An Exploration of Redox-Neutral Synthetic Methods Enabled by Dual-Catalysis, Electricity, and Light

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Synthetic chemistry relies on the interconversion of one or more functional groups into other functional groups to enact the transformation of simple building blocks into complex or value-added compounds. Oftentimes in synthesis, these manipulations take the form of redox reactions wherein the oxidation state of the molecule is adjusted by loss or gain of electrons, which typically occurs concurrently with the gain or loss of a C—X bond (X = any atom that is not carbon). In longer or more complex syntheses, the overall redox state of the molecule may be adjusted higher or lower than that of the target molecule during the synthesis due to limitations in known reactions and methods to affect a certain transformation (i.e. reduction of esters to aldehydes requires reduction to the alcohol then selective oxidation back up to the aldehyde). Some of these oxidation state changes therefore would become redundant provided alternative methods were available to enact the desired transformation with the minimum number of redox reactions, and therefore stand to shorten the synthetic route. Furthermore, in some instances, the desired oxidation state of the molecule has already been achieved and new redox-neutral methods would expand our ability to diversify these scaffolds (C—X to C—N, C—F, etc.). The strategic implementation of redox-neutral reactions can lead to improvements in step-count and atom economy of synthesis by avoiding unnecessary oxidation state changes. The use of a net redox-neutral reaction to drive the isomerization of aziridines into allylic amines was achieved by use of a dual-catalytic system. The initial reduction of the substrate was achieved with a titanocene catalyst and re-oxidation of the intermediate by a cobalt(II) salen co-catalyst furnished the desired isomerization product. A detailed substrate scope study highlighted the efficiency of this method to access challenging to make allylic amines and demonstrated key differences in regioselectivity compared to net oxidative methods that rely on C-H bond amination. Further studies on the nature of the cobalt hydride (CoIII—H) intermediate disclosed in the aziridine isomerization project led to the design of a new photochemical mode to access CoIII—H via SET with an excited state iridium photoreductant. We found that this CoIII—H could effectively deliver H∙ to alkenes via MHAT and that the nascent C-centered radical could be oxidized by the oxidized iridium leading to turnover of the catalyst and formation of carbocation that could be used to trap fluoride. Exploring this redox-neutral hydrofluorination further led to the development of a suite of cobalt catalysts that could affect selective hydrofunctionalization of disparate alkene classes potentially due to differences in rate of hydrogen atom transfer (HAT) to the substrate alkene. Finally, a deuterodehalogenation method was developed that employed a radical-polar-crossover mechanism to generate stabilized carbanions electrochemically. A net reductive protocol was employed for the net deuterodehalogenation of benzyl halides that tolerated a range of reductively sensitive functional groups. Further exploration of the system led to the discovery that the anodic process could be implemented concurrently with the cathodic process to effect substrate oxidation at the same time as substrate reduction, allowing us to showcase deuterodehalogenation and sulfide oxidation of a range of molecules under one reaction system. This formally redox-neutral variant was found to be mediated by anodic formation of an electrophilic chloride equivalent that could affect the two-electron oxidation of sulfide moieties to the corresponding sulfoxide. With these examples, we believe that we have demonstrated the potential for redox-neutral methods to improve synthesis through strategically retaining the oxidation state of a molecule.

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220 pages


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Lin, Song

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Lambert, Tristan
Collum, David

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Chemistry and Chemical Biology

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Ph. D., Chemistry and Chemical Biology

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Doctor of Philosophy

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