Dissertation
Synthesis of phosphine and phosphoramidite ligands derived from 1,8,10,9-triazaboradecalin and their reactivity with late transition metals
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2021
DOI: 10.17077/etd.006262
Abstract
Metal complexes containing Lewis acidic boron ligands play key roles in modern research efforts centered around the development of chemical sensors, catalysts, materials, and biologically and environmentally relevant technologies. Motivated by these applications, the Daly research group has been investigating a class of triaminoborane-bridged diphosphorus ligands called RTBDPhos (where R indicates the substituents bound to P) that can undergo cooperative ligand-centered reactions at the 1,8,10,9-triazaboradecalin (TBD) backbone while bound to metals. It was shown that treating (PhTBDPhos)MCl2 complexes (where M = Ni or Pd) with Brønsted acids and hydrated fluoride salts, for example, yielded net trans addition of H-X (X = OH, OR, Cl, and F) across the bridgehead N-B bond. However, these prior studies revealed a significant knowledge gap as to what controls ligand-centered reactivity in TBDPhos complexes. Initial investigations, for example, revealed that ligand-centered reactivity can be significantly hampered by altering the metal coordination environment or exchanging phosphorus substituents despite these modifications being significantly removed from the TBD backbone where reactions occur. This thesis describes fundamental studies that assisted in elucidating how chemical modifications control ligand-centered reactivity in TBDPhos complexes and explore the potential of these complexes for medicinal and catalytic applications. Chapter 1 provides a brief survey of different classes of boron ligands and describes factors that control cooperative ligand-centered reactivity in TBDPhos complexes. Chapters 2 – 4 then address three major domains of scientific inquiry: 1) the evaluation of the potential of water-soluble TBDPhos complexes with palladium and platinum as bifunctional anticancer metallodrugs and [18F]-positron emission tomography (PET) imaging, 2) modular synthesis and characterization of an extended library of Group 10 complexes with phosphoramidite TBDPhos ligands, and 3) investigations of TBDPhos ligands for C-F activation chemistry with low-valent late transition metals. A brief summary of each chapter is described in the following paragraphs.
One of the keys to decreasing metallodrug side effects is identifying chemical modifications that attenuate distribution in healthy tissues and increase drug localization in tumors. The high Lewis acidity and fluorophilicity of borane-containing ligands make them promising candidates for rapidly tagging metal complexes with 18F isotope to access novel anticancer metallodrugs that can be tracked in vivo using [18F]-positron emission tomography (PET) imaging. Toward this goal, Chapter 2 describes the synthesis and characterization of water-soluble Pd(II) and Pt(II) complexes containing MeOTBDPhos and defines how this ligand can be rapidly fluorinated using simple fluoride salts and HBF4·Et2O. Time-resolved NMR screening studies demonstrate that complexes (MeOTBDPhos)PdCl2 and (MeOTBDPhos)PtCl2 dissolve in water with H-OH addition across the bridgehead N-B bond in the TBD backbone. Once dissolved, the water-bound complexes (MeOTBDPhos-H2O)MCl2 are relatively stable with respect to decomposition and formation of boric acid. The B-OH bonds in the water-bound complexes undergo rapid displacement with fluoride (~10 min) when they are treated with CsF in MeCN. It was also found that fluoride-bound complex (MeOTBDPhos-HF)PtCl2 can also be prepared by addition of KF to (MeOTBDPhos)PtCl2 in the presence Kryptofix 222 and (HNEt3)Cl. Moreover, it was shown how monomeric (MeOTBDPhos)PtCl2 can be fluorinated with HBF4·Et2O to form the dinuclear complex [(MeOTBDPhos-HF)Pt](μ-Cl)2](BF4)2. The B-F bonds in (MeOTBDPhosHF)PtCl2 undergo rapid hydrolysis when dissolved in water or saline, but [(MeOTBDPhos-HF)Pt](μ-Cl)2](BF4)2 is relatively stable for days based on 19F and 11B NMR analysis. pH Dependency studies revealed that reducing the aqueous pH to 2 or lower stabilizes the B-F bond in (MeOTBDPhosHF)PtCl2. Overall, these results demonstrate the aqueous solubility, hydrolytic stability, and rapid fluorination of MeOTBDPhos complexes, which are desirable for applications in metallodrug PET imaging with 18F.
Phosphoramidites are a class of trivalent phosphorus molecules that contain one P-NR2 and two P-OR bonds, and they have generated significant interest for their use in biotechnological applications and asymmetric catalysis. The MeOTBDPhos ligand utilized in Chapters 1 and 2 was the first phosphoramidite TBDPhos borane that was prepared using synthetic route that incorporates a base and chlorodimeothoxyphosphine ClP(OMe)2. In Chapter 3, a reliable synthetic route to access a wider-range of new diphosphoramidite TBDPhos ligands is reported using alcohols and the chlorinated precursor ClTBDPhos. Synthesis and characterization of several late transition complexes with Group 10 metals are described. Ligand-centered reactivity studies with (iPrOTBDPhos)PtCl2 showed that bulky alkoxy substituents for this class of TBDPhos ligands do not eliminate ligand-centered reactivity, as observed for similar complexes with alkyl-substituted iPrTBDPhos.
Hydrodefluorination (HDF) is a desirable method to activate aryl C-F bonds, using late transition metals, for the synthesis of partially fluorinated organic substrates used in pharmaceuticals or agrochemicals. The established fluorophilicity of TBDPhos suggest that these ligands may be well poised for assisting low-valent Group 10 metals in C-F activation by serving as a fluoride acceptor. Chapter 4 describes the synthesis and characterization of low-valent Group 10 complexes and precursors with EtTBDPhos and ancillary hydride and alkyl ligands, as well as attempts to prepare similar complexes with PhTBDPhos. Preliminary thermolysis studies are reported.
Details
- Title: Subtitle
- Synthesis of phosphine and phosphoramidite ligands derived from 1,8,10,9-triazaboradecalin and their reactivity with late transition metals
- Creators
- Johnathan D Culpepper
- Contributors
- Scott R Daly (Advisor)Louis Messerle (Committee Member)Johna Leddy (Committee Member)Scott K Shaw (Committee Member)James B Gloer (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Autumn 2021
- DOI
- 10.17077/etd.006262
- Publisher
- University of Iowa
- Number of pages
- xxxi, 287 pages
- Copyright
- Copyright 2021 Johnathan D. Culpepper
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references
- Public Abstract (ETD)
Transition metal complexes are molecules that typically contain one central metal atom which is surrounded by groups of organic atoms (carbon, oxygen, nitrogen) known as ligands. Metal complexes containing platinum, especially a drug known as cisplatin, have been used for decades for cancer treatment despite severe side effects due to off-target localization in healthy tissues. In addition to life-saving drugs, metal complexes with transition metals in the same group as platinum (i.e. nickel and palladium) have been used to prepare new organic molecules for pharmaceuticals and related applications.
This dissertation reports my work to prepare and characterize metal complexes with nickel, palladium, and platinum as the central atoms with a class of reactive ligands called TBDPhos. These ligands are unique because they have a boron-containing reactive site that can undergo chemical reactions independent of the metal. I use this reactive site to create fluorine-containing molecules commonly used in pharmaceuticals and an important medical imaging process known as positron emission tomography (PET imaging). The synthesis, structures, and spectroscopic data of new ligands and complexes are described alongside fundamental studies aimed at understanding how different ligand modifications affect the reactivity and properties of TBDPhos complexes.
- Academic Unit
- Chemistry
- Record Identifier
- 9984210748602771
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