Late-Stage Fluorination With 19F− and 18F− via Concerted Nucleophilic Aromatic Substitution
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CitationNeumann, Constanze N. 2016. Late-Stage Fluorination With 19F− and 18F− via Concerted Nucleophilic Aromatic Substitution. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe formation of C–F bonds has long been considered a challenging transformation and C–F bonds commonly had to be formed early on in a synthetic sequence towards complex organofluorides. Late-stage fluorination reactions are reactions with a broad substrate scope and extensive functional group tolerance that can be performed on complex molecules. Many classic fluorination reactions fail to qualify as late-stage transformations either due to severe limitations in their substrate scope or because the required reaction conditions are incompatible with many functional groups.
Nucleophilic aromatic substitution (SNAr) is widely used for the aromatic functionalization with 19F and by far the most common method to introduce 18F fluoride into aromatic molecules. Classic SNAr reactions proceed with the formation of a negatively charged Meisenheimer intermediate upon fluoride attack on the aromatic nucleus. Because only arenes with electron-withdrawing substituents can sufficiently stabilize the Meisenheimer intermediate to allow nucleophilic substitution to proceed efficiently, SNAr is restricted to electron-deficient arenes.
In Chapter 1 of this work an unusual concerted mechanism for nucleophilic aromatic substitution with fluoride is presented. Unlike the classic two-step mechanism, the concerted (CSNAr) mechanism does not proceed via a Meisenheimer intermediate, and build-up of negative charge on the arene ring is minimized. For the deoxyfluorination reaction with the PhenoFluor reagent a concerted mechanism is favored over a stepwise displacement and the resultant minimization of negative charge build-up over the course of the reaction allows deoxyfluorination to take place on electron-rich arene substrates. Based on detailed mechanistic studies a functional-group tolerant deoxyfluorination reaction with 18F-fluoride for the synthesis of high specific activity 18F-PET probes was developed. Chapter 2 of this work describes attempts to develop novel deoxyfluorination reagents with reduced reaction barriers guided by mechanistic insights into the deoxyfluorination. Computational results indicate that the introduction of substituents that are capable of forming hydrogen bonds to fluoride at specific positions on the reagent can reduce the activation barrier for deoxyfluorination through transition state stabilization.
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