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Synthesis and applications of N- and S-substituted 1,2,4-triazolium salts as stable radical and carbene precursors

SMITH, MATTHEW,STEPHEN (2024) Synthesis and applications of N- and S-substituted 1,2,4-triazolium salts as stable radical and carbene precursors. Doctoral thesis, Durham University.

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Author-imposed embargo until 22 May 2025.


1,2,4-Triazolium salts, and the triazolylidine NHC generated from deprotonation at the pre-carbenic site, have shown a broad range of applications within the literature. Herein we report the synthesis of 1,2,4-triazolium salts with C(3)-N-Ar and C(3)-S-Ar substitution, enabling studies into the rearrangement to stable Blatter radicals, organocatalysis, and antiproliferative activity against cancer cell lines.

Nitron is a 1,2,4-triazolium salt with a C(3)-N anilino substituent, which enables a tautomerisation between the C(3)-N and C(5) positions. As a result, Nitron partially exists in a carbenic tautomer at levels too low for NMR observation. The work herein continues from our initial report whereby Nitron can undergo an unusual rearrangement to stable Blatter radicals, a species of growing interest particularly within the fields of photochemistry, magnetochemistry and organic electronics. The synthesis of Nitron is revisited to enhance the scope and yields compared to the published route. The analogues of Nitron are explored within the transformation to Blatter radical, allowing for the isolation of 16 new radicals. Evaluation of the propensity of Nitron analogues to undergo transformation to Blatter radical, including computational and kinetic analysis, has allowed the role of the carbenic tautomer of Nitron in Blatter radical formation to be investigated. The potential organocatalytic activity of Blatter radicals in oxidative coupling is also explored.

S-triazolium salts, with a C(3)-S-Ar substituent, are scarcely described within the literature. This work describes the development of a high-yielding synthetic methodology enabling 26 novel salts to be synthesized. The route consists of a Ullmann coupling to a S-triazole, followed by N-alkylation. The selectivity of this alkylation step is explored computationally and through isolation of both S-triazolium salt isomers. The use of azolium-derived carbenes for organocatalysis, in particular the carbene obtained by deprotonation of 1,2,4-triazolium salts, is a continually growing field. We report studies on the H/D exchange of S-triazolium salts isolated in this work, which shows an acidifying effect of the sulfur atom on C(5)-H. The collection of single-crystal XRD data allows for the development of structural relationships to the rate of C(5)-H/D exchange, enabling the approximation of second-order rate constants for the exchange process from XRD data only. Initial investigations into the organocatalytic activity of S-triazolium salts in the benzoin and Stetter reaction are also described.

Blatter radicals have been implicated in the mechanism of action of the experimental anticancer prodrug Tirapazamine, a benzotriazine-1,4-dioxide that exhibits enhanced activity under hypoxic conditions. Within this work Tirapazamine is synthesized, with the synthetic route explored towards the development of benzotriazine-1,4-dioxide analogues. Based on literature reports, 3-amino-1,2,4-benzotriazine is investigated in the synthesis of Blatter radicals by the addition of organolithium reagents. This work has discovered an intriguing transformation of the benzotriazine scaffold under literature conditions, which has been explored through reaction with organolithium and Grignard reagents.

The compounds isolated in this work are further explored in tissue culture assays to evaluate their antiproliferative activity. Blatter radicals are seen to show promising cytotoxic activity against 2 cancer cell lines, with the potential of Nitron analogues as a prodrug form of the Blatter radical explored through prolonged incubation assays. Blatter radicals are also described within the literature as scavengers of reactive oxygen species – initial work herein provides the foundation for the development of antioxidant nanoparticles containing Blatter radicals.

Item Type:Thesis (Doctoral)
Award:Doctor of Philosophy
Keywords:Triazolium; Carbene; Radical; Organocatalysis; Kinetic evaluation; Protofugality; Anti-cancer; Antioxidant
Faculty and Department:Faculty of Science > Chemistry, Department of
Thesis Date:2024
Copyright:Copyright of this thesis is held by the author
Deposited On:22 May 2024 14:41

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