Triazol bağlı yeni nesil ksanten sentezi
Novel triazole based xanthene synthesis
Yazar: ÖZGE ÖZÜKANAR
Danışman: DOÇ. DR. İBRAHİM VOLKAN KUMBARACI
İstanbul Teknik Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Yüksek Lisans, 2018
Konu: Kimya = Chemistry

Özet:
Ksantenler, kristal bir yapıya sahip olan, antiviral, antibakteriyel ve ödem çözücü gibi birçok biyolojik ve farmasötik özellikleri bulunan heterohalkalı bileşiklerdir. Ayrıca azid-alkin siklokatılma reaksiyonu sonucunda oluşan 1,2,3-triazoller hem katyonları hem de anyonları bağlama özellikleri sayesinde organik kimyada oldukça fazla ilgi çeken bileşiklerdir. Tez kapsamında ise çeşitli aktivitelere sahip ksanten bileşikleri üzerine birçok metal ve ametali seçici olarak tutabilecek özelliklere sahip 1,2,3-triazol ünitesinin bağlanması planlanmış ve triazol bağlı yeni nesil ksanten sentezleri gerçekleştirilmiştir. Bunun için ilk olarak 2,7-dihidroksinaftalen bileşiğinden yola çıkılarak asidik ortamda, bütün fonksiyonel grupları hidroksil olan ksanten türevi sentezlenmeye çalışılmış ancak başarılı olunamamıştır. Dolayısıyla 4-hidroksibenzaldehit bileşiğinden, K2CO3 ve aseton kullanılarak, para konumu propargil eter olan benzaldehit bileşiği sentezlenmiştir. Sentezlenen aldehit bileşiği kullanılarak, serbest hidroksil grubu içeren dibenzoksanten bileşikleri elde edilmiştir. Daha sonra, serbest olan fenolik hidroksiller propargil bromür ile eterleşme reaksiyonu sonucu üçlü bağ içeren ksanten bileşiklerine dönüştürülmüştür. Diğer kısımda, (azidometil)benzen ve 9-(azidometil)antrasen bileşikleri sentezlenmiştir. Daha sonra elde edilen ksanten bileşikleri ile Cu(I) katalizörlüğünde 1,3-dipolar siklokatılma reaksiyonları sonucu triazol yapıları içeren ksanten bileşikleri sentezlenmiştir. Triazol ünitesi üzerinde floresans aktiviteye sahip olabilecek antrasen yapısı eklenmesi ile yeni tip floresans kemosensör elde edilebileceği düşünülmüştür. Serbest hidroksil gruplarının sentezler sırasında kompleks oluşturması sebebi ile azid-alkin siklokatılma reaksiyonları öncesinde uygun bir koruma grubu ile korunması gerekmiştir. Koruma grubunun seçiminde, azid-alkin siklokatılma reaksiyonları sırasında bozunmaması ve koruma gruplarının kaldırılması sırasında triazol gruplarının bozunmaması göz önünde bulundurulmuştur. Bu sebeplerden dolayı asetil gruplarının kullanılmasına karar verilmiştir. Reaksiyonlar gerçekleştirildikten sonra koruma grubu bazik ortamda kaldırılmış ve böylece farklı moleküler kaviteye sahip olabilecek üçlü ve tekli triazol içeren ksanten bileşikleri sentezlenmiştir. Sentezlenen bileşiklerin yapıları 1H-NMR ve 13C-NMR yardımıyla aydınlatılmıştır.

Abstract:
Xanthenes are heterocycle compounds which have many biological and pharmaceutical properties, such as being antiviral, antibacterial and antiinflammatory, having a crystalline structure. Xanthene derivatives such as rhodamine and amsacrin are known to have biological activity. For these biological activities, xanthene derivatives have been frequently investigated in organic chemistry. Other applications of dibenzoxanthenes that are used in the study, are dyes, fluorescence materials which are used for the imaging of biomolecules and laser technology. Because of the usage of dibenzoxanthenes in various fields, the synthesis of these compounds plays an important part in organic chemistry.
There are many synthesis methods for xanthenes and their derivatives in the literature. Some of those are; reaction of β-naphthol with 2-naphthol-1-methanol, reaction of benzaldehyde derivatives with acetophenone derivatives, and intermolecular reactions of benzene derivatives with phenol derivatives.In addition, xanthene derivatives were synthesized with low level toxicity and wastes, by using different catalysts and green chemistry methods.
The ether derivatives of the dibenzoxanthene derivatives in the appropriate position have the property of being attractive molecular tweezers due to their adjustable cavity properties. These structures have suitable structural motifs to develop molecular receptors. Molecular tweezers are a variety of synthetic receptors with cavities that can bind another molecule or ion. Molecular tweezers are compounds that usually have two aromatic rings and fixed cavities. In this contex, triazole bounded dibenzoxanthene molecules synthesized within the scope of the study are thought to have properties that can hold ions.
In the second part of the study triazole compounds were obtained. Although the synthesis of the first triazole unit is based on very old dates, it is a subject that is currently being worked on thanks to its wide range of applications. The Huisgen 1,3- dipolar cycloaddition reactions are exergonic fusion processes that combine two unsaturated reactants and give a wide variety of five-membered heterocycle products. The 1,3-dipolar cycloaddition reactions discovered by Huisgen and named after them, give both 1,4- disubstituted and 1,5- disubstituted 1,2,3-triazole products since this process is done with temperature. Since the non-selective Huisgen reactions generates both isomers, the yields were lower than desired. However, it was determined that Sharpless and his group could perform asymmetrical synthesis in 2000s. By using the Cu (I) catalyst, the 1,5-disubstituted 1,2,3-triazole product can be eliminated and the 1,4-disubstituted 1,2,3-triazole product can be obtained in a regioselectively. Due to the regioselective acquisition of the 1,4-disubstituted product, Sharpless and his group developed the concept of click chemistry . These reactions, which are carried out with high efficiency, have also provided great convenience in the field of organic chemistry. It also helped 1,2,3-triazoles to find new usage areas. The reaction of the azide-alkyn cycloaddition is carried out using the Cu (I) catalyst is known to take place in several stages, but its mechanism has not been fully elucidated.
1,2,3-Triazole structure is stable to metabolic degradation and can make hydrogen bond which is suitable for binding of biomolecular targets and for solubility. Synthetic molecules containing 1,2,3-triazole units show various biological activities such as being antibacterial, antiallergic and antifungicide.
Moreover, 1,2,3-triazoles are formed as a result of azide-alkyne cycloaddition reaction having a great interest in organic chemistry and biology fields thanks to both cations and anions binding properties. Due to the critical roles of anions and cations in the environment, triazoles have been frequently used in this area. Heavy metals have negative effects on human health. Heavy metals in the environment begin to accumulate in human body over time. In the excessive exposure of these metals, irreversible damage can occur in the human body. For these reasons, it is important that anions and cations can be detected and kept on molecules.
In the literature, anion and cation retention experiments of various compounds containing triazole units were made and the compounds obtained against certain ions were selective. Their selectivity to ions was determined by changes in the UV spectrum.
The usage of metal-bound triazole compounds as catalysts in asymmetric syntheses has been determined by studies in the literature. In comparison with classical metal catalysts, the catalysts containing 1,2,3-triazole are biocompatible and they are suitable for green chemistry conditions.
In the scope of the thesis, it was planned to bind the 1,2,3-triazole unit with the properties that can selectively hold many metals and anions on the xanthene compounds. For this purpose, it was tried to synthesize hydroxy xanthane derivatives in acidic medium by starting from 2,7-dihydroxynaphthalene compound but it was not successful. Thus, using the 4-hydroxybenzaldehyde compound, K2CO3 and acetone, the benzaldehyde compound having propargyl ether group at para position was synthesized. Using the synthesized aldehyde compound, the free hydroxy group containing dibenzoxanthene compounds were obtained. It was then converted to xanthene compounds containing triple bonds as a result of the etherification reaction with the free phenolic hydroxyls and propargyl bromide. At this stage, the appropriate intermediate product was synthesized for the compounds intended to contain the triazole ring. Diversification of the cavity is important for the study because it is thought that the synthesized compounds can be used as a sensor to provide recognition of anions and cations. Therefore, the azide derivatives were diversified and the resultant products with different cavities were obtained. Synthesis of (azidomethyl)benzene was carried out using sodium azide and benzyl bromide. 9-(azidomethyl)anthracene was synthesized using anthracene 9-ylmethanol and sodium azide. It was thought that new type of fluorescence chemosensor could be obtained by adding anthracene structure which may have fluorescence activity on triazole unit.
Then,using previously synthesized xanthene compounds, triazole containing xanthene compounds were synthesized by Cu (I) catalyzed 1,3-dipolar cycloaddition reactions .
First, both the phenolic hydroxyl group and the propargyl ether substituted dibenzoxanthene compound were put directly into the azide-alkyne cycloaddition reaction, but the desired product could not be obtained. From this experiment, the free hydroxyl groups were thought to prevent the reaction from being carried out successfully, and the complex was formed between the hydroxyl groups and the Cu (I) catalyst.Therefore, the synthesis method was altered. The free hydroxyl groups had to be protected with a suitable protecting group prior to the azide-alkyne cycloaddition reactions due to the complexation with metal catlayst during the synthesis. The selection of the protecting group must not degrade during the azide- alkyne cycloaddition reactions and the triazole groups were not degraded during the removal of the protecting groups. For these reasons, it was decided to use acetyl groups. The hydroxyl groups were converted to acetyl groups using triethyl amine and acetic anhydride. The 1,3-dipolar cycloaddition reactions with these synthesized acetyl substituted dibenzxanthene compounds were successfully carried out. After carrying out the reactions, the protecting group was removed in the basic medium.
In order to diversify the cavity, two different products were obtained from two different azide derivatives. Thus, both the phenolic hydroxyl groups and the triazole unit containing dibenzoxane compounds were obtained.
At the end of the study, four different final products were obtained with different molecular cavity.
The structures of the synthesized compounds were illuminated by 1H-NMR and 13C- NMR.