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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

The Pentafluorosulfanyl Group:A Substituent is Born

Joseph B. Binder

Raines Lab

September 14, 2006

substituent of the future
“Substituent of the Future”

A. M. Thayer, Chem. Eng. News 2006, 84, 27-32.

outline
Outline
  • Background
  • Synthetic Strategies: Aliphatics
  • Synthetic Strategies: Aromatics
  • Applications
  • Conclusions and Outlook
why fluorinate organics
Why Fluorinate Organics?
  • Fluorination imparts unusual properties
    • Small size
    • Lipophilic
    • High electronegativity
    • Low reactivity

W. R. Dolbier, Jr.,Chimica Oggi 2003, 21, 66-69.

options for fluorination
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.

properties size
Properties: Size
  • Very bulky
  • Larger cross-sectional area than –CF3

P. G. Nixon, et al., Chem. Mater. 2000, 12, 3108-3112.

properties lipophilicity
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.

properties electronics
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.

properties stability
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.

outline10
Outline
  • Background
  • Synthetic Strategies: Aliphatics
    • Vigorous Fluorination
    • SF5X Addition
    • Incorporation of -SF5 Building Blocks
  • Synthetic Strategies: Aromatics
  • Applications
  • Conclusions and Outlook
first organic sf 5 derivative
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.

vigorous fluorination
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.

sf 5 x addition
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.

sf 5 x addition14
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.

sf 5 x addition mechanism
SF5X Addition: Mechanism
  • Mechanistic observations

A. D. Berry, et al., J. Org. Chem. 1978, 43, 365-7.

sf 5 x addition mechanism16
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.

sf 5 x addition et 3 b initiation
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.

versatility of sf 5 derivatives
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.

versatility of sf 5 alkyl halides
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.

synthetic strategies aliphatics
Synthetic Strategies: Aliphatics
  • Initially limited to harsh fluorinations
  • Selective SF5X addition preferred
  • More accessible through Et3B initiation
  • Versatility of aliphatic SF5-derivatives
outline21
Outline
  • Background
  • Synthetic Strategies: Aliphatics
  • Synthetic Strategies: Aromatics
    • Vigorous Fluorination
    • SF5X Addition
    • Incorporation of -SF5 Building Blocks
  • Applications
  • Conclusions and Outlook
agf 2 fluorination
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.

agf 2 fluorination further study
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.

agf 2 fluorination further study24
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.

direct fluorination
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.

sf 5 x addition26
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.

building block approach
Building Block Approach
  • Many m-, p-SF5 derivatives available
  • Allow a variety of transformations

R. D. Bowden, et al., Tetrahedron 2000, 56, 3399-3408.

synthetic strategies aromatics
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
outline29
Outline
  • Background
  • Synthetic Strategies: Aliphatics
  • Synthetic Strategies: Aromatics
  • Applications
    • Thin films and polymers
    • Liquid crystals
    • Biologically-active compounds
  • Conclusions and Outlook
applications of sf 5 derivatives
Applications of -SF5 Derivatives
  • Often used as –CF3 replacement
  • Yet displays unique behavior
polyimide polymers
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.

sf 5 functionalized polyimides
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.

sf 5 functionalized polyimides33
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.

sf 5 functionalized polyacrylates
SF5-Functionalized Polyacrylates
  • Monomer synthesis:
  • Photoinitiated polymerization
    • Homopolymer or copolymer with HEMA

R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.

x ray photoelectron spectroscopy
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.

sf 5 functionalized polyacrylates36
SF5-Functionalized Polyacrylates
  • XPS of copolymer:
    • 50Å depth, varying %HEMA
    • Nonstoichiometric -SF5

surface enrichment

R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.

sf 5 functionalized polyacrylates37
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.

liquid crystals design
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;

liquid crystals design39
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.

liquid crystals synthesis
Liquid Crystals: Synthesis

P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.

liquid crystals synthesis41
Liquid Crystals: Synthesis

P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.

liquid crystals results
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.

liquid crystals o substitution
Liquid Crystals: o-Substitution
  • o-Fluorination enhances Δε
  • o-Fluorination reduces -SF5 contribution

P. Kirsch, et al., Eur. J. Org. Chem. 2005, 3095-3100.

liquid crystals trifluoromethylation
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.

biologically active compounds
Biologically-Active Compounds
  • Provides a means to modulate activity
  • May improve bioavailability

Insecticide

Pharmaceutical

pesticides fipronil
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.

pesticides sf 5 fipronil
Pesticides: SF5-Fipronil
  • Synthesis

P. J. Crowley, et al., Chimia 2004, 58, 138-142.

pesticides results
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/

nhe inhibitors
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.

benzoylguanidine nhe inhibitors
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.

nhe inhibitors synthesis
NHE Inhibitors: Synthesis

G. Schubert, et al., Int. Pat. App. WO 2005047241 2005.

nhe inhibitor evaluation
NHE Inhibitor: Evaluation
  • IC50 for NHE1 in fibroblasts
  • Improved bioavailability and half-life in vivo

relative to other NHE inhibitors

2nd Generation: 1.9 nM

1st Generation: 14.5 nM

H.-W. Kleemann, US Pat. App. US 2003216476 2003;

H.-W. Kleemann, US Pat. App. US 2005043401 2005.

applications of sf 5 derivatives53
Applications of -SF5 Derivatives
  • -SF5 enhances molecules with its
    • Chemical and thermal stability
    • Fluorous behavior
    • Electron-withdrawing character
    • Lipophilicity
    • Steric bulk
  • Further systematic study needed
conclusions
Conclusions

-SF5

  • Displays unique and useful properties
  • More accessible through recent improvements in synthesis
  • Beginning to impact industry through applications as a fluorinated substituent
outlook
Outlook
  • Substituent of the future
  • Investigation of -SF5 only beginning
    • Improved synthetic strategies
    • Convenient reagents
    • Understanding of functional characteristics
  • Accessibility will drive applications
    • When -SF5 is as easy to introduce as -CF3, it will become as prevalent
acknowledgements
Acknowledgements
  • Professor Ron Raines
  • Raines Lab
  • Practice Talk Attendees
    • Frank Kotch
    • Matt Shoulders
    • Daniel Gottlieb
    • Katie Partridge
    • Kim Peterson
  • Luke Lavis