Hydrogen bonding phase-transfer catalysis with alkali metal fluorides: enantioselective synthesis of β-fluoroamines from reaction development to scale-up
<p>This thesis reports the development of hydrogen bonding phase-transfer catalysis (HB PTC) for asymmetric fluorination with alkali metal fluorides. This catalytic manifold harnesses the ability of fluoride to engage in hydrogen bonding to promote solubilisation of the inorganic fluoride salt...
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| Formato: | Tese |
| Idioma: | English |
| Publicado em: |
2020
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| _version_ | 1826311995777875968 |
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| author | Vicini, AC |
| author2 | Gouverneur, V |
| author_facet | Gouverneur, V Vicini, AC |
| author_sort | Vicini, AC |
| collection | OXFORD |
| description | <p>This thesis reports the development of hydrogen bonding phase-transfer catalysis (HB PTC) for asymmetric fluorination with alkali metal fluorides. This catalytic manifold harnesses the ability of fluoride to engage in hydrogen bonding to promote solubilisation of the inorganic fluoride salt, with concomitant formation of a reactive chiral catalyst fluoride complex. Herein, HB-PTC has been applied to the synthesis of enantioenriched β fluoroamines, with a focus on the industrial application of the methodology.</p>
<p>Chapter 1 introduces the challenges associated with enantioselective nucleophilic fluorination with alkali metal fluorides and the strategies reported in the literature for fluoride activation. An overview of properties and applications of β-fluoroamines is also included. Chapter 2 opens with a summary of the previous work on HB-PTC. Next, the chapter is devoted to describing the development of the asymmetric synthesis of β fluoroamines with KF and CsF via HB-PTC. Computational modelling is used to rationalise the observed selectivity and scope. Chapter 3 describes the development of a practical and scalable (> 10 g) synthesis of the novel N-alkyl bis-urea introduced in Chapter 2. Different synthetic routes are explored, and advantages and drawbacks of each are compared. Chapter 4 reports the study of the scale up (200 g) of the enantioselective fluorination in a mechanically stirred 1 L reactor, representing the proof of principle that HB PTC can be applied in industrial settings. Thermal safety tests and preliminary calculations on the mixing requirements are included. The chapter concludes with the analysis of the recyclability of the catalyst and of its degradation products. Chapter 5 contains additional screening tables, synthetic procedures, and characterisation data from compounds of Chapters 2‒4.
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| first_indexed | 2024-03-07T08:19:29Z |
| format | Thesis |
| id | oxford-uuid:feec5683-f68c-4b5a-826e-1f66b48d1b4c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:19:29Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | oxford-uuid:feec5683-f68c-4b5a-826e-1f66b48d1b4c2024-01-22T08:22:02ZHydrogen bonding phase-transfer catalysis with alkali metal fluorides: enantioselective synthesis of β-fluoroamines from reaction development to scale-upThesishttp://purl.org/coar/resource_type/c_db06uuid:feec5683-f68c-4b5a-826e-1f66b48d1b4cEnantioselective catalysisChemistry, OrganicFluorinationEnglishHyrax Deposit2020Vicini, ACGouverneur, V<p>This thesis reports the development of hydrogen bonding phase-transfer catalysis (HB PTC) for asymmetric fluorination with alkali metal fluorides. This catalytic manifold harnesses the ability of fluoride to engage in hydrogen bonding to promote solubilisation of the inorganic fluoride salt, with concomitant formation of a reactive chiral catalyst fluoride complex. Herein, HB-PTC has been applied to the synthesis of enantioenriched β fluoroamines, with a focus on the industrial application of the methodology.</p> <p>Chapter 1 introduces the challenges associated with enantioselective nucleophilic fluorination with alkali metal fluorides and the strategies reported in the literature for fluoride activation. An overview of properties and applications of β-fluoroamines is also included. Chapter 2 opens with a summary of the previous work on HB-PTC. Next, the chapter is devoted to describing the development of the asymmetric synthesis of β fluoroamines with KF and CsF via HB-PTC. Computational modelling is used to rationalise the observed selectivity and scope. Chapter 3 describes the development of a practical and scalable (> 10 g) synthesis of the novel N-alkyl bis-urea introduced in Chapter 2. Different synthetic routes are explored, and advantages and drawbacks of each are compared. Chapter 4 reports the study of the scale up (200 g) of the enantioselective fluorination in a mechanically stirred 1 L reactor, representing the proof of principle that HB PTC can be applied in industrial settings. Thermal safety tests and preliminary calculations on the mixing requirements are included. The chapter concludes with the analysis of the recyclability of the catalyst and of its degradation products. Chapter 5 contains additional screening tables, synthetic procedures, and characterisation data from compounds of Chapters 2‒4. </p> |
| spellingShingle | Enantioselective catalysis Chemistry, Organic Fluorination Vicini, AC Hydrogen bonding phase-transfer catalysis with alkali metal fluorides: enantioselective synthesis of β-fluoroamines from reaction development to scale-up |
| title | Hydrogen bonding phase-transfer catalysis with alkali metal fluorides: enantioselective synthesis of β-fluoroamines from reaction development to scale-up |
| title_full | Hydrogen bonding phase-transfer catalysis with alkali metal fluorides: enantioselective synthesis of β-fluoroamines from reaction development to scale-up |
| title_fullStr | Hydrogen bonding phase-transfer catalysis with alkali metal fluorides: enantioselective synthesis of β-fluoroamines from reaction development to scale-up |
| title_full_unstemmed | Hydrogen bonding phase-transfer catalysis with alkali metal fluorides: enantioselective synthesis of β-fluoroamines from reaction development to scale-up |
| title_short | Hydrogen bonding phase-transfer catalysis with alkali metal fluorides: enantioselective synthesis of β-fluoroamines from reaction development to scale-up |
| title_sort | hydrogen bonding phase transfer catalysis with alkali metal fluorides enantioselective synthesis of β fluoroamines from reaction development to scale up |
| topic | Enantioselective catalysis Chemistry, Organic Fluorination |
| work_keys_str_mv | AT viciniac hydrogenbondingphasetransfercatalysiswithalkalimetalfluoridesenantioselectivesynthesisofbfluoroaminesfromreactiondevelopmenttoscaleup |