Biyolojik uygulamalara yönelik ftalosiyanin-BODIPY konjugatlarının sentezi
Synthesis of phthalocyanine-BODIPY conjugates for biological applications
Yazar: HANDE TELSEREN
Danışman: PROF. DR. ESİN HAMURYUDAN
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Yüksek Lisans, 2022
Konu: Kimya = Chemistry
Dizin: BODIPY bileşikleri = BODIPY compounds ; Fotodinamik tedavi = Photodynamic therapy ; Ftalosiyaninler = Phthalocyanines ; Çıtçıt kimyası = Click chemistry

Özet:
Tetrapirol türevlerinin bir üyesi olan ftalosiyaninler 1928 yılında İskoçya daki bir boya
farbrikasında, ftalimid üretimi sırasında tesadüf eseri ortaya çıkmış, birbirine 1,3
konumlu aza köprüleri ile bağlı dört kısım izoindol yapısı içeren makrosiklik
bileşiklerdir. 18 π elektrona sahip delokalize olabilen bu sistem sayesinde ftalosiyanin
bileşikleri yakın IR bölgesinde kuvvetli absorbsiyon vermeleri, termal açıdan ve de
diğer çevresel koşullar açısından yüksek kararlılığa sahip olmaları, yoğun renkleri,
boyar madde oluşu, çeşitli fonksiyonel gruplar sayesinde türevlendirilebilir ve yeni
özellikler kazanabilir olmaları sayesinde büyük ilgi odağı olmuşlardır.
Ftalosiyaninler, merkezinde bulunabilen farklı metal atomları sayesinde de
fotokimyasal, fotofiziksel ve spektral özelliklerinde çeşitlilik kazanabilirler. UV-vis
spektroskopisinde Q bandında 600-750 nm aralığında tek veya çift pik göstermesine
bağlı olarak metal atomu içerip içermediği hakkında fikir yürütülebilir olması da
ayrıca analiz anlamında kolaylık sağlamaktadır.
Ftalosiyaninler, keşfedildiği günden bugüne kadar üstün fiziksel ve kimyasal
özellikleri sayesinde birçok uygulama alanında yaygın olarak kullanılmaktadırlar.
Uygulama alanları için gerekli fonksiyonlara sahip yeni türlerin eldesi için
ftalosiyaninlerin eksenel, periferal ve nonperiferal pozisyonlarına amaca uygun
gruplar sübstitüe edilmesi ve merkezdeki metal iyonunun farklı olması, uygulama
alanlarındaki çeşitliliği arttıran faktörler arasındadır. Bu şekilde ftalosiyaninlerin
çözünürlüğü artttırılabildiği gibi fotofiziksel, fotokimyasal, elektriksel iletkenlik ve
redoks potansiyelleri gibi uygulama alanları açısından önemli özelliklerinin oluşması
ve genişletilmesi sağlanabilmektedir.
Benzer şekilde yüksek kararlılığa sahip boyar madde olan 4,4-difloro-4-bora-3a,4adiaza-s-indasen (BODIPY) bileşikleri de kullanımı son zamanlarda oldukça
yaygınlaşan bileşiklerdir. Fotofiziksel ve fotokimyasal açıdan değerli olan bu
bileşiklerde de oldukça çeşitli kullanım alanları bulunmaktadır. Yüksek florensans
kuantum verimine sahip floresans özellik gösteren florofor grup BODIPY boyaları
dar absorpsiyon ve emisyon bandına sahiplerdir. BODIPY çekirdeğine farklı
sübstitüentlerin bağlanması sayesinde, suda çözünebilir hale gelmesi, batokromik
kayma yaşanması ve singlet oksijeninde meydana gelen artma gibi farklı özellikler
kazandırılabilir.
BODIPY'ler son yıllarda özellikle antibakteriyel, antioksidan, enzim inhibisyonu,
sitotoksik/fototoksik antikanser ve fotodinamik terapi (PDT) gibi farmakolojik ve
biyolojik uygulamalar, organik tabanlı fotonik, OLED teknolojisi ve hücre
görüntüleme için floresans problar, kanser hücrelerine seçici teşhisinde ya da
öldürülmesinde kullanılan kemosensörler gibi birçok alanda kulllanılabilmektedir.
Birçok ileri özelliğe ve yaygın kullanım alanına sahip bu iki yapının aynı molekül
içinde yer aldığı bu tez çalışması ile literatüre yeni bileşiklerin kazandırılması ve
genişletilmiş fiziksel ve kimyasal özellikleri ile farklı kullanım alanlarına hitap eden
orijinal bir çalışmanın meydana gelmesi sağlanmıştır.
Bu çalışmada, biyolojik uygulamalarda kullanılmaya aday pentaflorofenil grubu
taşıyan BODIPY yapıları ile konjuge edilmiş çinko ftalosiyanin moleküllerinin sentezi
ve bu yapıların çeşitli spektral teknikler kullanılarak karakterizasyonu hedeflenmiştir.

Abstract:
Phthalocyanines, a member of the tetrapyrrole derivatives, are macrocyclic
compounds containing four parts of isoindole structures connected to each other by
1,3-position aza bridges, which emerged by chance during the production of
phthalimide in a dye factory in Scotland in 1928. Thanks to this system that can be
delocalized with 18 π electrons, phthalocyanine compounds have great potential, their
strong absorption in the near IR region, high stability in terms of thermal and other
environmental conditions, intense colors, dyestuffs, derivatization and new properties
associated with via various functional groups have been the focus of attention.
They can gain diversity in their photochemical, photophysical and spectral properties
with different metal atoms in their center. The fact that it contains a metal atom or not,
depending on whether it shows a single or double peak in the Q band in the range of
600-750 nm in UV-vis spectroscopy, also provides convenience in terms of analysis.
Phthalocyanines have been widely used in many application areas thanks to their
superior physical and chemical properties since the day they were discovered. In order
to obtain new species with the necessary functions for the application areas, the
substitution of groups suitable for the axial, peripheral and non-peripheral positions of
the phthalocyanines and the difference in the metal ion in the center are among the
factors that increase the diversity in the application areas. In this way, the solubility of
phthalocyanines can be increased, as well as the formation and expansion of important
properties in terms of application areas such as photophysical, photochemical,
electrical conductivity and redox potentials.
Phthalocyanines were first seen as a by-product during the synthesis of Ocyanobenzamide in London in 1907. At another time, in 1927, Diesbach and Von der
Weid, at the University of Friborg, encountered a blue product as a result of heating
ortho-dibromobenzene with copper cyanide in a pyridine solvent at 200 °C and could
not elucidate its structure as phthalocyanine. In the real sense, the clarification of the
structure of phthalocyanines occurred on Linstead's studies in 1934, and upon this, it
was definitively determined as a result of X-ray studies by Robertson.
Phthalocyanines, which are a member of the tetrapyrrole structures from macrocyclic
structures, do not exist spontaneously in nature like porphyrins. It is produced
synthetically in the laboratory environment and resembles the structure of porphyrin.
Structurally, they are seen as tetraazatetrabenzo analogues. Phthalocyanines are
formed as a result of the bonding of pyrrole rings with nitrogen atoms instead of C-H
atoms in the porphyrin skeleton.
Similarly, 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) compounds, which
are highly stable dyestuffs, are compounds that have become very common in recent
times. These compounds, which are photophysically and photochemically valuable,
also have a wide variety of uses. BODIPY dyes with high fluorescence quantum yield
and fluorescent fluorophore group have narrow absorption and emission bands.
Thanks to the binding of different substituents to the BODIPY core, different
properties such as water solubility, bathochromic shift and increase in singlet oxygen
can be gained.
BODIPYs have been used in recent years, especially in pharmalogical and biological
applications such as antibacterial, antioxidant, enzyme inhibition,
cytotoxic/phototoxic anticancer and photodynamic therapy (PDT), organic-based
photonics, OLED technology and fluorescent probes for cell imaging;furthermore, in
many fields, it is used such as selective diagnosis or killing of cancer cells can be used.
In this thesis study, in which these two structures, which have many advanced features
and common usage areas, are located in the same molecule, it has been ensured that
new compounds have been introduced to the literature and an original study that
addresses different areas of use with its various physical and chemical properties.
In this study, the synthesis of zinc phthalocyanine molecules conjugated with BODIPY
structures carrying pentafluorophenyl group, which are candidates for use in biological
applications, and the characterization of these structures using various spectral
techniques are aimed. Phthalocyanines have very common usage areas. It is seen in
many fields such as the pharmaceutical industry, the extraction stage while obtaining
metals, the electrical and electronic industry, the use of as a catalyst in the textile
industry due to the removal of water hardness and dyestuff, its use as a disinfectant
and antioxidant in polymerization reactions, and its use as a catalyst in the removal of
bad odors. We can say PDT, which is a photodynamic cancer treatment, which has
attracted attention in recent years in optics, electronics, gas sensors, liquid crystal
materials, semiconductors, non-linear optical materials, fuel and solar cells.
BODIPY has a wide range of uses due to its many features such as high fluorescence
quantum efficiency and stable structure. It can be used in many areas such as labeling
agent in biomolecules, biosensors, intracellular imaging, energy transfer cassettes,
chemosensors, laser dyes, dye industry, textile dyes. In recent years, an important area
of use has emerged as PDT. It is an important molecule used in studies on the diagnosis
and killing of cancer. Fully synthetically obtained phthalocyanines are widely used in
many application areas thanks to their superior physical and chemical properties. In
order to obtain new derivatives, substitution of groups suitable for different positions
of phthalocyanines, and the diversification of the metal ion in the center can
significantly increase the solubility, as well as provide the acquisition and expansion
of new properties in terms of application areas.
4,4-Difluoro-4-borata-3a-azonia-4a-aza-s-indacene compounds are called boron
dipyrromethene in short and BODIPY in short. It is a structure formed by connecting
a disubstituted boron atom (BF2) to the dipyrromethene compound, which is formed
by connecting two pyrrole rings with a bridge. It took many years for the BODIPY
compounds, which were discovered as a result of the work of two scientists, Treibs
and Kreuzer, who lived in 1968, to gain importance. The important features of these
compounds, which first came to the fore with their fluorescent and optical properties,
are high quantum efficiency, resistance and stability against effects such as oxygen,
light, temperature, pH, good solubility, extremely good thermal and photo stability,
and substituted groups. It is a compound that is practical to be modified by adding.
BODIPY, also called boron dipyrromethene, is one of the most striking fluorophore
groups in recent years due to its many properties. Among these features; It has high
quantum efficiency, high stability, strong absorption around 500 nm and high
solubility in many organic solvents. With the modifications made in the structure of
these molecules, which are also called the younger brother of porphyrin due to their
structure, their fluorescence properties can be changed for the target purpose. For this
reason, they are frequently used structures especially in biochemistry, sensor and
energy transfer studies.Within the scope of this study, with the inclusion of many
advanced and widely used groups such as BODIPY, phthalocyanine, fluorine in the
same molecule; It is planned to introduce new compounds to the literature, to
synthesize and characterize new hybrid compounds that appeal to different areas of
use, especially in biological applications. Synthesis stages; Synthesis of
dipyrromethane compounds, synthesis of BODIPY compounds, synthesis of
phthalonitrile derivatives, synthesis of phthalocyanines and synthesis of
phthalocyanine-BODIPY conjugation products were determined. The intermediate
and target compounds obtained were characterized by FT-IR, UV-Vis, 1H-NMR, 13CNMR, 19F-NMR and MALDI-TOF methods.