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

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Presentation on theme: "The Pentafluorosulfanyl Group: A Substituent is Born Joseph B. Binder Raines Lab September 14, 2006."— Presentation transcript:

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

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

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

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

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

6 6 Properties: Size Very bulky Larger cross-sectional area than –CF 3 P. G. Nixon, et al., Chem. Mater. 2000, 12,

7 7 Properties: Lipophilicity π x = logP x – logP H (P = 1-octanol/water partition coefficient) π x can correlate with bioavailability XSCF 3 SF 5 OCF 3 CF 3 FNO 2 πxπx R. E. Banks (Ed.), Organofluorine Chemicals and Their Industrial Applications, 1979.

8 8 Properties: Electronics Electron-withdrawing W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, ; C. J. Byrne, et al., J. Chem. Soc., Perkin Trans , ; J. Shorter, Pure Appl. Chem. 1997, 69,

9 9 Properties: Stability Typically thermally stable >300 °C Inert to wide range of transformations More stable than –CF 3 W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, ; R. D. Bowden, et al., Tetrahedron 2000, 56,

10 10 Outline Background Synthetic Strategies: Aliphatics –Vigorous Fluorination –SF 5 X Addition –Incorporation of -SF 5 Building Blocks Synthetic Strategies: Aromatics Applications Conclusions and Outlook

11 11 First Organic –SF 5 Derivative Unexpected product –Attempted preparation of CF 3 SF –Produced more highly fluorinated CF 3 SF 5 Attractive properties sparked interest –Very chemically inert –Excellent electrical insulator G. A. Silvey, et al., J. Am. Chem. Soc. 1950, 72, ; R. Geballe, et al., J. Appl. Phys. 1950, 21,

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

13 13 SF 5 X Addition Photochemical addition –Allows introduction of –SF 5 selectively at unsaturation –Requires specialized conditions V. K. Brel, Synthesis 2005, ; J. R. Case, et al., J. Chem. Soc. 1961,

14 14 SF 5 X Addition Thermal addition –Effective with both SF 5 Cl and more reactive SF 5 Br –Requires specialized conditions –Side reactions include formal XF addition J. R. Case, et al., J. Chem. Soc. 1961, ; R. Winter, et al., J. Fluorine Chem. 2001, 107, 23-30; R. Winter, et al., J. Fluorine Chem. 2000, 102,

15 15 SF 5 X Addition: Mechanism Mechanistic observations A. D. Berry, et al., J. Org. Chem. 1978, 43,

16 16 SF 5 X Addition: Mechanism Proposed mechanism –Consistent with stereochemical outcome –Sterically governed ·SF 5 addition A. D. Berry, et al., J. Org. Chem. 1978, 43,

17 17 SF 5 X Addition: Et 3 B 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,

18 18 Versatility of –SF 5 Derivatives Cycloadditions –Diels-Alder reaction –[3+2] Dipolar cycloadditions V. K. Brel, Synthesis 2006, ; F. W. Hoover, et al., J. Org. Chem. 1964, 29, ; V. K. Brel, Synthesis 2006,

19 19 Versatility of –SF 5 Alkyl Halides P. G. Nixon, et al., J. Fluorine Chem. 2004, 125, ; R. P. Singh, et al., Inorg. Chem. 2003, 42, ; 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,

20 20 Synthetic Strategies: Aliphatics Initially limited to harsh fluorinations Selective SF 5 X addition preferred More accessible through Et 3 B initiation Versatility of aliphatic SF 5 -derivatives

21 21 Outline Background Synthetic Strategies: Aliphatics Synthetic Strategies: Aromatics –Vigorous Fluorination –SF 5 X Addition –Incorporation of -SF 5 Building Blocks Applications Conclusions and Outlook

22 22 AgF 2 Fluorination First reported by Sheppard Versatile reactivity of –SF 5 benzenes W. A. Sheppard, J. Am. Chem. Soc. 1960, 82, ; W. A. Sheppard, J. Am. Chem. Soc. 1962, 84,

23 23 AgF 2 Fluorination: Further Study Extended to o-fluorine substituents –Steric bulk may stop reaction at -SF 3 stage –o-Substituent may be interchanged A. M. Sipyagin, et al., J. Fluorine Chem. 2001, 112,

24 24 AgF 2 Fluorination: Further Study Investigation of electronic effects –Electron-poor substrate essential –May be limited to –NO 2 and -CF 3 A. M. Sipyagin, et al., J. Fluorine Chem. 2001, 112,

25 25 Direct Fluorination F 2 fluorination recently achieved –Improved yield relative to AgF 2 process –Extended to other substituents including –CF 3 –Less expensive but operationally difficult R. D. Bowden, et al., Tetrahedron 2000, 56,

26 26 SF 5 X Addition Et 3 B-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, ; F. W. Hoover, et al., J. Org. Chem. 1964, 29,

27 27 Building Block Approach Many m-, p-SF 5 derivatives available Allow a variety of transformations R. D. Bowden, et al., Tetrahedron 2000, 56,

28 28 Synthetic Strategies: Aromatics Accessible with AgF 2 or F 2 Requires electron-poor substrates May be constructed from aliphatics Participate in usual aromatic reactions Convenient building blocks available

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

30 30 Applications of -SF 5 Derivatives Often used as –CF 3 replacement Yet displays unique behavior

31 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,

32 32 SF 5 -Functionalized Polyimides Properties of –SF 5 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,

33 33 SF 5 -Functionalized Polyimides Improved glass transition temperature (T g ) –Average 13°C higher than –CF 3 analog –Allows use at higher temperatures, harsher conditions Consistently higher density Lower solubility 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, T g = 305 °C ε (10 GHz) = 2.51 ρ = g/cm 3 Colorless

34 34 SF 5 -Functionalized Polyacrylates Monomer synthesis: Photoinitiated polymerization –Homopolymer or copolymer with HEMA R. Winter, et al., Chem. Mater. 1999, 11,

35 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,

36 36 SF 5 -Functionalized Polyacrylates XPS of copolymer: –50Å depth, varying %HEMA –Nonstoichiometric -SF 5 surface enrichment % atom Wt % SF 5 monomerFSC (theory) % HEMA (theory) R. Winter, et al., Chem. Mater. 1999, 11,

37 37 SF 5 -Functionalized Polyacrylates XPS of 1% SF 5 -monomer film –Varying composition controls depth of fluorous layer Surface enrichment of –SF 5 side chains –Fluorous components “bloom” to surface –Allows unique surface chemistry at low monomer% R. Winter, et al., Chem. Mater. 1999, 11, Wt % SF 5 Monomer Analysis Depth (Å) % atom FSC Composition Depth Profile

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

39 39 Liquid Crystals: Design Improve Δε with polarizing head groups -CN head group solvates ionic impurities -SF 5 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, ; P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38,

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

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

42 42 Δε improved, but lower than anticipated Calculated vs. experimental structure Suggests o-substitution may improve Δε Liquid Crystals: Results C-S-F eq angle α calc = 95.6° α exp = 92.3° P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38,

43 43 Liquid Crystals: o-Substitution o-Fluorination enhances Δε o-Fluorination reduces -SF 5 contribution P. Kirsch, et al., Eur. J. Org. Chem. 2005,

44 44 Liquid Crystals: Trifluoromethylation Axial-CF 3 expected to increase polarity Reduced polarity may result from deformed C-S-F eq angle Promising for bioactive compounds P. Kirsch, et al., Eur. J. Org. Chem. 2006,

45 45 Biologically-Active Compounds Provides a means to modulate activity May improve bioavailability InsecticidePharmaceutical

46 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 47 Pesticides: SF 5 -Fipronil Synthesis P. J. Crowley, et al., Chimia 2004, 58,

48 48 Pesticides: Results SF 5 -fipronil consistently more potent CompoundFipronil-SF 5 Fipronil-SF 5 Fipronil-SF 5 StrainMusca Musca(R) Blattella LC 50 (ppm) *1* (R) indicates dieldrin resistant strain *Relative potency Musca domestica: housefly Blattella germanica: German cockroach P. J. Crowley, et al., Chimia 2004, 58, ; R. Salmon, Int. Pat. App. WO

49 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,

50 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, ; L. Counillon, et al., Mol. Pharmacol. 1993, 44, ; M. Baumgarth, et al., J. Med. Chem. 1997, 40,

51 51 NHE Inhibitors: Synthesis G. Schubert, et al., Int. Pat. App. WO

52 52 NHE Inhibitor: Evaluation IC 50 for NHE1 in fibroblasts Improved bioavailability and half-life in vivo relative to other NHE inhibitors 1 st Generation: 14.5 nM 2nd Generation: 1.9 nM H.-W. Kleemann, US Pat. App. US ; H.-W. Kleemann, US Pat. App. US

53 53 Applications of -SF 5 Derivatives -SF 5 enhances molecules with its –Chemical and thermal stability –Fluorous behavior –Electron-withdrawing character –Lipophilicity –Steric bulk Further systematic study needed

54 54 -SF 5 Displays unique and useful properties More accessible through recent improvements in synthesis Beginning to impact industry through applications as a fluorinated substituent Conclusions

55 55 Outlook Substituent of the future Investigation of -SF 5 only beginning –Improved synthetic strategies –Convenient reagents –Understanding of functional characteristics Accessibility will drive applications –When -SF 5 is as easy to introduce as -CF 3, it will become as prevalent

56 56 Acknowledgements Professor Ron Raines Raines Lab Practice Talk Attendees –Frank Kotch –Matt Shoulders –Daniel Gottlieb –Katie Partridge –Kim Peterson Luke Lavis

57 57


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