Thesis
Mechanism-inspired understanding of ynamine reactivity in (3+2) cycloadditions with azides
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2025
- Thesis identifier
- T17457
- Person Identifier (Local)
- 201856312
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Bioorthogonal chemistry has been proven to be a very useful tool in the field of drug discovery and chemical biology. It allows for the in vivo study of biomolecules in their natural environment. Applications range from imaging, cargo delivery, cell engineering, protein tagging and DNA-labelling. Over the years, many different chemical tools have been developed to perform these highly selective tasks in cells and organisms. For the past two decades, click chemistry in general has been praised, with their inventors decorated with the Nobel prize in chemistry in 2022. The aromatic ynamine is an excellent reaction partner with azides, forming triazoles via the Cu(I) catalysed alkyne azide cycloaddition (CuAAC) reaction. Its applications in bioorthogonal chemistry are currently under investigation by the Burley group. Unlike regular alkynes, the aromatic ynamine uses a Cu(II) source, without a reductant. It was postulated that the ynamine CuAAC undergoes Glaser-Hay homocoupling to form Cu(I). Additionally, the ynamine had outcompeted regular alkynes in competition experiments – it was postulated that the ynamine is able to bind to the catalyst, meanwhile activating its alkyne moiety. The formation of diyne during the early stages of the reaction was studied using systematically conducted HPLC experiments in which it was found that the ynamine does indeed form diyne under various conditions. Complemented by advanced NMR experiments, using isotopologues of various key compounds, the effect of paramagnetic Cu(II) on the aromatic ynamine was studied. Later, similar experiments were conducted when the azide was present – allowing for the monitoring of the ynamine CuAAC reaction. Other crucial data was acquired using X-ray crystallography and LC-MS, to confirm the structures of ynamine and triazole complexes with Cu(II). Key findings revealed that the aromatic ynamine performed the CuAAC reaction in a divergent matter. The ynamine binds strongly to Cu(II), allowing for its reduction to Cu(I). It then forms a bivalent Cu(I)/(II) complex that is catalytically active. When the CuAAC is done, the triazole product binds the catalyst, which is postulated to reorganise to sperate catalytically inactive Cu(II) and Cu(I) complexes.
- Advisor / supervisor
- Burley, Glenn A.
- Fazakerley, Neal J.
- Resource Type
- DOI
- Embargo Note
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File | 2025-09-23 | Embargo |