrat sübstitüe çinko ftalosiyanin  Maillard ve arkadaşları tarafından 1989 yılında rapor edilmiş ve nonperiferal türevi ise Ng ve arkadaşları tarafından 2008 yılında sentezlenmiştir. Hanack, Zieglar ve arkadaşları ilk anomerik glukoz sübstitüe çinko ftalosiyanin bileşiğini hazırlamış ve günümüze kadar birçok glukoz sübstitüe ftalosiyanin bileşiği rapor edilmiştir. Bununla birlikte glukoz sübstitüe ftalosiyaninlerin bazılarının sentezi oldukça karmaşık olabilmektedir. Son zamanlarda karbonhidrat sübstitüe ftalosiyaninler geleneksel sentezinin yanında yeni bir metod olan klik reaksiyonu ile sentezlenmiştir.
Klik kimyası; hızlı, kantitatif, tekrarlanabilir, yan reaksiyonlara ve reaksiyon koşullarına karşı dayanıklı olduğu için malzeme bilimi, polimer kimyası ve farmasötik bilimler de dahil olmak üzere birçok araştırma alanında uygulamaya sahiptir. En çok bilinen klik reaksiyonu Cu(I) katalizli Huisgen 1,3-dipolar azid alkin arasındaki siklo katılmadır ve sübstitüe ftalosiyaninlerin sentezinde daha az tercih edilmiştir. 
Bu yaklaşımla, tez çalışmamızda, öncelikle C-3 pozisyonunda alkin fonksiyonu taşıyan yeni ftalonitril bileşiği sentezlenmiştir. Daha sonra, bu ftalonitril bileşiğinin alkin uç grubu korunmaksızın, metal tuzları ve/veya DBU varlığındaki siklotetramerizasyonuyla nonperiferal tetra terminalalkinil-sübstitüe ftalosiyaninlerin sentezi gerçekleştirilmiştir. Ayrıca nonperiferal pozisyonda terminalalkin grubu içeren çinko ftalosiyanin ve azid uç grubu taşıyan glukoz bileşiği arasındaki klik reaksiyonu ve Zemplen şartları kullanılarak gerçekleştirilen deasilasyon reaksiyonuyla suda çözünür nonperiferal tetra glukoz sübstitüe çinko ftalosiyanin bileşiği elde edilmiştir. Sentezlenen bileşikler, 1H NMR, 13C NMR, FT-IR, UV-Vis, mass spektroskopi yöntemleri kullanılarak karakterize edilmiştir.Sonuç olarak yapılan bu çalışmada nonperiferal pozisyonlarda terminal alkinil sübstitüe metalli ve metalsiz ftalosiyaninler ile glukoz sübstitüe çinko ftalosiyanin sentezlenmiş ve spektroskopik özellikleri incelenmiştir.

Abstract:
The word phthalocyanine is derived from the Greek for naphtha (rock oil) and cyanine (blue). It was first used by Linstead in 1933 to describe a new class of organic compounds consist of metal free and metallo phthalocyanine derivatives. 
Phthalocyanines (Pcs) are an important class of aromatic macrocycles with high chemical and thermal stability that possess unique physical and chemical properties. Phthalocyanines are synthetic materials. Unlike porphyrin molecule, which are commonly found in nature such as chlorophyll, hemoglobin and vitamin B12, phthalocyanines can not be found in nature. Phthalocyanine is a planar and aromatic macrocycle complexes having 18-π electronic system. Phthalocyanines are generally blue-green in color due to the intense π→π* bands associated with the planar heteroaromatic π-conjugation system. As a consequence, phthalocyanines have been used extensively in dyes and pigments. The central part of the molecule consists of four nitrogens directly involving complexation, and two imino hydrogens. The core is capable of coordinating almost all metal ions and this in turn enables the macrocycle to have a broad spectrum of properties. If it is considered that electrophilic and nucleophilic substitution reactions can easily be applied to aromatic systems, phthalocyanines will also have a great range of substitution opportunities. 
Phtalocyanines are able to entrap more than 70 metal and ametal cations inside their innerring spaces. Furthermore, it is possible to bind a variety of substitue mixture, which changes electronic structure of the system, to macrocyclic molecule. These groups can improve Pc's solubility. 
Since the accidentally discovery of the phthalocyanines (Pcs), many efforts have been devoted on tailoring of their properties to produce molecular materials and technological devices. Recently they have found use as sensors, non-linear optics, dye sensitized solar cells, organic light emitting devices, molecular electronics, liquid crystals, semiconductors, catalysts, photodynamic reagents for cancer therapy (PDT), among others. The properties of phthalocyanines are closely depended on their structure that can be modified by metallation or substitution variations: number, position, and nature. Incorporation of the substituents at the nonperipheral (np) sites as opposed to the peripheral (p) positions ensures good solubility and limited aggregation in most hydrophobic solvents and leads to significant bathochromic shifts of the Q absorption band. In addition, np- substituted compounds often crystallize well enough to enable X-ray crystallographic structure determinations. Nonperipherally substituted octa- and tetra-alkyl, alkyloxy or alkylthio phthalocyanines were reported in the literature. However, studies on non-peripherally substituted Pc derivatives especially tetra substituted examples are still limited. During the last decade, a large number of mono- and poly-alkynyl-containing Pc-systems have been synthesized mainly following two different synthetic strategies consisting of the cyclotetramerization of alkynyl-substituted phthalonitriles and the incorporation of the alkynyl-containing moieties onto the preformed Pc macrocycle via some metal catalyzed coupling reactions. However, terminalalkynyl substituted phthalonitriles have hitherto been rarely accessible for elaboration into terminalalkynyl phthalocyanines that are potential building blocks for 'click' chemistry with any molecule bearing terminal azide group Click chemistry has been applied in a wide variety of research areas, including material science, polymer chemistry, and pharmaceutical sciences due to its being fast, quantitative, reproducible, resistant to side reactions and highly tolerant to reaction conditions. The best known click reaction is the copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition between azides and alkynes is less used for the synthesis of substituted phthalocyanines. 
To the best of our knowledge, there is only one example of nonperipherally terminalalkynyl substituted phthalocyanine, that is 1,8,15,22-tetrakis (propargyloxy) phthalocyaninato-zinc(II) announced by Leznoff and coworkers in 1998. Besides, up to now, there are yet no any reports about the nonperipherally terminalalkynyl substituted phthalocyanines involved in click reaction.
Photodynamic therapy (PDT) has developed over last century and is now becoming a more widely used for the treatment of cancer. It involves the delivery of a nontoxic dyes known as photosensitizers (PS), followed by the irradiation with visible light of a specific wavelength, typically in the red region of the spectrum (620−690 nm). Activated photosensitizers transfer energy to molecular oxygen which results in the generation of reactive oxygen species mainly singlet oxygen (1O2) which in turn cause the destruction of tumors. The development of efficient photosensitizers in terms of tumor-selectivity and reactive oxygen species (ROS)-producing ability is the main topic of many ongoing research programs. Phthalocyanine derivatives exhibit several optimal characteristics for being good PSs such as a high molar absorption coefficient in the visible region of the spectrum, a long lifetime of the triplet excited state, and an increased oxidative stability that allows their use as stable aqueous solutions. However, the lack of selective accumulation of these photo actively molecules within tumor tissue, the insolubility and aggregation in physiological fluids are major problems in PDT. The phthalocyanines conjugated with carbohydrate moieties have attracted considerable interest, with the aim of developing targeted photosensitizers and eventually the PDT efficacy. 
The first carbohydrate substituted zinc(II) phthalocyanine was reported in 1989 by Maillard et al. and its nonperipherally substituted analogue was synthesized in 2008 by Ng and coworkers. Hanack, Ziegler and co-workers prepared the first example of an anomerically glycosylated zinc(II) phthalocyanine in 2006 and after that several carbohydrate substituted phthalocyanines have been reported so far. However, the synthesis of some of the glycosylated phthalocyanines can be rather complicated and not easy. Recently, carbohydrate conjugated phthalocyanines were synthesized by Click reaction as a novel method instead of traditional synthesis method. 
Incorporation of alkyne functionalities on the non-periphery of a Pc will facilitate alkyne-azide click chemistry, allowing for a variety of high-functioning substituents be used. With this approach, a library of Pcs can be prepared from a single Pc core. Based on the aforementioned statements, in this study, firstly a novel phthalonitrile compound bearing an alkyne function in the C-3 position was designed to attain nonperipherally tetra terminalalkynyl substituted phthalocyanines by its cyclotetramerization in the presence of metal salts and/or DBU without protection/deprotection. In addition, to prove the viability of click reaction concept, we have chosen the resulting ZnPc derivative and the click reaction between nonperipherally tetra terminalalkynkyl substituted ZnPc and 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl azide then deacylation under Zemplén conditions provided water soluble nonperipherally tetra glucose substituted ZnPc in high yield. The chemical structures of new compounds were characterized by 1H NMR, 13C NMR, FT-IR, UV-Vis, mass spectrometry and elemental analysis.
As a result, a novel phthalonitrile derivative, its nonperipheral terminalalkynyl substituted  metallophthalocyanines and glucose substituted zinc phthalocyanine were synthesized and chracterizied in this study. The main purpose of glucose substituted zinc phthalocyanine phthalocyanines is to obtain water soluble phthalocyanine in order to use them as photosensitier for photo dynamic therapy.