Aktif metilen bileşiklerinin alkilasyonu
Alkylation of active methylene compounds
Yazar: HAMDİYE ECE
Danışman: PROF. DR. EMİNE NACİYE TALINLI
İstanbul Teknik Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı
Derece: Yüksek Lisans, 2015
Konu: Kimya = Chemistry

Özet:
Yapılan çalışmada 1,3-dikarbonil bileşiklerinden asetilasetonun ve dibenzoilmetanın enon ve alkol türevi bileşikleriyle asit karakterli Amberlyst-15 katalizörlüğünde alkilasyon reaksiyonları incelenmiş ve elde edilen ürünlerin saflaştırma işlemlerinden sonra yapı tayin analizleri yapılmıştır.  
Dikarbonil bileşiklerinin  alkilasyon reaksiyonlarında genel olarak alkil halojenürler kullanılmaktadır. Halojenli bileşiklerin çevre etkisi düşünüldüğünde alkil halojenürler yerine alkoller de kullanılabilmektedir. Benzilik ve allilik alkol türevlerinin alkilasyonu sırasında belirli zorluklarla karşılandığı bilinmektedir. Hidroksil grubunun zor ayrılan grup olmasından kaynaklanan sorunlar literatürde türevlendirme ile çözülmeye çalışılmıştır. Ancak bu türevlendirme sonucunda elde edilen molekülün reaksiyonları incelendiği vakit yüksek sıcaklıkta gerçekleştirildiği görülmüştür. Yüksek sıcaklık katalizör kullanımını doğurmuş ve Lewis asitlerinin tercih edildiği görülmüştür. Ancak Lewis asitlerinin kullanılması allilik alkol türevlerinde verimli bir şekilde istenilen ürün elde edilirken benzilik alkol türevlerinde sorunlarla karşılaşılmıştır. Bunun yanında Lewis asitlerinin kullanılması hem reaksiyon sırasında hem de reaksiyon sonrası saflaştırma basamaklarında dikkatli çalışmayı gerektirdiğinden reaksiyon süresini uzatmıştır.
Literatür çalışmaları sonucunda asit karakterli Amberlyst-15'in reaksiyon ortamından kolayca uzaklaştırılabildiği, literatürde kullanılan diğer katalizörlerle aynı etkinliğe sahip olduğu, reaksiyon sırasında yüksek sıcaklığa ihtiyaç duymadığı ve  saflaştırma basamaklarını kısalttığı anlaşıldığından aktif metilen bileşikleri ve çeşitli benzilik veya allilik alkollerin deneyleri sırasında kullanılmıştır.
Çalışma sırasında ilk başta literatürde de bulunan asetilasetonun 1-fenil etanol ve benzhidrol bileşikleri ile Amberlyst-15 karalizörlüğünde reaksiyonları denenmiş ve istenilen alkilasyon ürünü elde edilmiştir. Bu deney sırasında ortam şartları belirlenerek daha sonraki deneysel çalışmalara temel oluşturmuştur.
Asetilaseton ile olan denemelerden sonra 1,3-dikarbonil bileşiği değiştirilerek dibenzoilmetan seçilmiştir. Dibenzoilmetanın 1-feniletanol ve benzhidrol bileşikleri ile Amberlyst-15 katalizörlüğünde reaksiyonu yapılmış ve beklenen ürünler elde edilmiştir.
Alkol türevleriyle olan reaksiyonlardan sonra reaktif olarak enon türevlerinden benzalaseton, 2-siklopenten-1-on ve 2-siklohekzen-1-on bileşikleri seçilerek aynı ortam şartlarında Amberlyst-15 katalizörlüğünde dibenzoilmetan ve asetilaseton ile reaksiyonları denenmiştir. Dibenzoilmetan denemelerinde beklenen alkilasyon ürünleri verimli bir şekilde gerçekleşmiştir. Enon türevi olarak benzalaseton ve 2-siklopenten-1-on seçilerek asetilaseton ile yapılan denemeler sonucunda alkilasyon ürünüyle beraber molekül içi halkalaşma ürününün de oluştuğu yapılan yapı analizleri sonucunda anlaşılmıştır. Analizler sonucunda ise 2-siklohekzen-1-on ile yapılan denemede ise beklenilen alkilasyon ürünü yerine sadece molekül içi halkalaşma ürünü sentezlenmiştir.
Sonuç olarak bu çalışmada literatürde ilk kez enonlar kullanılarak 1,3-dikarbonil bileşiklerinin alkilasyonu gerçekleştirilmiştir. Amberlyst-15 kullanılarak hem geri kazanılabilen cevreye duyarlı bir katalizör kullanılmış hem de deneysel işlemler kolaylaştırılmıştır.

Abstract:
In this study, alkylation reactions between 1,3-dicarbonyl compounds and benzylic alcohols or enone derivatives in the presence of acidic catalyst Amberlyst-15 were studied. 
The alkylation of 1,3-dicarbonyl compounds is a useful transformation involving C-C bond formation. Generally, these reactions are carried out in the presence of base. Because of some significant drawbacks of these procedures, new synthetic methods are developed especially without using halides. Instead of halides, benzylic and allylic C-H bonds or allylic/benzylic alcohols or diene/triene and cyclic enol ethers were preferred for alkylation. Oxidative coupling of benzylic and allylic C-H bonds with 1,3- dicarbonyl compounds were carried out using sulfonic acid-oxygene, Cu(ClO4) or DDQ as catalysts. Also, FeCl3–catalysed direct alkylation with benzylic/allylic alcohols have also been developed.
In principle, direct nucleophilic substitution of the hydroxy group in alcohols with nucleophiles generally requires preactivation of the alcohol because of its poor leaving ability.Therefore, hydroxyl groups are generally converted into some appropriate groups, which can easily leave from compounds. However, transforming hydroxyl group  requires high temperatures or usage of catalyst. In most cases, Lewis acides are chosen as a catalyst during the reactions. Most of Lewis acides works well only with allylic alcohols but not wth benzylic alcohols.Because of requiring, the harsh conditions, long reaction times, high temperatures, and use of expensive, toxic and moisture sensitive reagents in most of the above methods, the practical utility in organic synthesis has been limited. Besides that, DDQ is soluble in the water. Because of this, when DDQ is chosen as a catalyst , it has reaction with water and  hydrogen cyanide which is environmentally harmful is occured in short time. 
In addition to this, direct carbon-carbon bond formation between active methylene compound with Amberlyst-15 catalyst in ionic liquid has been reported. The alykalated products were obtained with high yield. Ionic liquid is a solution from anions and cations which allows not using solvents during reactions. The ionic liquid is environmentally friendly and does not have any harmful impact on reactants or catalyst. Unfortunately, it is economically expensive.
Herein, we report Amberlyst-15 as an acidic catalyst for direct carbon-carbon bond formation between active methylene compounds and various benzylic alcohols in organic solvents. Commercially available Amberlyst-15 has played an important role in organic synthesis and versatile synthetic applications of Amberlyst-15 in different chemical transformations. Reactions include esterification, transesterification, Michael addition, aza-Michael addition, Prins cyclization, Friedel-Crafts alkylation, acylation, metal free hydroarylation, hydroalkylation, halogenation, protection of carbonyls, amines, deprotection of acetals, acetates, Boc-protected amines, cleavage of epoxides, crossed-aldol condensation, synthesis of quinolines, pyrazolines, indolinones, acridines, calix[4]pyrroles, xanthenes, coumarins,benzopyrans theaspirane, furans, and substituted phosphonates. The catalysts can be regenerated and recycled.
For our initial studies, we chose alkylation reactions between acetylacetone with 1-phenylethanol and benzhydrol in the presence of Amberlyst-15 catalyst. Firstly, for reactions with acetyacetone and dibenzoylmethane, we studied synthesis of 1-phenyethanol. We obtained 1-phenyethanol from acetophenone in methanol medium. Secondly, we tried alkylation reaction between acetylacetone and 1-phenylethanol in the presence of Amberlyst-15 catalyst. The alkylated products were obtained in short time and with high yield. After getting product from first alykalation reaction, we studied reaction between acetyacetone and benzhydrol with Amberlyst-15 catalyst in chloroformmedium. The alkylated products were obtained with high yield and in short time. We tried to optimize the reaction conditions, such as time , heat and solvent type. Chloroform was the best solvent and most of the rection was run for 24 hours. 
In addition to this, we chose dibenzoylmethane as an active methylene compunds and examined alkylation reaction in the presence of Amberlyst-15 catalyst. We tried alkylation reaction between acetylacetone and 1-phenylethanol in the presence of Amberlyst-15 catalyst. The alkylated products were obtained in short time and with high yield. After getting product from this reaction, we studied reaction between acetyacetone and benzhydrol with Amberlyst-15 catalyst in dichloromethane medium. The alkylated products were obtained with high yield and in short time. We tried to optimize the reaction conditions, such as time , heat and solvent type. Dichloromethane was the best solvent and most of the reaction was run for 5 hours. 
After reactions with alcohol derivatives, we prefered to study alkylation reaction  with enone derivatives. Dibenzoylmethane and acetylacetone reacted with these compounds in presence of Amberlyst-15. Firstly we studied, alkyltion reaction between dibenzoylmethane and 2-cyclo-hexen-1-one in the presence of Amberlyst-15 catalyst in dicholoromethane medium.  After analyzing the structure of product,we studied alykalation reaction between dibenzoylmethane and 2-cyclo-penten-1-on in the presence of Amberylst-15 in dicholoromethane medium. After this, we tried alkylation reaction between dibenzoylmethane and benzalacetone in the presence of Amberylst-15 catalyst in dicholoromethane medium. After analyzing the structure of products, it was observed the alykalated products in short time with high yields. We tried to optimize the reaction conditions, such as time , heat and solvent type. Dichloromethan was the best solvent and most of the reaction was run for 5 hours. 
After successfully accomplishing direct direct carbon-carbon bond formation between dibenzoylmethane and enone derivatives, we studied alkylation reaction with acetyacetone in the presence of Amberlyst-15 catalyst. we studied, alkylation reaction between acetylacetone and 2-cyclo-hexen-1-one in the presence of Amberlyst-15 catalyst in dicholoromethane medium.  After analyzing the structure of product,we studied alykalation reaction between dibenzoylmethane and 2-cyclo-penten-1-on in the presence of Amberylst-15 in dicholoromethane medium. After this, we tried alkylation reaction between dibenzoylmethane and benzalacetone in the presence of Amberylst-15 catalyst in dicholoromethane medium. After analyzing the structure of products, it was observed the alykalated products in short time and that not only alkylation products but also ring closure products were obtained.
In this study, first time the alkylation of 1,3-dicarbonyl compounds with enone derivatives has been accomplished by Amberlyst-15. In addition, by using Amberlyst-15, recyclable and environmentally friendly catalyst was used and the experimental procedure has been shortened and became much more easier.