Periodic Reporting for period 1 - e-AlcToRad (Electrochemistry-enabled Reductive Alkyl Radical Generation from Alcohols)
Reporting period: 2023-08-01 to 2025-07-31
Transition metal-catalysed cross-coupling reactions are considered landmark achievements in organic synthesis. Their influence was recognised by the 2010 Nobel Prize in chemistry, and they quicky became core elements in many undergraduate organic chemistry textbooks and laboratory courses. Their importance cannot be overstated which is highlighted by, for example, their prevalence in medicinal chemistry even 40 years after their discovery and the sheer number of industrial processes using them. Thus, a modern organic chemist’s toolbox is filled with methods building C(sp2)-C(sp2) bonds using organic halides and organometallic reagents to rapidly access structural diversity. However, the myriad of tetrahedral carbon atoms in organic molecules alongside the ever-growing interest in drug discovery and development to access the tree-dimensional chemical space has encouraged chemists to develop cross-couplings that involve C(sp3) atoms. Such efforts have been pioneered using alkyl organometallic reagents and later extended to alkyl carboxylic acids and alkyl halides, but significant limitations are still present as C(sp3)-C(sp3) bonds are notoriously challenging to form.
Despite their ubiquitous nature, however, the most available sources of functionalised C(sp3) atoms, alcohols, are underutilised in cross-coupling reactions due to the difficulty associated with the C(sp3)-O cleavage step. Their mainstream adaptation for cross-coupling reactions would unlock a previously untapped chemical space by virtue of their structural diversity, stability, and convenience. Furthermore, shifting the focus from halides to more environmentally benign alcohols offer a green and sustainable future by minimising manufacturing costs and toxic waste.
Traditional approaches for C(sp3)-O cleavage and functionalisation are centred around functional group interconversion. The free alcohol is turned into an active leaving group, such as a tosylate, mesylate, or halide, followed by nucleophilic substitution (SN1 or SN2) to yield the desired new functionality. In the face of their straightforwardness, they rely on added extra chemical steps and purifications consequently generating of a large amount of waste. Moreover, each mechanism has their associated drawbacks, for example, in the case of SN1, carbocationic rearrangements, hydride shifts, and a need for a cation-stabilising group. On the other hand, SN2 reactions are limited by the steric environment around the leaving group, thus, most notably, extremely challenging with tertiary substrates. Furthermore, both are plagued by unproductive olefin formation via elimination pathways. All of these make SN1 and SN2 reactions very difficult to merge with deoxygenative TM-catalysed cross-couplings forging C(sp3)-C(sp3) bonds in order to explore the vast chemical space alcohols offer.
Once thought to be uncontrollable and of little synthetic use, the power of radical reactivity to circumvent these issues has been recognised by many. The 1975 seminal report from Barton and McCombie, using xanthate ester activation, remained the state-of-the-art radical deoxygenative strategy yielding C(sp3)-H bonds until the 2010s, when modern photochemical, electrochemical, and TM-catalysed methods were developed.
As radical reactions experience a renaissance since the introduction of mild and controlled radical generation processes using photoredox catalysis and synthetic electrochemistry various methods are available to exploit such species. Accordingly, significant process has been made in the field of single electron transfer (SET) triggered deoxyfunctionalisation to immediately harness the generated radical intermediates. Innovative activating group design has enabled some of the most sought-after transformations in organic chemistry, such as the formation of C(sp3)-C(sp3), C(sp3)-C(sp2), and C(sp3)-C(sp) bonds from C(sp3)-OH precursors. Despite this surge in interest, most oxidative deoxygenative radical functionalisation protocols rely on oxalate esters; however, these require ex situ installation and suffer from substrate generality. Recently, N-heterocyclic carbenes have been utilised for the mild and general metallaphotoredox facilitated deoxygenative transformations of alcohols. On the other hand, reductive activations, especially electrochemical methods, are still in their infancy due to the need for a laborious activating group installation and subsequent purification, substrate specificity, and functional group incompatibility. To date, there is no general, user-friendly reductive deoxyfunctionalisation strategy that addresses these issues. A reductive activation method would enable, besides other reactions, the overall redox-neutral coupling of the two most abundant source of functionalised C(sp3) atoms, without the need for activation of carboxylic acids.
This project, e-AlcToRad, offers a potential paradigm shift in organic chemistry by turning the most abundant native functional group, alcohol, into the dominant radical precursor. This open-shell intermediate would be generated using the precise control and selectivity offered by electrochemistry, then exploited in TM-catalysed carbon-carbon and carbon-heteroatom bond forging cross-coupling reactions. Electrochemistry offers the greenest way to interact with molecules as it uses the most renewable source of electrons, electricity itself. Even though several industrial scale processes, such as aluminium production and oxidation of p-methoxytoluene, use electrosynthesis, it has been neglected in organic synthesis since its introduction to the community over a century ago. However, as a result of an available user-friendly and standardised equipment, and active deconstruction of its perceived high barrier of entry this methodology has re-emerged in laboratory-scale organic synthesis. Therefore, this proposal aims to utilise the unique reactivity and selectivity of organic electrochemistry.
The overarching goal of this proposed research programme is to devise new, generally applicable, and modular methodologies in organic chemistry to address the long-standing challenge of alkyl radical generation from alcohols; thus, making the C(sp3)-OH bond a mainstream radical cross-coupling handle. This rebirth of the functionality as a versatile radical building block would furnish an enabling technology for molecule-makers.
Despite their ubiquitous nature, however, the most available sources of functionalised C(sp3) atoms, alcohols, are underutilised in cross-coupling reactions due to the difficulty associated with the C(sp3)-O cleavage step. Their mainstream adaptation for cross-coupling reactions would unlock a previously untapped chemical space by virtue of their structural diversity, stability, and convenience. Furthermore, shifting the focus from halides to more environmentally benign alcohols offer a green and sustainable future by minimising manufacturing costs and toxic waste.
Traditional approaches for C(sp3)-O cleavage and functionalisation are centred around functional group interconversion. The free alcohol is turned into an active leaving group, such as a tosylate, mesylate, or halide, followed by nucleophilic substitution (SN1 or SN2) to yield the desired new functionality. In the face of their straightforwardness, they rely on added extra chemical steps and purifications consequently generating of a large amount of waste. Moreover, each mechanism has their associated drawbacks, for example, in the case of SN1, carbocationic rearrangements, hydride shifts, and a need for a cation-stabilising group. On the other hand, SN2 reactions are limited by the steric environment around the leaving group, thus, most notably, extremely challenging with tertiary substrates. Furthermore, both are plagued by unproductive olefin formation via elimination pathways. All of these make SN1 and SN2 reactions very difficult to merge with deoxygenative TM-catalysed cross-couplings forging C(sp3)-C(sp3) bonds in order to explore the vast chemical space alcohols offer.
Once thought to be uncontrollable and of little synthetic use, the power of radical reactivity to circumvent these issues has been recognised by many. The 1975 seminal report from Barton and McCombie, using xanthate ester activation, remained the state-of-the-art radical deoxygenative strategy yielding C(sp3)-H bonds until the 2010s, when modern photochemical, electrochemical, and TM-catalysed methods were developed.
As radical reactions experience a renaissance since the introduction of mild and controlled radical generation processes using photoredox catalysis and synthetic electrochemistry various methods are available to exploit such species. Accordingly, significant process has been made in the field of single electron transfer (SET) triggered deoxyfunctionalisation to immediately harness the generated radical intermediates. Innovative activating group design has enabled some of the most sought-after transformations in organic chemistry, such as the formation of C(sp3)-C(sp3), C(sp3)-C(sp2), and C(sp3)-C(sp) bonds from C(sp3)-OH precursors. Despite this surge in interest, most oxidative deoxygenative radical functionalisation protocols rely on oxalate esters; however, these require ex situ installation and suffer from substrate generality. Recently, N-heterocyclic carbenes have been utilised for the mild and general metallaphotoredox facilitated deoxygenative transformations of alcohols. On the other hand, reductive activations, especially electrochemical methods, are still in their infancy due to the need for a laborious activating group installation and subsequent purification, substrate specificity, and functional group incompatibility. To date, there is no general, user-friendly reductive deoxyfunctionalisation strategy that addresses these issues. A reductive activation method would enable, besides other reactions, the overall redox-neutral coupling of the two most abundant source of functionalised C(sp3) atoms, without the need for activation of carboxylic acids.
This project, e-AlcToRad, offers a potential paradigm shift in organic chemistry by turning the most abundant native functional group, alcohol, into the dominant radical precursor. This open-shell intermediate would be generated using the precise control and selectivity offered by electrochemistry, then exploited in TM-catalysed carbon-carbon and carbon-heteroatom bond forging cross-coupling reactions. Electrochemistry offers the greenest way to interact with molecules as it uses the most renewable source of electrons, electricity itself. Even though several industrial scale processes, such as aluminium production and oxidation of p-methoxytoluene, use electrosynthesis, it has been neglected in organic synthesis since its introduction to the community over a century ago. However, as a result of an available user-friendly and standardised equipment, and active deconstruction of its perceived high barrier of entry this methodology has re-emerged in laboratory-scale organic synthesis. Therefore, this proposal aims to utilise the unique reactivity and selectivity of organic electrochemistry.
The overarching goal of this proposed research programme is to devise new, generally applicable, and modular methodologies in organic chemistry to address the long-standing challenge of alkyl radical generation from alcohols; thus, making the C(sp3)-OH bond a mainstream radical cross-coupling handle. This rebirth of the functionality as a versatile radical building block would furnish an enabling technology for molecule-makers.
During the extensive research for novel and convenient C(sp3)-OH bond activators yielding radicals, alkyl diazenes were discovered as redox-neutral radical precursors. This functional group not only yields a radical upon treatment with an organic base upon heating but also provides an electron for the transition metal catalytic cycle thus erasing the requirement for exogenous redox manipulations associated with radical precursors. This highly attractive approach offers a simple means to achieve radical C(sp3)-C(sp3), C(sp3)-C(sp2), and C(sp3)-C(sp) cross-couplings by reducing cost and the complexity of reaction setup. Alkyl diazenes have been invoked since the late 1930's yet their use in organic synthesis has been sporadic and mainly relegated to 2e–-defunctionalization methods such as the classic Wolff–Kishner reduction and related reaction. A standalone report from Taber in 1993 showed that diazenes can be derived in situ from sulfonyl hydrazides. Building on this precedent, we developed a remarkably general platform for redox-neutral radical cross-couplings driven by in situ derived alkyl diazenes to forge a variety of C–C bonds linkages in a practical, "dump and stir" fashion, obviating the need for any external redox-activation. The precursor alkyl sulfonyl hydrazides are crystalline and bench stable, and easily synthesised from alcohols via Mitsunobu reaction or from carbonyl compounds in two steps.
This newly discovered platform for radical cross-couplings enables the convenient and easily scalable synthesis of C(sp3)-C(sp3), C(sp3)-C(sp2), and C(sp3)-C(sp) bonds without exogenous redox manipulations. The wide impact of this methodology is underlined by its adoption of at least seven major pharmaceutical companies. Further uptake and popularisation will be facilitated by follow-up research projects building on this platform.