Benzodioksinonlar üzerinden çözücüsüz ortamda salisilat türevlerinin sentezi
Solvent free synthesis of salicylate derivatives via benzodioxinones
Yazar: SEMRA ÖZDEMİR
Danışman: PROF. DR. EMİNE NACİYE TALINLI
İstanbul Teknik Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı / Organik Kimya Bilim Dalı
Derece: Yüksek Lisans, 2016
Konu: Kimya = Chemistry

Özet:
Benzodioksinonlar üzerinden termoliz ve fotoliz ile oluşan α-oksoketen yapıları oldukça reaktif ara yapılardır. Bu yapılar ortamdaki nükleofil karakter taşıyan hidroksil ve amin grubu içeren bileşiklerle kolaylıkla reaksiyona girip ester ya da amid yapılarını oluştururlar [2].
Benzodioksinonlardan yola çıkılarak α-oksoketen ara yapıları iki alternatif yolla elde edilebilmektedir. Bu yollardan birincisi uyarılmış bir singlet halden doğrudan                         α-oksoketen oluşturmak üzere retro [4+2] halka açılmasıdır. Diğeri ise,  uyarılmış bir triplet halden homolitik C-O bağı kırılmasıdır. Bu kırılmayla oluşan biradikal ara yapı parçalanmayla α-oksoketen oluşturmaktadır [3].
Benzodioksinonlarının termolizi veya fotolizi ile elde edilen oldukça reaktif α-oksoketen yapılarından birçok doğal bileşiğin yapı iskeletinde bulunan salisilik asit esterler ve amidler yüksek verimlerle elde edilebilmektedir.
Bu tez kapsamında yapılan çalışmada ise, benzodioksinonların çeşitli alkol türevleriyle reaksiyonu sonucu salisilik asit türevi esterlerin sentezi gerçekleştirilmiştir. Ancak bu çalışmadaki amaç, çözücü kullanılmadan, oda koşullarında ve oldukça kısa sürede salisilat türevi esterleri sentezlemektir.
Literatürde buna benzer moleküllerin sentezi gerçekleştirilmiş ancak çözücüsüz ortam ve oda koşullarında bu reaksiyonlar denenmemiştir. Bu çalışmada kullanılan alkol türevleri; doymuş alkol olarak butanol ve 2-bromoetanol, doymamış alkol olarak 3-metil-2-buten-1-ol, 2-metil-3-butin-2-ol ve diol olarak da cis-2-buten-1,4-diol ve 2-butin-1,4-diol'dur.
Oda koşullarında gerçekleştirilen reaksiyonlarda başlangıç bileşiği olarak 2,2-dimetil-[2H,4H]-1,3-benzodioksin-4-on ve 7-(2-bromoetoksi)-2,2-dimetil-4H- benzo[d][1,3]-dioksin-4-on sentezlenerek kullanılmıştır.
Deneysel çalışmaların ilk basamağında doymamış alkol türevi olarak 3-metil-2-buten-1-ol seçilmiştir. Reaksiyon ilk olarak oda koşullarında denenmiştir ancak istenilen ürün elde edilememiştir. Bunun nedeni fotoliz ve termoliz yoluyla oluşan oldukça reaktif bir ara yapı olan ketenin oda koşullarında oluşmamasıdır. Bunun sonucunda da nükleofiliteyi arttırmak için ortama sodyumun katalizör olarak ilave edilmesi düşünülmüştür.
İlk olarak 3-metil-2-buten-1-ol'den sodyum katalizörlüğünde alkoksit oluşturulmuş ve oluşan nükleofilin benzodioksinon halkasına nükleofilik atağı sonucu ana ürün olarak beklenen 3-metil-2-buten-1-il-2-hidroksi benzoat bileşiği oluşmuştur.Yapılan literatür çalışmaları sonucunda elde edilen ürüne literatürde rastlanılmıştır, ancak uygulanan yöntem oldukça farklıdır.
Deneysel çalışmaların ikinci basamağına başlangıç bileşiği olarak 2,4-dihidroksi benzoik asit türevlerinden hazırlanan dioksinon bileşiği ile devam edilmiştir ve istenen ürünlerin yapılan spektroskopik yapı tayinler ile elde edildiği görülmüştür.
Sonuç olarak, benzodioksinonlardan yola çıkılarak oda koşullarında salisilat türevleri literatürde olmayan bir yöntemle oldukça kısa sürede sentezlenmiştir. Özellikle doymamış alkol yapılarının kullanılmasındaki amaç triazol, epoksit gibi yeni fonksiyonel gruplarla orjinal esterlerin elde edilmek istenmesidir. Reaksiyonların biri hariç oda koşullarında gerçekleşen reaksiyonlarda verimler oldukça yüksektir ve klasik esterleşme reaksiyonlarına göre oldukça çevre dostu bir yöntemdir , çünkü klasik esterleşme reaksiyonlarında ortama katılan derişik asidin daha sonra ortamdan giderilmesi işlemi çevreye oldukça zararlıdır. Ayrıca çözücü kullanılmamış olması da önemlidir.

Abstract:
The main subject of the thesis, reactions that use benzodioxinones generally  proceed highly reactive intermediate structure, α-oxoketenes , by thermolysis  or photolysis of benzodioxinones. Therefore, it is necessary to investigate the properties of α-oxoketenes chemistry.  Herman Staudinger, 100 years ago, discovered unstable ketenes like difluoroketenes, in subsequent studies he achieved to make stable bisketenes with the silyl substituents at room conditions and was able to isolate them.
Ketenes, by their chemical structures are very reactive intermediate structures. They are linear structures which have also carbon-carbon double bond and the double bond attached  an extra π bond (C=O). The middle of the C atom has sp hybridization. One of the important properties of ketenes is having cumulative structure. Another feature is the presence of the ketene plane perpendicular to the HOMO level and LUMO level which is parallel to the plane of ketene. This feature is defined by the positive charge on the oxygen atom and negative charge on the second carbon atom. In this case, it is expected nucleophiles to attack to the second carbon and electrophiles attack to negatively charged oxygen and positively charged first carbon atom. Considering the resonance structures of ketenes, it is understood that they show electrophilic property. It is expected the positive charge to be intense on the first carbon atom and negative charge to be intense on the second carbon atom.
Dipol moment of the ketenes was clarified by understanding of resonance structures. In the ketenes which have low dipol moment (1.45 D) than formaldehyde (2.27 D) , it has been proposed to be negative charge on the second carbon atom while less negative charge than ketones and aldehydes proposed to be on the oxygen atom.
It is seen in the literature that the intermediate α-oxoketenes, which formed by the thermolysis of benzodioxinones, are very reactive species and can undergo reactions with nucleophilic groups, such as hydroxyl and amine groups to form ester and amide structures [2].
Two general ways are suggested for the formation of α-oxoketene intermediates [3]. The first way is the retro [4+2] ring opening from an excited singlet state to form directly an   α-oxoketene. The other one is a C-O bond cleavege from an excited triplet state. This cleavege forms biradical intermediate which then yield α-oxoketene by thermolysis. 
α-oxoketenes which are very reactive species are obtained by the thermolysis or photolysis of benzodioxinones. In the presence of alcohols and amines, salicyclic esters and amides which are present in pretty much framework of natural products can be acquired in high yields.
In the presented work, ester functionalized macromolecules were synthesized via nucleophilic oxygen attacks to benzodioxinones. In this work our aim is to synthesize ester macromolecules without solvent in a relatively  short time in the room temperature.
Some molecules synthesized is found in the literature but none of them is synthesized with our process which is synthesizing molecules without solvent in the room temperature in a relatively  short time. In this work the alcohol derivatives are used; saturated alcohols ( buthanol and 2-bromoethanol) , unsaturated alcohols ( 3-methyl-2-butene-1-ol, 2-methyl-3-butyne-2-ol) and diols (cis-2-butene-1,4-diol and 2-butyne-1,4-diol). The initial compounds  used during the experiments are 2,2-dimethyl-[2H,4H]-1,3-benzodioxin-4-on ve 7-(2-bromoetoxy)-2,2-dimethyl-4H-benzo[d][1,3]-dioxin-4-on.
In the first step of the experiments, 2,2-dimethyl-[2H-4H]-1,3-benzodioxin-4-on  is synthesized depends on the procedure in the literature.  Firstly, 2-hydroxy  benzoic acid (1 eq) and benzophenon (1.5 eq) are placed into the two-necked flask under the nitrogen atmosphere. The  flask is cooled from the outside until the temperature is reached to 00C. Then, TFA (trifluoro acetic acid, 10 mL for 12 mmol benzoic acid) and TFAA (trifluoro acetic anhydride, 10 mL for 12 mmol benzoic acid) are added to the mixture. The prepared mixture is brought to the room temperature and then stirred up during 24 hours. At the end of the reaction, TFA and TFAA is evaporated with the rotary evaporator. Crude product is solved in ethylacetate and washed with the NaHCO3 until the acidity is eliminated. After organic phase is dried with the Na2SO4 , solvent is evaporated. At the end , crude product is purified with the column chromatography and molecular mass of the compound is detected with the GC-MS spectrum and found 178 as expected.
Then, the second initial compound , 7-(2-bromoetoxy)-2,2-dimethyl-4H-benzo[d][1,3]-dioxin-4-on , is synthesized with the protection procedure. First of all, at room temperatures K2CO3 in acetone is placed into the two-necked flask and then 7-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]-dioxin-4-on is added to the flask. At the last step 1,2-dibromoethane is added to the mixture and it is refluxed during 24 hours.
After refluxing, the crude product is washed with acetone and evaporated and then it is purified with the column chromatography.
In the second step of the work, 3-methyl-2-butene-1-ol is selected to use as an alcohol derivative. Because the ester found in the literature (3-methyl-2-butene-1-yl-2-hydroxy benzoate) is synthesized before with different method in high yields. In the literature, it is synthesized at room temperature with ZrCl4/NaBH4 catalyst in the dichloromethane medium with 96 % yield but the procedure takes 1.5 hours.
The reaction first of all is tried in the room temperature without any catalyst but the expected product is not formed since α-oxoketenes (the reactive intermediates) are not formed in the room temperature. They are just formed by thermolysis or photolysis and consequently to increase the nucleophilic feature, sodium is decided to add to the medium as a catalyst.
In the second trial, sodium is added to the medium to form alkoxide from 3-methyl-2-butene-1-ol and then the nucleophile formed is attacked to the benzodioxinone ring. The result of nucleophilic attacks to the benzodioxinone ring, 3-methyl-2-butene-1-yl-2-hydroxy benzoate is synthesized as expected. 
The H-NMR , C-NMR and FT-IR spectra of the 3-methyl-2-butene-1-yl-2-hydroxy benzoate is taken and all the datas are consisten with the literature. Therefore, all the products are synthesized with this procedure.
In the next step of the thesis, 2-bromoethanol is used to produce 2-bromoethyl-2-hydroxy benzoate with 70 % yields. According to the literature , the products synthesized in the next phase has not been demonstrated in the literature to any derivative of salicylate ester structure. 
Reactions were continued with the compound of dioxins was prepared from 2,4-dihydroxy benzoic acid derivative. The reason for this is to provide connecting potential to  many different functional groups to the molecule via free OH. Furthermore, the molecule does not react with itself is prevented. The molecule is made as functional by using 2-bromoethane. In this way, etheric bond  and bromine group is added to the structure. Then, new groups may be attached via bromine groups.
Consequently, starting from benzodioxinones, the procedure of salicylate derivatives are synthesized in a relatively short period of time is not in the literature. Specifically, the aim of using unsaturated alcohol structure is desired to obtain original esters with new functional groups such as triazole and epoxide.
Yields are very high in the reaction taking place at room conditions, except for one and is very environmentally friendly method according to the conventional esterification reactions, because the removal of the concentrated acid from the medium is very harmful to the environment. It is also important not to be used solvent in the reactions.