Person: Neumann, Constanze N.
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Neumann
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Constanze N.
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Neumann, Constanze N.
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Publication Late-Stage Fluorination With 19F− and 18F− via Concerted Nucleophilic Aromatic Substitution(2016-09-09) Neumann, Constanze N.; Ritter, Tobias; Kahne, Daniel; Schreiber, Stuart L.The 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.Publication Introduction of Fluorine and Fluorine-Containing Functional Groups(Wiley-VCH Verlag Berlin, 2013) Liang, Theresa; Neumann, Constanze N.; Ritter, TobiasOver the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C[BOND]F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal—fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.Publication Concerted nucleophilic aromatic substitution with 19F− and 18F−(2016) Neumann, Constanze N.; Hooker, Jacob; Ritter, TobiasNucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain a 18F for use in PET imaging.1 A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales.2 During SNAr, attack of a nucleophile at a carbon atom bearing a ‘leaving group’ leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s).3 In this manuscript, we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favored over a stepwise displacement. Mechanistic insights enabled us to develop a functional group–tolerant 18F-deoxyfluorination reaction of phenols, which can be used to synthesize 18F-PET probes. Selective 18F introduction, without the need for the common, but cumbersome, azeotropic drying of 18F, can now be accomplished from phenols as starting materials, and provides access to 18F-labeled compounds not accessible through conventional chemistry.Publication Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation(Public Library of Science, 2013) Kamlet, Adam Seth; Neumann, Constanze N.; Lee, Eunsung; Carlin, Stephen M.; Moseley, Christian K.; Stephenson, Nickeisha A; Hooker, Jacob; Ritter, TobiasNew chemistry methods for the synthesis of radiolabeled small molecules have the potential to impact clinical positron emission tomography (PET) imaging, if they can be successfully translated. However, progression of modern reactions from the stage of synthetic chemistry development to the preparation of radiotracer doses ready for use in human PET imaging is challenging and rare. Here we describe the process of and the successful translation of a modern palladium-mediated fluorination reaction to non-human primate (NHP) baboon PET imaging–an important milestone on the path to human PET imaging. The method, which transforms [18F]fluoride into an electrophilic fluorination reagent, provides access to aryl–18F bonds that would be challenging to synthesize via conventional radiochemistry methods.Publication A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging(American Association for the Advancement of Science, 2011) Lee, Eunsung; Kamlet, Adam Seth; Powers, David C.; Neumann, Constanze N.; Boursalian, Gregory; Furuya, Takeru; Choi, Daniel C.; Hooker, Jacob; Ritter, TobiasThe unnatural isotope fluorine-18 \((^{18}F)\) is used as a positron emitter in molecular imaging. Currently, many potentially useful \(^{18}F\)-labeled probe molecules are inaccessible for imaging because no fluorination chemistry is available to make them. The 110-minute half-life of \(^{18}F\) requires rapid syntheses for which \([^{18}F]\)fluoride is the preferred source of fluorine because of its practical access and suitable isotope enrichment. However, conventional \([^{18}F]\)fluoride chemistry has been limited to nucleophilic fluorination reactions. We report the development of a palladium-based electrophilic fluorination reagent derived from fluoride and its application to the synthesis of aromatic \(^{18}F\)-labeled molecules via late-stage fluorination. Late-stage fluorination enables the synthesis of conventionally unavailable positron emission tomography (PET) tracers for anticipated applications in pharmaceutical development as well as preclinical and clinical PET imaging.