Electrochemical and Photochemical Benzylic C(sp3)-H Functionalisation

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Electrochemistry and photoredox chemistry are useful modern techniques that facilitate
unique reactivity and provide new routes to compounds of high interest. Chapter 1
explores the importance of the benzylic position and how these technologies can be
leveraged to functionalise C(sp3
)–H bonds at this position. Important recent examples that
rely on the use of these technologies have been highlighted.
Chapter 2 explores the use of electrochemistry to generate and fluorinate highly reactive
primary benzylic cations. Direct current electrolysis was unsuccessful due to overoxidation
of product and mass transport limitations. By using alternative electrolysis waveforms,
specifically pulsed electrolysis, these problems could be addressed, and the reaction
outcome improved. Pulsed electrolysis was found to outperform direct current electrolysis
for the fluorination of primary benzylic substrates. Control reactions suggested that the
introduction of a resting period between anodic pulses was beneficial as it limited
overoxidation and improved mass transport processes.
In chapter 3, carboxylic acids are employed as nucleophiles to make benzylic esters via an
electrochemical C–O bond forming reaction. Previous examples of this transformation
used carboxylate ions as nucleophiles and suffered from competitive ring functionalisation
products. The increased oxidation potential of the protonated carboxylate source favours
selective benzylic substrate oxidation which proves effective at directing selectivity to the
benzylic position. Acetic acid as a co-solvent for direct current electrolysis is demonstrated
as a suitable method for introducing acetate groups at secondary benzylic positions. Lower
loadings of more functionalised carboxylic acids can also be used as coupling partners to
make various benzylic esters. This reaction is demonstrated on gram-scale using flow
electrochemistry.
Chapter 4 explores the use of photoexcited DDQ to try and broaden the range of
substrates that can be functionalised by this oxidant. Under non-photochemical
conditions DDQ-mediated benzylic transformations are limited to electron-rich substrates
only. Azolation of electron-deficient benzylic C(sp3
)–H bonds using this photochemical
approach was unsuccessful and instead a benzylic DDQ-adduct was observed.
Optimisation for this unexpected product identified reaction conditions that could achieve
good yields of the adduct. This was demonstrated on various scale in batch and in flow.
The utility of the DDQ-adduct was explored and conditions to access benzylic alcohols and
chlorides from the adduct were identified.
Date of Award7 May 2024
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorAlastair J J Lennox (Supervisor)

Keywords

  • Fluorination
  • C-H Functionalisation
  • Electrochemistry
  • Organic Synthesis

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