HANOI UNIVERSITY OF SCIENCE AND TECHNOLOGY MASTER THESIS Synthesis and Characterization of immobilized Pyrimidopteridine-derived Photoredox catalysts DAO XUAN HUY Huy.vn Master of Science in Chemistry Supervisor 1: Dr. Nguyen Duc Trung Institute: School of Chemical Engineering Signature Supervisor 2: Dr. Jola Pospech Viện: Leibniz Institute for Catalysis (LIKAT) Signature HANOI, OCTOBER 2023 MASTER’S THESIS TITLE Synthesis and Characterization of immobilized Pyrimidopteridine-derived Photoredox catalysts Supervisor 1 Supervisor 2 Dr. Nguyen Duc Trung Dr.
Jola Pospech Acknowledgements First and foremost, I want to thank Dr. Jola Pospech, my supervisor at Likat - University Rostock. She welcomed me into the lab and began teaching me the fundamentals of organic synthesis. I appreciate her help as someone who is fresh to the organic area.
Working in her lab inspired and provided me with many new experiences. I'd like to thank Dr. Dirk Hollman and Dr. Esteban Mejia, who are in charge of the Rohan Fellowship program in Germany, and Prof.
Le Minh Thang, who is co- director of the Hanoi University of Science and Technology - Double-Degree program. Everyone, who has given me a scholarship and the opportunity to study and work at Likat, one of the world's most renowned catalysis institutions. Furthermore, my mentors in Vietnam, Dr. Nguyen Duc Trung and Dr.
Nguyen Ngoc Tue, who have supported and advised me during my difficult moments. Everyone has given me the confidence to continue my research and studies. It is an honor for me to work at Likat. I've been working with some incredible people here.
They assist me with education, safety when conducting research, and sharing culture and life in Germany. Many thanks to Tobias, Jannik, Thea, Johannes, and Xinzhe. I like conversing and engaging in extracurricular activities with everyone since I perceive us as a family with no linguistic or cultural barriers. While learning and working at Likat, I had a beautiful and unique experience.
I'd like to thank Likat's analytical department for preparing and measuring; IR, GC-MS. You guys have been helpful. And, of course, important in this wonderful adventure, I'd want to thank my family and friends for their assistance. I don't know how I would have survived without them.
They have been by my side and encouraged me during my time at Likat, giving me advice and assisting me in finding a better balance between work and life. Table of Contents Acknowledgements Table of Contents List of Abbreviations 1.1 Photochemistry and photocatalysis .2 Heteroarene N-oxides and the development of pyrimidopteridine N- oxide photo-redox catalyst. Results and Discussion .1 Synthesis of substituted urea derivatives .2 Towards the synthesis of N,N,N-face 1-ethoxy-2-methyl-1-oxopropan- 2-yl-substituted pyrimidopteridinetetraones .3 The synthesis of CO,N,CO-face 1-ethoxy-2-methyl-1-oxopropan-2-yl- substituted pyrimidopteridinetetraones .4 Synthesis of 3,7 bis(1-(benzyloxy)-2-methyl-1-oxopropan-2-yl)- 2,4,6,8-tetraoxo-1,9-dipropyl-1,2,3,4,6,7,8,9-octahydropyrimido[5,4-g] pteridine 5-oxide (21) .5 Characterization of pyrimidopteridine photosensitizers. Summary and Outlook .5 Nuclear Magnetic Resonance Spectroscopy .70 List of Abbreviations [M+] molecular ion peak eV electron volt Ac acetyl g gram Ad adamantyl GC gas chromatography Alk alkyl h hours aq.
aqueous Hex n-hexyl Ar aryl HPLC high-performance liquid Bn benzyl chromatography Bu n-butyl HRMS high resolution mass calcd. calculated spectrometry Cat catalytic Hz Hertz DCM Dichloromethane IR infrared spectroscopy DG directing group isol. isolated DMF N,N-dimethylacetamide J coupling constant DMSO dimethylsulfoxid L ligand Ed. Editor m multiplet ee enantiomeric excess [M] metal e.
for example Me methyl EI electron ionization MeCN acetonitrile ESI electrospray ionization MeOH methanol Et Ethyl m. melting point equiv. equivalent m/z mass-to-charge ratio EI-MS electron ionization mass min minute spectrometry mL milliliter Ph phenyl mmol millimol ppm parts per million MS mass spectrometry iPr isopropyl NMR nuclear magnetic R rest resonance spectroscopy rt room temperature OAc acetate sat. saturated THF tetrahydrofuran solv solved TLC thin layer t time chromatography T temperature chemical shift PPh3 Triphenylphosphine δ trimethylsilyl P-(n-Bu)3 Tributylphosphine TMS cyclic voltammetry DPV Differential CV dicyclohexylcarbodiimid pulse voltammetry DCC 4- BnOH Benzyl alcohol DMAP (dimethylamino)pyridine o.n Overnight Nanometer PIDA Phenyliodine(III) diacetate nm Wavelength Net3 Triethylamine λ PPT Pyrimidopteridine tetraone PPTNO Pyrimidopteridine tetraon N-oxide r.t Room temperatur UV Ultraviolet (280-380 nm) 1.1 Photochemistry and photocatalysis Photochemistry and photoredox catalysis have received a great deal of interest in the chemical world during the last decade, particularly in the field of synthetic organic chemistry.[1] Photochemistry is more than just a method of harnessing light energy.
Photochemistry is also important in processes that determine the composition of materials in interstellar space, as well as in the production of atmospheric pollutants.[2] Photocatalytic processes may be employed to influence chemical equilibria and to turn light into chemical energy as occurs naturally in photosynthesis. The catalyst in conventional catalysis supports each stage of the catalytic cycle and so acts as a reaction partner. Photoredox catalysts, on the other hand, in many circumstances merely induce the production of reactive radical species with enough energy to engage in a chemical reaction without the close association to the catalyst in terms of chemical bonding. Thus, maintaining the connection between the radical species and the chiral catalyst is a special problem in asymmetric photoredox catalysts.
Photoredox catalysis is a technology that enables a wide range of chemical reactions with great selectivity under modest visible light conditions. Some advantages of heterogeneous catalysts include ease of separation from the reaction mixture, increased optical and chemical stability due to reduced rotation and solid-state effects, the capacity to construct fixed catalytic layers, and, more broadly, "reusability.2 Heteroarene N-oxides and the development of pyrimidopteridine N- oxide photo-redox catalyst Heteroaromatic N-oxides have a 1,2-dipolar nitrogen-oxygen bond in which the nitrogen atom is a member of the heteroaromatic ring. The formally negatively charged oxygen has a significant influence on the physical characteristics and reactivitiy of the arene ring, which may be explained largely through electron delocalization [4]. Heteroarene N-oxides can be used as oxidants in organic reactions and in some cases can be used as the oxygen source in an oxygen atom transfer reaction.[5] Pyridine N-oxides are weak bases that are less basic than pyridines.
The conjugate acids of the corresponding pyridines have pKa values 1 about 5 and the pKa values of the conjugate acids of pyrimidine N-oxides in water are 1. Photoexcition of N-oxides. Zhang revealed in 2021, the development of pyridine N-oxide derivatives as effective photoinduced hydrogen atom transfer (HAT) catalysts for site-selective C-H functionalization. Gryko’s group proposed pyridine N-oxides as hydrogen atom transfer reagents in C-C bond formation processes.
Photoinduced pyridine N-oxide based HAT catalyst for C-H functionalization. Furthermore, it has recently been demonstrated that stable N-oxide intermediates can be produced in flavoenzymes without flavin reductase activity, preventing the creation of generally recognized flavin peroxide species.[9] Thus, heteroarene N- oxides have only lately emerged as participants in biological oxygenation processes. A substance class that is of interest and closely related to our research are the flavin. Flavins are cofactors in monooxygenases (flavoenzymes or flavin- dependent monooxygenases) and may activate molecular oxygen to insert one oxygen atom into an organic molecule (oxyfunctionalization reaction) via two- electron redox reactions.[10] Riboflavin (RF), generally known as vitamin B2, is a well-known photoreceptor dye that participates in biological redox processes as a 2 coenzyme.
Because RF and its derivatives are yellow compounds, they may absorb visible light with the greatest absorption in the blue range. Illustration of flavin derivatives. It is assumed that the oxygen atom transfer takes place via a hydroperoxyflavin species as a crucial step. However, new research suggests that flavin-N5-oxide acts as a viable intermediate in enzyme-catalyzed oxygenation reactions.
In 2013, the group Bradly S. Moore proposed that the flavin-N(5)-oxide acts as an active intermediate in an internal flavin-dependent monooxygenase that catalyzes the hydroxylation-dehydrogenation process. Proposed nucleophilic flavin-oxgen adducts. The stable flavin-N5-oxide has been proposed to engage in processes involving [12] EncM monooxygenase, causing oxidative carbon rearrangement , dibenzothiophene catabolism[13] and oxidative cleavage of uracil amides.[14] Pyrimidopteridines possess a flavin-like scaffold, with a much higher redox כ כ potential in the excited state (riboflavin ܧௗ ൌ ͳǤͷͲ୰ୣୢ ൌ ʹǤ͵ʹܸ݁ሻ.
Maki's team applied BuPPT N-oxide as an oxidizing agent for the selective metabolism of N-oxide/DMA ground state charge-transfer complex after their successful synthesis[16], investigated the hydroxylation of aliphatic and aromatic substrates. Oxidative demethylation of dimethylaniline b. Photooxygenation of alkenes c. Photooxidative decarboxylation of phenylacetic acid d.
Photochemical oxygenation towards phenols. In 2019, Pospech and co-workers extended the survey to some other pyrimidopteridine N-oxides including: tetramethyl MePPT N-oxide, tetrapropyl PrPPT N-oxide, tetrabutyl BuPPT N-oxide and tetraphenyl PhPPT N-oxide catalysts.[15] Pyrimidopteridine N-oxides can be in foure step from N,N’- disubstituted ureas or in two steps from commercially available aminouracil.besides, there was a development to replace lead (IV) actate by (diacetoyiodo)benzene (PIDA) which is less toxic and more environmentally friendly (Scheme 6). Synthesis PPT N-oxide with PIDA. Pospech’s group examined the photophysical and electrochemical properties of the prymidopteridine N-oxides and showed potent excited state oxidants potential of +2.30 V vs SCE in MeCN and higher.
Meaning, they were well suited for many application as oxidizing agents in organic photocatalysis. Their excited state redox potentials of all the PPT N-oxides. Pospech and co-workers found out that pyrimidopteridine-N-oxides serve as precatalyst to pyrimidopteridines (PPT) as catalytically active species. The synthesis of pyrimidopteridines (PPT) is possible via the deoxygenation of PPT N- oxides.
These compounds possess similarly high excited state reduction potentials of greater than + 2.09 eV versus SCE in MeCN (PrPPNT: E*red = +2.09 eV vs SCE in MeCN), allowing them to oxidize a wide spectrum of substrates.[15] They are conveniently accessible and stable on the bench. They are thus used as effective photoredox catalysts. Structure of the PPT photoredox catalysts. Organic photocatalysts generally possess lower productivity as compared to ruthenium and iridium catalysts, often due to catalyst degradation or deactivation pathways.[21] Nevertheless, organic photoredox catalysts remain attractive due to 5 their low costs and low toxicity.[22] Pospech’s group investigated and applied the photo-mediated formal addition of carboxylic acids to activated alkenes, which was catalyzed by a pyrimidopteridine photoredox catalyst.
The presence of electron-rich alkenes inhibits the decarboxylation of aliphatic carboxylic acids during single-electron oxidation, resulting in hydroacetoxylation.[23] The pyrimidopteridine photoredox catalyst was also used, in a photomediated hydrodecarboxylation of several primary, secondary, and tertiary carboxylic acids. Applications of the pyrimidopteridines. In the past ten years, there has been a significant expansion in the utilization of diverse organocatalysts for a wide array of organic transformations. In contrast to metal-catalyzed organic reactions, organocatalysts have demonstrated promising prospects for industrial applications.
They typically exhibit stability in air and are not easily rendered ineffective by process impurities, which is a crucial characteristic in the development of efficient procedures for industrial use[42]. The application of a transition-metal-free organocatalytic approach is very desirable 6 within the pharmaceutical sector owing to its ability to eliminate heavy metal residues from active medicinal components. An illustrative instance in this context is graphitic carbon nitride, which has garnered global recognition owing to its manifold benefits, including the abundant availability of nitrogen-rich raw materials, cost-effectiveness, expeditious and straightforward synthesis, sensitivity to visible light, and exceptional chemical stability.[46,47] Homogeneous catalysts have important advantages over their heterogeneous couterparts. It is often possible to tune the chemoselectivity, regioselectivity, and enantioselectivity of the catalyst.[26] In recent research, the synthesis of heterogeneous catalyst based on immobilized homogeneous catalyst can be divided into two types.
In the first, the catalyst is linked to a soluble or insoluble support, and the separation is accomplished by filtering. This procedure is also known as heterogenizing homogeneous catalysts. Mobilization on includes insoluble: ligand anchored onto solid material such as inorganic oxides (TiO2, silica, etc) or polymers.[27] The other kind immobilization includes designing the catalyst to be solubilized in a solvent that is immiscible with the reaction. In recent years, the creation of low-cost and environmentally friendly solid catalysts that are apt for industrial applications has gained much attention.[28] A method for hydroformylation processes was published in which a ligand from the highly selective Xantphos family was derivatized with a hydrocarbon chain terminating in a triethoxysilyl group.[29] This ligand was introduced into a sol-gel solution to focus silica and the subsequently supported ligand, was bound to rhodium.
