Karbenoid reaksiyonlarında katalizörler
Catalysts of carbenoid reactions
Yazar: DİLHAN TOPÇU
Danışman: PROF. DR. OLCAY ANAÇ
İstanbul Teknik Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı
Derece: Yüksek Lisans, 2016
Konu: Kimya = Chemistry

Özet:
Günümüzde diastereomerlerin, enantiyomerlerin detaylı ayırımı, tanımı ve seçici sentezleri çalışmaları bir üst aşama araştırmalar olarak öne çıkmaktadır. Bu bağlamda deney koşullarının modifiye edilmesi, kemo-seçici reaksiyonların sağlanması hedefli bileşiklerin saf ve daha iyi verimlerle sentezlenebilmesinde önem arzetmektedir.
Günümüzde diazo bileşikleri R2N2 genel gösterimli ve termodinamik olarak sahip oldukları N2'yi kolay vermelerinden dolayı oldukça reaktif moleküllerdir. Termal olarak oldukça kararsızdırlar ve ısı ile kolaylıkla serbest karben oluşturmaktadırlar. Karben bir nötral karbon üzerinde 2 tane eşleşmemiş elektron çifti ve iki de bağ bulunduran bir moleküldür. Serbest karbenin reaktivitesini kontrol eden karbenoidler ,karben-benzeri karbonun bir metal ile çoklu bağ yapmasıyla oluşur. Bu tez kapsamında daha önce grubumuzca çalışılmış karbenoid reaksiyonlarında seçilen hedefli üç reaksiyon tekrar ele alınmıştır. Hedef seçilen bu üç reaksiyon ilid oluşumu üzerinden gerçekleşen karbenoid reaksiyonlarıdır. İlidler pozitif yük taşıyan bir heteroatom ve onun bağlı olduğu, ortaklaşmamış elektron çiftine sahip karbon atomundan (karbanyondan) meydana gelen arayapılardır. İlid oluşumu için kullanılan bir yöntem, karbenlerin ortaklaşmamış elektron çifti taşıyan heteroatomlarla etkileşmesidir. Metalokarbendeki karbenik karbon Lewis asidi gibi davranarak, Lewis bazı olan bu heteroatomların sunduğu ortaklaşmamış elektron çiftini alır ve ilid yapısını oluşturur.
Diastereomerik-seçicilik için farklı katalizörlerin [satılan (hazır) /sentezlenen bilinen/sentezlenen orijinal katalizörlerin]  kullanılması söz konusu olabilmektedir. Bu tür seçicilik çalışmalarında katalizörlerin yanına hedefli seçilmiş katkıların da ilavesi de olasıdır. Katkılı katalizör çalışmalarında;
I.	Katkı katalizöre geçici koordinatif bağlanma ile seçicilik etkinliğini gösterebilir.
II.	Katkı katalizörle kalıcı bir reaksiyona girebilir (reaksiyon ortamında in-situ yeni bir katalizör oluşturabilir).
III.	Katkı reaksiyon ortamındaki (katalizör dışındaki) reaktiflerle reaksiyona girip yeni bir katkı oluşturabilir ve bu yeni katkı I ve II şıklarındaki görevleri üstlenebilir.
Çalışmanın amacı önce kemo-seçiciliğin sağlanmasıdır. Sonraki aşamada da stereokimyaları tam olarak tanımlanamamış diastereomer çiftleri var ise bunların yapılarının detaylı aydınlatılmasıdır. Son amaç ise tanımlanmış yapıdaki bu diastereomerlerin kendi içlerindeki seçiciliğine etkin olması düşünülen parametrelerin deneneceği sistemlerin alt yapılarının oluşturulmasıdır. Bu amaçlarla bu çalışmada daha önce ön çalışma olarak ele alınmış fakat ürün çeşitliliği ve seçiciliği anlamında tekrar incelenmesi amaçlanan hedefli üç tepkime ayrıntılı incelenmiştir. Bu tepkimeler;
I. 2-oktinal bileşiği ile 1-diazo-1-fenilpropan-2-on
II. α-İonon ile dimetil diazomalonat
III. β-İonon ile etil diazoasetoasetat tepkimeleridir.
Diastereomer oranlarını değiştirme bakımından α-İonon ile dimetil diazomalonat bileşiklerinin CuPc katalizörlüğünde ve CuCl/AgSbF6 katalizörlüğünde 2,2'-bipiridin katkısı ile gerçekleştirilen reaksiyonlarında bir miktar farklı yönlere değişim gözlenmiştir. Fakat genel anlamda kullanılan yöntemlerin, furan türevlerinin diastereomer oranlarını değiştirmek için etkin olmadığı tespit edilmiştir.

Abstract:
Diazo compounds having a general formula of R2N2 are highly reactive molecules due to the fact that they can give N2 thermally and or photochemically and or catalytically. Diazo compounds are not stable under the photochemical conditions and under heat and can easily decompose to free carbenes.  A free carbene (:CR2) is a molecule with two unpaired/paired electrons and two covalent bonds on a neutral carbon atom. On the other hand carbenoids are metal-carbene complexes (LnMCR2)    which can only be produced from catalytic conditions. In a carbenoid the carbenic carbon is capable of making multiple bonds with metal atom and these carbenoids can control the reactivities and selectivities of the corresponding free carbene. Transition metals are the most general species in the formation of carbenoids.
In this thesis, three different model of carbenoid reactions were studied. All these three carbenoid reactions could yield reactive ylides that produce the target molecules. Ylides are intermediates with the positively charged heteroatom directly bonded to a negatively charged carbon atom with unpaired electrons (R1R2C-−X+CR3R4). These ylide formations reaction can be easily occurred between a carbene and heteroatom with the unpaired electron. Similarly a carbenoid can produce a ylide:  
(Ln-M−C+R1R2 ) LnM=CR1R2  + XCR3R4 → Ln -MCR1R2  −X+ CR3R4  →  LnM       +  R1R2C-−X+CR3R4.
In these transformation, transition metal being a Lewis acid pulls the unpaired electron pair.
Generally in a large number of reactions, more than one product is formed. With respect of the yield of each novel product this diversity is not favourable. Similarly in this study, the chosen three different model of carbenoid reactions may produce several different novel compounds. So, modifying the experimental conditions to provide chemoselective reactions is very important with respect of the synthesize the main targeted compound in pure and better yields. As known, in nature almost all vital compounds are chiral - diastereomers, enantiomers- . So the diastereomeric formations in the product distribution can also be mentioned. Nowadays, better separation and identification of diastereomers is a highly important research topics. 
In this study, three targeted carbenoid reactions which are previously studied by our research group were discussed again. The primary aim of the study is to provide chemo-selectivity in these reactions. The next step is the detailed defination of their stereochemical structures in these chemoselective reactions. In our reactions diastereomer pairs formations are point at issue. The deteremination of the exact stereochemistries of the related diastereomers is needed. The last aim of this study is to clarify of reaction conditions in which parameters considered to be effective in the selectivity of these diastereomers within the defined structure are to be tested. It is possible to use different catalysts (such as commercially available catalysts, the ones that can be synthesized according to present literature or synthesized original catalysts) for diastereomeric selectivity. In such selectivity studies, it is also possible to add targeted selective additives nearby the catalysts. In catalytic studies additives can be used three different ways: 
1.	The additive may exhibit selectivity by coordinatively bonded to metal of the metal catalyst. 
2.	The additive may enter into a permanent reaction with the catalyst. (The additive can form a new in-situ catalyst in the reaction medium.)
3.	The additive may undergo a reaction with reactives (except catalysts) and form a new additive. Then this additive can act like defined on previous step.
For this purpose, three preliminary studies have been re-examined in terms of product diversity (chemoselectivity) and diastereoselectivity. Experimentally completed reactions are briefly;
1.	2-Octynal and 1-diazo-1-phenylpropane-2-on reaction:
Three different experimental methods have been tried with the reaction between 2-octynal and 1-diazo-1-phenylpropane-2-on. In this thesis extent, reaction conditions are changed with the use of different reactant ratios, different catalysts and additives.
The reaction between 2-octynal and 1-diazo-1-phenylpropane-2-on with the reactant ratio of 1.5:1 is resulted in the small amount of dioxolane formation in the presence of Rh2(OAc)4 catalyst.
When the reactant ratio is 1:1, the formation of dioxolane have not been observed and epoxy isomers were obtained dominantly in the presence of Rh2(OAc)4 catalyst. Trace amount of eninone compound is formed in this method.
The reaction between 2-octynal and 1-diazo-1-phenylpropane-2-on (in the ratio of 1:1) in the presence of CuCl/AgSbF6 catalyst system with 2,2'-isopropylidenebis[(4S)-4-phenyl-2-oxazoline] additive is yielded epoxy diastereomers nearby a major eninone compound. We determined that eninone compound was  totally derived from epoxy compounds: At the first stage of the reaction, epoxy derivative re-reacts with another diazo compound in the reaction media and forms 1-phenyl propane-1,2-dione with the eninone derivative besides.
Synthesis of eninone stereoisomers are supported by a newly published article in the literature. In this article, commercially obtained epoxy derivatives are reacted with two diazo compounds to give eninone compounds.
As a summary, under the third conditions we can produce diastereoselective reaction of 2-octynal and 1-diazo-1-phenylpropane-2-on.
2.	α-Ionone and dimethyl diazomalonate reaction:
Seven different experimental methods have been tried for the reaction of α-ionone and dimethyl diazomalonate. These reaction conditions are altered with the use of different reactant ratios, different catalysts and additives.
Furofuran was a side product of the reaction between two molecules of dimethyl diazomalonate and one molecule of α-ionone compound. Firstly, formation of undesired furofuran derivative was prevented with the controlled addition of dimethyl diazomalonate to reaction medium drop by drop. Increasing the reactant ratio of α-ionone in order to prevent furofuran formation is not a helpful process. Even though the higher dimethyl diazomalonate ratio was used in the reactions with additive, furofuran derivatives formation have not been observed.
In the two methods containing CuPc and CuCl/AgSbF6 catalyst system with 2,2'-bipyridine additive, the diastereomer ratios have changed. However, it has been determined that the methods used in the general sense are not effective to change the ratio of diastereomers of furan derivates.