Dissertation
Photoredox-mediated radical functionalization of unactivated diamondoid C–H bonds
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2023
DOI: 10.25820/etd.006839
Abstract
Efficient carbon-hydrogen (C–H) bond functionalization is pivotal in organic synthesis and drug development. Hydrogen atom transfer (HAT) methods (both thermal and photochemical) enable the direct transformation of a C–H bond to C–C or C–X bonds. Yet, challenges persist in reactivity and selectivity, particularly for substrates like diamondoids which have multiple types of C–H sites.
Diamondoids are polycyclic hydrocarbons which currently present a challenging yet promising class for functionalization. Radical C–H functionalization methods on diamondoid substrates are reviewed herein, with an emphasis on key reactions relevant to the subsequent research. From the discovery of adamantane in crude oil reserves to its efficient Lewis acid-mediated synthesis, adamantane became the first diamondoid to be popularized. Commercial accessibility and discovery of early amino-diamondoid drugs heightened interest into diamondoids, leading to diverse C–H functionalization strategies. Adamantanes are integral in pharmaceuticals and materials and inspire numerous ligands and catalysts. Radical reactions which involve the adamantyl radical include acylation, alkylation, alkenylation, alkynylation, and arylation, all of which showcase the versatility of diamondoids in C–H activation.
Advancements in photochemical HAT methods have modernized direct C–H functionalization, eliminating pre-functionalization steps in drug synthesis. Despite numerous advances in HAT-mediated C–H transformations, challenges persist in regioselectivity for complex substrate classes like diamondoids. Our group reports a strategy which merges HAT and photoredox to enable selective radical generation from diamondoid C–H donors. Adamantane, the simplest diamondoid and a valuable model C–H donor, demonstrated exceptional regiocontrol in aminoalkylation via photoredox and HAT dual catalysis. This approach yielded over 17 monofunctionalized adamantanes in 28-87% yields, including a key intermediate for saxagliptin. In addition to a dual catalytic system featuring an iridium complex and amine HAT catalyst, we found that a direct quinone HAT catalyst was an efficient catalyst for asymmetric aminoalkylation with chiral sulfinamines. Water, previously used as a proton shuttle agent, was found unnecessary in the aminoalkylation conditions described herein. Reductive cleavage of protecting groups led to free amino-diamondoid pharmacophores.
Previous group members’ attempts to apply the dual-photoredox method to diamantane, a higher diamondoid with multiple 3° C–H bonds, revealed low regioselectivity ratios with a ~1.2:1 ratio of medial:apical products. Our exploration of cationic pyrylium dyes as photoredox catalysts coupled with inorganic Brønsted bases seeks to address these challenges. Despite an unexpected average 3.4:1 medial:apical product ratio, the method stands as efficient, metal-free, and promising for higher diamondoid functionalization. Water and base were discovered to be detrimental to the reaction yield, as confirmed by optimization studies. Leveraging NMR spectroscopy for accurate yield quantification and optimizing drying agents, we obtained isolated yields up to 98%. Our proposed mechanism involves photooxidation of diamantane, proton loss, and trapping of the diamantyl radical. Stern-Volmer experiments and EPR analysis support this mechanism, corroborating diamantyl radical formation upon a photooxidation event by the pyrylium.
Details
- Title: Subtitle
- Photoredox-mediated radical functionalization of unactivated diamondoid C–H bonds
- Creators
- Hoang Thai Dang
- Contributors
- David B. C. Martin (Advisor)Florence Williams (Committee Member)Ned B Bowden (Committee Member)Scott K Shaw (Committee Member)Elizabeth A Stone (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Autumn 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006839
- Number of pages
- xviii, 159 pages
- Copyright
- Copyright 2023 Hoang Thai Dang
- Language
- English
- Date submitted
- 12/04/2023
- Description illustrations
- illustrations (some color), graphs
- Description bibliographic
- Includes bibliographical references (pages 156-159).
- Public Abstract (ETD)
- Diamondoids are an interesting class of molecules in the context of drugs and materials and are the focus of this dissertation. A key mode of chemical manipulation of these molecules is radical functionalization, which involves changing a hydrogen-bonded carbon into one that bears a single electron that can make new bonds. In two key projects, we 1) expanded the chemical transformation of adamantane with nitrogen-containing partners and 2) explored the more difficult transformation of more complex higher diamondoids, unique structures with applications across various domains. In the first project, we successfully changed adamantane using a combination of light and special agents called catalysts. This process lets us control which parts of the molecule are modified by the catalysts, improving the synthesis of these molecules and lowering environmental impact. Additionally, we found more effective pathways, contributing to the sustainability of the overall process. The second project involved more complex diamondoids such as diamantane. We developed a method to preferentially change specific bonds in this intricate structure. Even though we faced some unexpected challenges, we found a way to make the process efficient and ecofriendly, without using heavy metals. In summary, our research advances the synthesis of better diamondoid molecules. Through this, we expanded our toolkit for chemical transformations, paving the way for better innovation of diamondoid-based medicines and materials. The implications of this work could cause further interest in more creative methods to make these molecules, influencing the production of medicines you take and the materials you encounter in your daily life.
- Academic Unit
- Chemistry
- Record Identifier
- 9984546848202771
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