This thesis spans a number of diverse free radical chemistry fields, yet its findings have many interrelated applications and implications (Figure 6.6.1). In the course of this work the following key chemical discoveries were made:
• Negative charges stabilise resonance-stabilised radicals beyond the textbook
expectations due to the increased polarisability of the delocalised electrons. This stabilisation occurs through space, is non-directional and non-cancelling in chemical reactions, in which the extent of electron delocalisation changes. Moreover, when a stable radical and a remote negative charge are combined in a molecule, the latter has an
exotic non-aufbau (converted) orbital configuration.
• Conceptually new chemistry was devised to clarify for the first time the
mechanism of the Denisov cycle, by which hindered amine light stabilisers (HALSs) protect materials against the photo- and thermo-oxidative damage. This protective
action was found to occur via not one, but several different catalytic cycles depending
on the structures of the participating nitroxide and degrading material.
• This new chemistry of nitroxide radicals was also found to be pertinent to
nitroxide mediated polymerization (NMP), and a combination of theoretical calculations, kinetic modelling and analysis of literature experimental data revealed the key harmful side-reactions compromising NMP and their dependence on the chemical structures of the nitroxide and growing polymer chain.
• An extensive structure-reactivity analysis of the oxidation chemistry of
nitroxides, and its reversibility, was undertaken and utilised to design novel redox
mediators for the dye-sensitised solar cells (DSSCs). One of these in silico designed
species was subsequently and independently shown to almost double the cell’s energy conversion efficiency. The implications of this study for the future design of improved nitroxide-based medicinal antioxidants were also analysed.
• The development of improved HALSs also required that we clarify the
mechanisms underlying the oxidative damage in the absence of the stabilisers. The findings of this project challenged the long-standing basic autooxidation scheme and explained the surprising antioxidant effect of oxygen. In combination with the discovered pH switching, the work also implies that autooxidation of biological substrates, likewise, requires mechanistic re-examination.
Figure 6.6.1 Overview of the findings of this work and their implications and practical applications; future directions are shown in grey colour.
The discoveries presented in this thesis lead to a huge range of important implications and practical applications. In particular, the new mechanistic understanding of the autooxidation and the mechanism of action of nitroxide-based light-stabilisers now provide a tool for designing more inherently stable polymers, and improved antioxidants to protect them against the oxidative damage. Moreover, the pH switching of nitroxide radical stability can be utilised to further enhance their performance. These ideas form the basis for a recently commenced industry-funded project.
Furthermore, the switching of nitroxides’ reactivity by pH in conjunction with the clarified picture of NMP side-reactions presented in this work now provides a tool for designing improved NMP agents. Paper 12 describes the first steps towards a stable nitroxide control agent that could be reversibly (de)activated by pH, and, when activated, could allow NMP to be carried out at temperatures as low as 25 °C. Experimental implementation of these designed reagents is now in progress. Performing polymerization at a decreased temperature would also afford decreasing energy consumption, and provide a strategy for minimising unwanted side-reactions. Indeed, if the temperature for reversible radical release can be dropped low enough, such a reagent
may even be useful as a radical protecting group in natural product synthesis.
The work in this thesis also has useful practical applications in renewable energy and molecular electronics. In particular, the energy of sunlight can be harnessed more efficiently with the help of dye-sensitised solar cells that comprise novel redox mediator
nitroxides, designed in Chapter 5. Moreover, the pH switchable SOMO-HOMO orbital conversion, discovered in Chapter 6, paves the way for pH switchable molecules that, in their deprotonated form, oxidise preferentially to diradical species, sensitive to external electromagnetic fields. Among other things, such species may be used for pH sensing, both in materials and, potentially, in cells.
The implications of the work in this thesis for biochemistry are also wide-ranging. On the one hand, the finding that peroxyl radicals are only able to propagate
autooxidation via hydrogen transfer in special cases is equally applicable to biological
autooxidation, where such H-abstraction reactions are only likely to occur from unsaturated lipids and the polypeptides backbone. It is therefore probable that in other systems alternative route(s), involving either more reactive abstracting radicals (such as alkoxyl) or redox processes, mediate the damage. Moreover, as the preliminary calculations in Papers 10 and 11 indicate, the susceptibility of a number of key biological motifs to radical attack is strongly influenced by pH and the proximity of their acid-base groups to metal ions, as well as polarity of the surrounding medium.
Likewise, it is implied that the protonation states (pKa values) of the acid-base groups in
biomolecules change upon the radical attack. This in turn suggests that even subtle differences in the environment may play a key role in the sites and mechanisms of biochemical autooxidation, which in turn has important implications for antioxidant design. Although ostensibly aimed at materials chemistry, the radical trapping and NMP side-reactions of nitroxides, studied in Chapters 3 and 4, along with the redox chemistry, discussed in Chapter 5, also provide efficient strategies for the design of such dual-action nitroxide-based medicinal antioxidants.
Finally, discovered electrostatic effect on the radical stability has a potentially vital role in the enzyme catalysis, e.g. it is conceivable that the enzymes utilise dynamics to afford conformations, in which transition states of radical reactions are stabilised by electric fields. Indeed, this might provide an explanation of the remarkable catalysis of hydrogen abstraction and deprotonation reactions in low-polarity environments, exhibited by certain enzymes.