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The Pentafluorosulfanyl Group: A Substituent is Born

The Pentafluorosulfanyl Group: A Substituent is Born. Joseph B. Binder Raines Lab September 14, 2006. “Substituent of the Future”. A. M. Thayer, Chem. Eng. News 2006 , 84 , 27-32. . Outline. Background Synthetic Strategies: Aliphatics Synthetic Strategies: Aromatics Applications

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The Pentafluorosulfanyl Group: A Substituent is Born

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  1. The Pentafluorosulfanyl Group:A Substituent is Born Joseph B. Binder Raines Lab September 14, 2006

  2. “Substituent of the Future” A. M. Thayer, Chem. Eng. News 2006, 84, 27-32.

  3. Outline • Background • Synthetic Strategies: Aliphatics • Synthetic Strategies: Aromatics • Applications • Conclusions and Outlook

  4. Why Fluorinate Organics? • Fluorination imparts unusual properties • Small size • Lipophilic • High electronegativity • Low reactivity W. R. Dolbier, Jr.,Chimica Oggi 2003, 21, 66-69.

  5. Options for Fluorination • Why choose –SF5? • More bulky • More lipophilic • More electron-withdrawing • More chemically inert W. R. Dolbier, Jr.,Chimica Oggi 2003, 21, 66-69.

  6. Properties: Size • Very bulky • Larger cross-sectional area than –CF3 P. G. Nixon, et al., Chem. Mater. 2000, 12, 3108-3112.

  7. Properties: Lipophilicity • πx = logPx – logPH (P = 1-octanol/water partition coefficient) • πx can correlate with bioavailability R. E. Banks (Ed.), Organofluorine Chemicals and Their Industrial Applications, 1979.

  8. Properties: Electronics • Electron-withdrawing W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, 3072-76; C. J. Byrne, et al., J. Chem. Soc., Perkin Trans. 2 1987, 1649-53; J. Shorter, Pure Appl. Chem. 1997, 69, 2497-2510.

  9. Properties: Stability • Typically thermally stable >300 °C • Inert to wide range of transformations • More stable than –CF3 W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, 3064-72; R. D. Bowden, et al., Tetrahedron 2000, 56, 3399-3408.

  10. Outline • Background • Synthetic Strategies: Aliphatics • Vigorous Fluorination • SF5X Addition • Incorporation of -SF5 Building Blocks • Synthetic Strategies: Aromatics • Applications • Conclusions and Outlook

  11. First Organic –SF5 Derivative • Unexpected product • Attempted preparation of CF3SF • Produced more highly fluorinated CF3SF5 • Attractive properties sparked interest • Very chemically inert • Excellent electrical insulator G. A. Silvey, et al., J. Am. Chem. Soc. 1950, 72, 3624-6; R. Geballe, et al., J. Appl. Phys. 1950, 21, 592-4.

  12. Vigorous Fluorination • Harsh conditions • Many side products • Electrochemical • Elemental Fluorine F. W. Hoffmann, et al., J. Am. Chem. Soc. 1957, 79, 3424-9; A. F. Clifford, et al., J. Chem. Soc. 1953, 2372-5; H. N. Huang, et al., Inorg. Chem. 1991, 30, 789-94.

  13. SF5X Addition • Photochemical addition • Allows introduction of –SF5 selectively at unsaturation • Requires specialized conditions V. K. Brel, Synthesis 2005, 1245-1250; J. R. Case, et al., J. Chem. Soc. 1961, 2066-70.

  14. SF5X Addition • Thermal addition • Effective with both SF5Cl and more reactive SF5Br • Requires specialized conditions • Side reactions include formal XF addition J. R. Case, et al., J. Chem. Soc. 1961, 2066-70; R. Winter, et al., J. Fluorine Chem. 2001, 107, 23-30; R. Winter, et al., J. Fluorine Chem. 2000, 102, 79-87.

  15. SF5X Addition: Mechanism • Mechanistic observations A. D. Berry, et al., J. Org. Chem. 1978, 43, 365-7.

  16. SF5X Addition: Mechanism • Proposed mechanism • Consistent with stereochemical outcome • Sterically governed ·SF5 addition A. D. Berry, et al., J. Org. Chem. 1978, 43, 365-7.

  17. SF5X Addition: Et3B Initiation • Allows moderate conditions • Avoids side reactions • Ineffective with electron-deficient alkenes W.R. Dolbier, et al. J. Fluorine Chem. In Press; S. A. Mohand, et al., Org. Lett. 2002, 4, 3013-3015.

  18. Versatility of –SF5 Derivatives • Cycloadditions • Diels-Alder reaction • [3+2] Dipolar cycloadditions V. K. Brel, Synthesis 2006, 339-343; F. W. Hoover, et al., J. Org. Chem. 1964, 29, 3567-70; V. K. Brel, Synthesis 2006, 2665-267-0.

  19. Versatility of –SF5 Alkyl Halides P. G. Nixon, et al., J. Fluorine Chem. 2004, 125, 553-560; R. P. Singh, et al., Inorg. Chem. 2003, 42, 6142-6146; P. G. Nixon, et al., J. Fluorine Chem. 1998, 91, 13-18; R. J. Terjeson, et al., J. Fluorine Chem. 1997, 82, 73-78; R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.

  20. Synthetic Strategies: Aliphatics • Initially limited to harsh fluorinations • Selective SF5X addition preferred • More accessible through Et3B initiation • Versatility of aliphatic SF5-derivatives

  21. Outline • Background • Synthetic Strategies: Aliphatics • Synthetic Strategies: Aromatics • Vigorous Fluorination • SF5X Addition • Incorporation of -SF5 Building Blocks • Applications • Conclusions and Outlook

  22. AgF2 Fluorination • First reported by Sheppard • Versatile reactivity of –SF5 benzenes W. A. Sheppard, J. Am. Chem. Soc. 1960, 82, 4751-2; W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, 3064-72.

  23. AgF2 Fluorination: Further Study • Extended to o-fluorine substituents • Steric bulk may stop reaction at -SF3 stage • o-Substituent may be interchanged A. M. Sipyagin, et al., J. Fluorine Chem. 2001, 112, 287-295.

  24. AgF2 Fluorination: Further Study • Investigation of electronic effects • Electron-poor substrate essential • May be limited to –NO2 and -CF3 A. M. Sipyagin, et al., J. Fluorine Chem. 2001, 112, 287-295.

  25. Direct Fluorination • F2 fluorination recently achieved • Improved yield relative to AgF2 process • Extended to other substituents including –CF3 • Less expensive but operationally difficult R. D. Bowden, et al., Tetrahedron 2000, 56, 3399-3408.

  26. SF5X Addition • Et3B-catalyzed addition • No extensive purification until final step • High yielding and operationally simple • De novo aryl ring synthesis • Allows unusual substitution patterns T. A. Sergeeva, et al., Org. Lett. 2004, 6, 2417-2419; F. W. Hoover, et al., J. Org. Chem. 1964, 29, 3567-70.

  27. Building Block Approach • Many m-, p-SF5 derivatives available • Allow a variety of transformations R. D. Bowden, et al., Tetrahedron 2000, 56, 3399-3408.

  28. Synthetic Strategies: Aromatics • Accessible with AgF2 or F2 • Requires electron-poor substrates • May be constructed from aliphatics • Participate in usual aromatic reactions • Convenient building blocks available

  29. Outline • Background • Synthetic Strategies: Aliphatics • Synthetic Strategies: Aromatics • Applications • Thin films and polymers • Liquid crystals • Biologically-active compounds • Conclusions and Outlook

  30. Applications of -SF5 Derivatives • Often used as –CF3 replacement • Yet displays unique behavior

  31. Polyimide Polymers • High performance condensation polyimides • Thermal stability • Strength • Flexibility • Trifluoromethylation • More transparent • Better properties for electronics • Increased strength P. M. Hergenrother, Angew. Chem., Int. Ed. Engl. 1990, 29, 1262-8.

  32. SF5-Functionalized Polyimides • Properties of –SF5 may enhance polyimides • DASP condensed with several dianhydrides DASP A. Jesih, et al., Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 1993, 34, 383-4; A. K. St. Clair, et al., Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 1993, 34, 385-6.

  33. SF5-Functionalized Polyimides • Improved glass transition temperature (Tg) • Average 13°C higher than –CF3 analog • Allows use at higher temperatures, harsher conditions • Consistently higher density • Lower solubility Tg = 305 °C ε (10 GHz) = 2.51 ρ = 1.559 g/cm3 Colorless A. K. St. Clair, et al., Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 1993, 34, 385-6; A. K. St. Clair, et al., US Pat. 5,302,692 1994.

  34. SF5-Functionalized Polyacrylates • Monomer synthesis: • Photoinitiated polymerization • Homopolymer or copolymer with HEMA R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.

  35. X-Ray Photoelectron Spectroscopy • Quantitative elemental analysis for surfaces • Identify elements and bonding state • Analyzed thickness depends on angle of incidence (θ) • Limited by photoelectron mean free path • Increasing angle reduces the accessible depth H. R. Thomas, et al., Macromolecules 1979, 12, 323-329.

  36. SF5-Functionalized Polyacrylates • XPS of copolymer: • 50Å depth, varying %HEMA • Nonstoichiometric -SF5 surface enrichment R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.

  37. SF5-Functionalized Polyacrylates • XPS of 1% SF5-monomer film • Varying composition controls depth of fluorous layer • Surface enrichment of –SF5 side chains • Fluorous components “bloom” to surface • Allows unique surface chemistry at low monomer% Composition Depth Profile R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.

  38. Liquid Crystals: Design • Twisted-nematic cell: • Switching voltage affects power usage • Voltage response determined by dielectric anisotropy (Δε) • Δεcorrelates with molecular dipole P. Kirsch, et al., Angew. Chem., Int. Ed. 2000, 39, 4216-4235;

  39. Liquid Crystals: Design • Improve Δε with polarizing head groups • -CN head group solvates ionic impurities • -SF5 combines high dipole moment and lipophilicity for excellent LC properties Prototypic Liquid Crystal (LC)Scaffold P. Kirsch, et al., Angew. Chem., Int. Ed. 2000, 39, 4216-4235; P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.

  40. Liquid Crystals: Synthesis P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.

  41. Liquid Crystals: Synthesis P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.

  42. Liquid Crystals: Results • Δεimproved, but lower than anticipated • Calculated vs. experimental structure • Suggests o-substitution may improve Δε C-S-Feq angle αcalc = 95.6° αexp = 92.3° P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.

  43. Liquid Crystals: o-Substitution • o-Fluorination enhances Δε • o-Fluorination reduces -SF5 contribution P. Kirsch, et al., Eur. J. Org. Chem. 2005, 3095-3100.

  44. Liquid Crystals: Trifluoromethylation • Axial-CF3 expected to increase polarity • Reduced polarity may result from deformed C-S-Feq angle • Promising for bioactive compounds P. Kirsch, et al., Eur. J. Org. Chem. 2006, 1125-1131.

  45. Biologically-Active Compounds • Provides a means to modulate activity • May improve bioavailability Insecticide Pharmaceutical

  46. Pesticides: Fipronil • Fipronil introduced in US by Rhône-Poulenc in 1996 • Marketed in Frontline®, Maxforce®, Combat® for flea/tick, roach control • Blocks GABA-gated chloride channels M. J. O'Neil (Ed.), The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th ed., 2001.

  47. Pesticides: SF5-Fipronil • Synthesis P. J. Crowley, et al., Chimia 2004, 58, 138-142.

  48. Pesticides: Results • SF5-fipronil consistently more potent P. J. Crowley, et al., Chimia 2004, 58, 138-142; R. Salmon, Int. Pat. App. WO 9306089 1993. http://www.arkive.org/species/ARK/invertebrates_terrestrial_and_freshwater/Musca_domestica/

  49. NHE Inhibitors • Sodium-proton exchangers (NHEs) • Maintain intracellular pH • Seven identified isoforms (1-7) • NHE1 expressed in cardiac tissue, platelets • Involved in ischaemia and reperfusion injuries • NHE inhibitors protect tissues during • heart attack • organ transplant • cancer chemotherapy B. Masereel, et al., Eur. J. Med. Chem. 2003, 38, 547-554.

  50. Benzoylguanidine NHE Inhibitors • Guanidinium mimics Na+ to block transport • Benzoylguanidines more NHE1 selective • HOE-694 among the first of class • Enhanced by lipophilic bulk at 4-position HOE-694 A. Schmid, et al., Biochem. Biophys. Res. Commun. 1992, 184, 112-17; L. Counillon, et al., Mol. Pharmacol. 1993, 44, 1041-5; M. Baumgarth, et al., J. Med. Chem. 1997, 40, 2017-2034.

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