PCET-Mediated Photocatalytic Radical Generation from Alcohols: Mechanistic Insights and Synthetic Applications

Abstract

Visible-light photoredox catalysis has emerged as a powerful tool for forging carbon–carbon bonds under mild, sustainable conditions. This thesis presents new methodologies for the direct generation and synthetic exploitation of alkyl radicals from unfunctionalized aliphatic alcohols—traditionally challenging precursors due to their high O–H bond dissociation energy. By harnessing both metal-free and synergistic dual catalytic approaches, this work demonstrates that readily accessible alcohols can be transformed into versatile C-centered radicals, enabling efficient C(sp³)–C(sp³) and C(sp³)–C(sp²) bond formations. In the first part of this thesis, a metal-free photocatalytic protocol is developed for the alkylation of electron-deficient alkenes. Mild reaction conditions, relying on aliphatic secondary or tertiary alcohols as redox auxiliaries, deliver structurally diverse alkylated products with broad substrate scope. Mechanistic investigations, supported by density functional theory (DFT) calculations and steady-state as well as nanosecond transient absorption spectroscopy, reveal a complex manifold of competing pathways—most notably a base-independent, non-proton-coupled electron transfer (non-PCET) fragmentation and a concerted PCET pathway. These findings challenge the previously accepted view that stepwise PCET exclusively drives alkoxy radical formation, instead showing that multiple routes can operate in parallel. The second part of the thesis expands this reactivity to aryl halides via a dual photoredox–nickel catalytic platform. Here, alkyl radicals are generated through concerted PCET-mediated β-scission of aliphatic alcohols, facilitating the formation of C(sp³)–C(sp²) bonds under exceptionally mild conditions. Femtosecond transient absorption experiments confirm that PCET outcompetes direct fragmentation in this system, delivering high chemoselectivity and functional-group tolerance across a wide range of substrates, including challenging tertiary alcohols. Late-stage functionalization of bioactive molecules further underscores the synthetic utility of these methods. Finally, in the third part, the developed PCET-mediated generation of C-centred radicals are extended to monosaccharides, which are structurally more complex compounds. In this work, we also broadened the chemistry to allow for fragmentation-initiated hydrogenation, which presents a novel synthetic entry to this compound class. Collectively, the results presented in this thesis establish aliphatic alcohols as robust, readily available radical precursors for visible-light-driven bond formations. Beyond providing valuable synthetic transformations, the mechanistic insights gleaned—particularly regarding the interplay of non-PCET and PCET pathways—offer a deeper understanding of radical generation from alcohols. These discoveries pave the way for more efficient, sustainable, and versatile photoredox methodologies that harness readily accessible feedstocks in complex molecule construction.