Rh (I) katalizörlüğünde gerçekleşen regıodıvergent azit-alkin halka katılma tepkimesinin modellenmesi
Modelling of Rh (I) catalyzed regidovergent azide-alkyne cycloaddition reaction
Yazar: SUDE AYIK ERDEM
Danışman: PROF. DR. NURCAN TÜZÜN
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Yüksek Lisans, 2024
Konu: Kimya = Chemistry

Özet:
Metal katalizörlü azit-alkin halka katılma tepkimeleri sentetik kimyacıların ürün sentezinde çok sıklıkla başvurdukları bir yöntemdir. Klik kimyasının prototip tepkimesi olan bu tepkime çeşitli metallerle ve çeşitli bölge seçicilikle gerçekleşebilmektedir. Zheng ve grubu RSO2, RS ve RP(MeO)2 sübstitüye alkinin Rh-katalizli azit-alkin siklokatılma tepkimesinde çok yüksek oranda 1,4/1,5-halkalaşma seçiciliği gösterdiğini raporlamışlardır. Bu projenin amacı, Zheng ve grubu tarafından raporlanmış olan internal kükürt ve fosfat sübstitüye alkinler ve azit arasında Rh varlığında yüksek regioseçicilikle gerçekleşen 1,4 ve 1,5-halkakatılma tepkimelerinin mekanizmasını hesaplamalı kimya yöntemleriyle belirlemektir. Bu proje kapsamında kuantum mekanik hesaplamalar ile literatürde sunulmuş olan önerilere uygun olarak tepkime mekanizması modellenmiş, 1,4- ve 1,5-halka-kapanmasına etki eden sübstitüyent etkisi açıklanmıştır. Tez kapsamında yapılan DFT hesaplamalarında seçilen teorik seviyede deneysel secicilik doğrulanmıştır. Elde edilen mekanizmalardaki 1,4 ve 1,5-kapanmaya ait serbest enerji bariyerleri deneyleri doğrular niteliktedir Bu tepkimelerin tümünde seçiciliği belirleyen adımın azit ve alkin arasında bağlanmayı sağlayan ilk geçiş konumu olduğu görülmüştür. Bu geçiş konumlarının geometrik parametrelerinin Hammond prensibine uygun davrandığı gözlemlenmiştir. Geçiş konumlarının enerjilerine etki eden bir diğer faktörün sübstitüyelerin alkin karbonları üzerinde yarattıkları elektronik yükleri olduğu ortaya konmuştur. İncelenen sistemlerde seçiciliği belirleyen azit-alkin bağlanma aşamasında negatif yüklü azot atomunun kimyanın en temel prensiplerine uygun olarak daha pozitif yüklü olan karbon atomunu seçtiği gözlemlenmiştir. Hesaplamalardan elde edilen tepkime bariyerleri deneysel sonuçlarla uyum içerisindedir. Projenin devamında enerjilerin rafine edilmesi ve farklı başlangıç kompleks yapılara bağlı olarak seçiciliğin değişip değişmediğinin irdelenmesi önerilmektedir. Hesaplamalar DFT ile Gaussian 16 yazılımı kullanılarak M06-L fonksiyoneli ile gerçekleştirilmiştir. Rh metali için hem relativistik etkileri dikkate alması hem de ihtiyaç duyulan bilgisayar zamanını azaltması sebebiyle ECP kullanılmış ve Rh metalinin optimizasyonu LANL2DZ baz seti ile yapılmıştr. Geri kalan atomlar için ise 6-31+G(d,p) baz seti kullanılmıştır. Tüm atomların yükleri NBO yöntemi ile heaplanmıştır. Hesaplamalar, UHeM'de gerçekleştirilmiştir.

Abstract:
Metal-catalyzed azide-alkyne cycloaddition reactions are frequently used by synthetic chemists in product synthesis. This reaction, which is the prototype reaction of click chemistry, also known as 1,3-dipolar cycloaddition, enables the progression of a five-membered ring as a result of the reaction between a 1,3-dipole and a dipolarophile. This reaction is first discovered and summarized by Rolf Huisgen in the 1960s in the 20th century. The Huisgen cycloaddition reaction has found widespread application in various branches of organic chemistry, including drug discovery, materials science, and bioconjugation. This reaction offers a simple and efficient way to create heterocyclic compounds, which are essential building blocks in pharmaceutical research and other chemical industries. One of the best-known examples of the Huisgen cycloaddition reaction is the synthesis of 1,2,3-triazoles. The reaction proceeds via a [3+2] cycloaddition mechanism in which three atoms of the azide and two atoms of the alkyne combine to form a five-membered triazole ring. In the vast majority of 1,3-cycloadditions, the reaction rate is not significantly affected by the dielectric constant of the solvent medium in which the reaction is carried out. Although the discovery of Huisgen reactions enables the synthesis of a wide variety of chemicals in a short time, it poses difficulties in application. In the Husigen reaction, the process takes place under thermal conditions, and this requires both high temperatures and long reaction times. In 1,3-cycloadditions, the reaction rate is not significantly affected by the dielectric constant of the solvent environment in which the reaction is carried out. In 2001, Sharpless and Meldal's groups independently discovered the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. In this sense, the copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC) developed by Sharpless and his team has taken its place in the literature as an important breaking point in modern chemical synthesis methods. This reaction, in "click chemistry", forms 1,2,3-triazole triazole derivatives in the presence of a terminal alkyne, a copper and a catalyst. Following this discovery, the synthesis of various triazoles could be carried out with great ease in many areas of chemistry. This reaction is regioselective and ends with high efficiency even at low temperatures, yielding the desired triazole derivatives without any by-products. The same process is approximately 107 times faster than Huisgen's uncatalyzed procedure. That is, the CuAAC reaction designed and implemented by Sharpless and Meldal's team has almost completely eliminated the disadvantages of the Huisgen reaction. These features make copper-catalyzed azide-alkyne cycloaddition the most popular click reaction developed to date. Due to the success of copper metal, studies were carried out with different metal catalysts. There are different selectivities for metals such as Rh, Ag, Ru etc. and they vary depending on the ligands, azide and alkyne substitutions. Sulfur-containing substituents on the alkyne likewise led to different selectivities. In 2005, ruthenium metal, whose catalytic activity on alkynes is previously known, is found to be an effective catalyst for AAC, which produces 1,5-disubstituted triazoles. The metals
Ag and Au have also been tested as good candidates because they are congeners of the efficient Cu catalyst. The mechanisms of CuAAC reactions have been studied in depth by both experimental and computational chemistry methods. In these studies, various mechanisms including mononuclear or binuclear copper types have been proposed for the Cu(I) catalyzed reaction, and a general consensus on the mechanism has been achieved with studies conducted in recent years. Zheng and his group reported that RSO2, RS and RP(MeO)2 substituted alkynes show high selectivity for 1,4/1,5-cycloaddition in Rh-catalyzed azide-alkyne cycloaddition reactions. The aim of this project is to determine the mechanism of the highly regioselective 1,4- and 1,5-cycloaddition reactions between internal sulfur and phosphate substituted alkynes and azide in the presence of Rh, as reported by Zheng et al. Within the scope of this project, the reaction mechanism is modeled by quantum mechanical calculations in accordance with the suggestions presented in the literature. In the mechanism calculations, the experimentally proposed reaction mechanism is modelled by taking into account the information obtained from the literature and the suggestions of the scientists who performed the experiments and the substituent effect on 1,4- and 1,5-cycloaaddition is explained. The experimental selectivity is confirmed at the theoretical level chosen in the DFT calculations performed within the scope of the thesis. While RSO2 and RP(MeO)2 substituted alkynes prefer the reaction mechanism of the 1,4 pathway, RS substituted alkynes prefer the 1,5 pathway. The free energy barriers of 1,4- and 1,5-closure in the obtained mechanisms confirm the experiments. In all of these reactions, it is observed that the step that determines the selectivity is the first transition state that enables the bonding between azide and alkyne. The steric and electronic effects affecting these preferences ae investigated. The first of these is how the substituents attached to the alkyne affect the charge distribution. Depending on the electronic properties of these substituents, the charges of the C atoms on the alkyne group are differentiated and which atom is preferred / or not preferred during nitrogen-C attack changes: Especially in the SO2 substituted system, electronic effects have been shown to have a decisive effect at this point. The SO2 substitution had a clear effect on the charge of the alkyne carbons due to the strong electron-withdrawing effect of the group, resulting in a pronounced electronic effect on selectivity. In all three systems, the preferences between the 1,4 and 1,5-mechanisms can be explained by considering the Hammond Postulate based on the distance between the reacting centres in the transition state geometries and the corresponding azide-alkyne-Rh complexes. In RSO2 and RP(MeO)2 substituted alkynes, the energy difference between the transition positions at the stage determining the selectivity is quite large. However, RS does not show a significant difference. Therefore; starting from the initial structures of RS substituted alkynes, the bond and angle changes during the oxidative addition of the first transition position and the subsequent formation of the intermediate are analysed. It has been observed that the pathway requiring the formation of the intermediate, which is more differentiated than the initial geometry, is realised with a higher barrier. Since the mechanism preference of RS substituted alkynes is explained by the experimentalists with chelation, the transitions from the unpaired electrons of the S atom to the anti-bonding orbitals of the Rh atom and the energies of these transition state geometries are evaluated on the structures (int-II_a and int-II'_a) where chelation is likely to be observed. The calculations performed within the scope of the thesis show that there is a chelation-induced stability as suggested by the experimentalists, but its efficiency is not very high. However, since the energy differences between the structures in the 1,4 and 1,5 pathways are very low, it has been shown that even a chelation-induced stabilisation of this efficiency has an effect on the energy of the structure and thus has an effect on regioselectivity. Although results in agreement with experiment are obtained, the high 1,4 barrier in the RP(MeO)2 substituted system could not be explained. In the continuation of the project, it is proposed to refine the energies and examine whether the selectivity changes depending on different initial complex structures. Calculations are performed by DFT with the M06-L functional using Gaussian 16 software. For Rh metal, ECP is used since it takes relativistic effects into account and reduces the computer time needed, and the optimization of Rh metal is performed with the LANL2DZ basis set. For the remaining atoms, the 6-31+G(d,p) basis set is used. The charges of all atoms are calculated by the NBO method. The calculations are performed in UHeM.