Triazabutadiene Chemistry in Organic Synthesis and Chemical Biology
AdvisorJewett, John C.
MetadataShow full item record
PublisherThe University of Arizona.
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AbstractTriazabutadienes are nitrogen containing compounds with interesting acid-responsive behavior. These compounds are relatively stable, but once activated by an electrophile, for example through protonation, fall apart to yield diazonium and imine compounds. In general, diazonium compounds are unstable and require harsh methods of synthesis. Therefore, the use of triazabutadiene compounds as precursors to diazonium compounds, allows for a mild and more controlled access to this reactive moiety. This opens up diazonium chemistry to more complex chemical biology applications, as well as in the development of applications in organic synthesis. In an effort to design triazabutadiene systems that release diazonium compounds in physiological conditions, water-soluble imidazolium-based triazabutadienes were synthesized by coupling N-heterocycle imidazolium carbenes to aryl azides. These compounds were shown to have pH-dependent reactivity, generating aryl diazonium salts in buffered solutions ranging from pH 4-7. This reactivity made these compounds one of the mildest ways of generating aryl diazonium salts in aqueous solutions. Initial stability and reactivity studies were performed by NMR, and by altering the sterics of the imidazolium core and the electronics of the phenyl group. It was determined that the rate and stability were influenced by the sterics and electronics of the scaffold. Electron withdrawing substituents on the phenyl and steric bulk on the imidazole core resulted in stable triazabutadienes, with the opposite being observed for the electron donating substituents on the phenyl and small substituents on the imidazole. Water-soluble triazabutadienes were synthesized to be further utilized as chemical biology probes. In organic solvents, the triazabutadienes reacted with resorcinol, an electron-rich phenyl group to form stable azo compounds. In more physiologically relevant conditions, the triazabutadiene compound was stirred in a pH 6 phosphate/citric buffer solution with a tyrosine analogue and an azo adduct was isolated. This indicated it was possible to target tyrosine residues with a triazabutadiene delivered aryl diazonium through the formation of azo bonds that could be cleaved under mild reducing conditions using sodium dithionite. In addition, the triazabutadiene compounds were found to undergo light-induced isomerism generating the Z isomer in solution upon irradiation. The Z isomer was observed to be more reactive, and would degrade even in basic solutions when irradiated with 350 nm light. This light responsiveness was utilized to enhance the reactivity of triazabutadiene attached onto protein and viral surfaces, allowing the generation and capture of aryl diazonium salts by electron rich aryl-fluorophore conjugates as well as antibody proteins in the case of the virus. Alkyl triazabutadiene compounds were synthesized by coupling N-heterocycle carbenes onto alkyl azides. These compounds were then shown to be capable of delivering alkyl diazonium compounds to carboxylic acids for esterification. This method diversifies esterification from only methyl substituents, as is the case with diazomethane and TMS-diazomethane, to larger more diverse alkyl groups. In conclusion, this work shows that the triazabutadiene compounds have interesting activity that will be vital in the development of novel probes for the study of biological process, as well as the development of reagents for chemical synthesis.
Degree ProgramGraduate College