Thesis
Mechanism driven investigations into sustainable benzylic oxidation
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2026
- Thesis identifier
- T18098
- Person Identifier (Local)
- 202290826
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Phenones are versatile synthetic intermediates and are ubiquitous in active pharmaceutical ingredients and natural products, making them useful compounds in both research and industry. Although they can be accessed via Friedel-Crafts acylation, this requires strong acylating agents and the transformation can be inefficient for electron deficient arenes. As a result, phenones are often accessed via the oxidation of benzylic methylenes. However, these transformations are usually mediated by expensive and environmentally harmful transitionmetal based oxidants, meaning they are often avoided in process chemistry. This thesis builds on a metal-free oxidation procedure using sodium chlorite and N-hydroxypthalimide (NHPI) III first reported by Salvador, and recently developed by Wood, Grunshaw and co-workers (Scheme I). [Scheme I. A metal-free benzylic oxidation using sodium chlorite and NHPI III. - available in thesis text]. Building on their findings, attempts were made to expand the substrate scope by altering the steric and electronic properties of the catalyst. This showed that increasing electron density on the aromatic ring of the NHPI derivative increased the rate of reaction for the oxidation of 4,4′difluorodiphenylmethane IV, which was hypothesised to be a consequence of increased stability of the phthalimido-N-oxyl radical (Scheme II). 4,5-Dimethoxy-NHPI VI was shown to be the optimal catalyst for this transformation. Despite the increased reaction rates, the NHPI derivatives examined did not widen the substrate scope. [Scheme II. The rate of oxidation was increased when using electron-rich NHPI derivatives. - available in thesis text]. Conducting the oxidation in the presence of higher concentrations of chlorine dioxide allowed expansion of the substrate scope to encompass ethylbenzene substrates. Sixteen substrates were oxidised to their carbonyl derivatives, in yields ranging from 27–84% (Scheme III). [Scheme III. Optimsation of the conditions allowed sixteen substrates to be oxidised to their carbonyl derivatives. - available in thesis text]. Examination of the substrate scope revealed a strong correlation between reactivity and increasing electron density on the aromatic ring of the substrate, which was suggestive of a benzylic C—H bond activation mechanism that occurred via a proton-coupled electron transfer (PCET). This hypothesis was further substantiated through in-depth mechanistic studies. A hydrogen/deuterium kinetic isotope effect of 2.6 was observed, which was consistent with literature values for a PCET mechanism. Hammett plot analysis provided a ρ value of −1.4, which was also comparable with literature values for this mechanism. These investigations led to the proposal of a mechanism in which the substrate was oxidised to its derivative radical through a PCET process, before being further oxidised to the carbonyl derivative (Scheme IV). [Scheme IV. Mechanistic investigations indicated the operation of a PCET process. - available in thesis text].
- Advisor / supervisor
- Tomkinson, Nicholas C. O.
- Wood, Susie A.
- Wheelhouse, Katherine
- Resource Type
- DOI
- Funder
- Embargo Note
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File | 2026-07-21 | Embargo |