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Fluorine Chemistry How to make and to break C-F bonds?

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Presentation on theme: "Fluorine Chemistry How to make and to break C-F bonds?"— Presentation transcript:

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2 Fluorine Chemistry How to make and to break C-F bonds?

3 Fluorine History F 2 gaz isolated in 1886 by Henri Moissan (Nobel Prize 1906) Green-yellow gaz, very toxic, very strong oxidant, inflames organic materials by contact, makes bonds violently with almost every elements Electrochemical method Uses melted KHF 2 to increase the conductivity of the bath (HF too weak electrical conductivity) Platinium electrolyser, lower reaction temperature of the electrolyte bath (HF/KHF 2 ) to avoid corrosion: observation of gaz emission at the anode Moissan solved a major issue of the mineral chemistry at this time F 2 gaz isolated in 1886 by Henri Moissan (Nobel Prize 1906) Green-yellow gaz, very toxic, very strong oxidant, inflames organic materials by contact, makes bonds violently with almost every elements Electrochemical method Uses melted KHF 2 to increase the conductivity of the bath (HF too weak electrical conductivity) Platinium electrolyser, lower reaction temperature of the electrolyte bath (HF/KHF 2 ) to avoid corrosion: observation of gaz emission at the anode Moissan solved a major issue of the mineral chemistry at this time

4 Modifications Introduce by a Fluorine in Organic Compounds increases thermal and oxidative stability alters electronic effects increases lipophilicity closely mimics hydrogen steric requirements increases thermal and oxidative stability alters electronic effects increases lipophilicity closely mimics hydrogen steric requirements

5 Common Uses of Fluorine surfaces treatement: Teflon ®, Gore Tex ®, UV absorbent, anti burned meal, anti graffitti, anti reflect, anti flammable materials, biocompatible materials.... nanotechnology: nanocomposites, gaz filtration systems, silicium composant cleaning agronomy: herbicide, fongicide, insecticide medicine: active molecules in drugs, blood substitutes, diagnosis by PET (18F- fluorodesoxyglucose) surfaces treatement: Teflon ®, Gore Tex ®, UV absorbent, anti burned meal, anti graffitti, anti reflect, anti flammable materials, biocompatible materials.... nanotechnology: nanocomposites, gaz filtration systems, silicium composant cleaning agronomy: herbicide, fongicide, insecticide medicine: active molecules in drugs, blood substitutes, diagnosis by PET (18F- fluorodesoxyglucose)

6 Fluoride “this friend who wants you evil” ★ < 1 mg/day : prevents cavities ★ 2 mg/day : dental fluorosis risk ★ < 1 mg/day : prevents cavities ★ 2 mg/day : dental fluorosis risk

7 Fluoride “this friend who wants you evil” ★ < 1 mg/day : prevents cavities ★ 2 mg/day : dental fluorosis risk ★ 10 to 40 mg/day : skeletal fluorosis ★ 20 to 80 mg/day : ankylosing fluorosis ★ 100 mg/day : growth retardation ★ 125 mg/day : alteration of kidney function ★ 200 to 500 mg/day : lethal dose ★ < 1 mg/day : prevents cavities ★ 2 mg/day : dental fluorosis risk ★ 10 to 40 mg/day : skeletal fluorosis ★ 20 to 80 mg/day : ankylosing fluorosis ★ 100 mg/day : growth retardation ★ 125 mg/day : alteration of kidney function ★ 200 to 500 mg/day : lethal dose Do not swallow your toothpaste !!!

8 Montreal : 0,15 mg/l

9 C-F Bond Formation Fluorine chemistry can be more difficult because of the great reactivity of the fluorine itself. The problem is enhanced when a specific incorporation is required. (regio- or stereoselectivity) “F” as a nucleophile “F” as an electrophile Fluorine chemistry can be more difficult because of the great reactivity of the fluorine itself. The problem is enhanced when a specific incorporation is required. (regio- or stereoselectivity) “F” as a nucleophile “F” as an electrophile

10 “F” as a Nucleophile Small size of the atom and low polarisability encourages F - to act more like a base rather than a nucleophile C-F bond: 107 kcal/mol (strongest bond with carbon, driving force) Metal Fluorides Non metallic compounds Small size of the atom and low polarisability encourages F - to act more like a base rather than a nucleophile C-F bond: 107 kcal/mol (strongest bond with carbon, driving force) Metal Fluorides Non metallic compounds

11 Metal Fluoride KF, CsF, AgF, CuF 2... boiling and anhydrous polar solvents crown ethers are used to make ionic fluoride soluble in non polar solvents. KF, CsF, AgF, CuF 2... boiling and anhydrous polar solvents crown ethers are used to make ionic fluoride soluble in non polar solvents. Chem. Rev. 1992, 505.

12 Metal Fluoride Utilisation Example: Halex Reaction Angew. Chem. Int. Ed., 2006, 49, Using TBAF in DMSO at rt : conversion between 80 and >95% (mainly > 90%) activating groupement : NO 2, CF 3, Cl, CN, N intra cyclic, ketone must be in ortho or para position except for NO 2 must be in ortho or para position except for NO 2 leaving group: -NO 2, -Cl reaction time from 20 min to 14 days from 1.3 to 4 equiv. of TBAF

13 TASF: Ley’s synthesis of fluoroinositol tris(dimethylamino)sulfonium difluorotrimethylsilicate white solid Middelton Tet. Lett. 1989, 30, J. Chem. Soc., Chem. Commun. 1988, 1301

14 Baltz Schiemann Reaction Example of Metalloid Fluoride: J. Fluorine Chem 1994, 68, 141.

15 “F” as an Electrophile Not easily achieved at a first glance because ‘F’ is the most electronegative element. F 2 N-O reagents N-F reagents Not easily achieved at a first glance because ‘F’ is the most electronegative element. F 2 N-O reagents N-F reagents

16 F 2 itself reacts violently with alkenes giving mixture of products including degradation of the carbon chain.... few industrial processes (diluted fluorine, low temperature...) upon addition of alkenes, syn stereochemistry observed formation of  -fluorocarbocation mainly used to synthesize O-F and N-F reagents reacts violently with alkenes giving mixture of products including degradation of the carbon chain.... few industrial processes (diluted fluorine, low temperature...) upon addition of alkenes, syn stereochemistry observed formation of  -fluorocarbocation mainly used to synthesize O-F and N-F reagents

17 O-F Reagents Less used than N-F reagent because of their price Main O-F Reagent : Less used than N-F reagent because of their price Main O-F Reagent : depending on R yields from 37-60% Chem. Rev. 1996, 1717.

18 O-F Reagents In the case of concentrated reaction or neat olefin (usually electron-depleted) the radical pathway is observed : less regioselective reaction. Can be overcome with a radical inhibitor Chem. Rev. 1996, 1717.

19 O-F Reagents Chem. Rev. 1996, half life of 2h at rt

20 N-F Reagents said to be safer, easier to handle, selective source of electrophilic fluorine. Can be R 2 NF or R 3 N + FA - where A - is a non-nucleophilic anion. said to be safer, easier to handle, selective source of electrophilic fluorine. Can be R 2 NF or R 3 N + FA - where A - is a non-nucleophilic anion. Chem. Rev. 1996, 1737.

21 N-F Reagents Chem. Rev. 1996, 1737.

22 N-F Reagents: How They Are Made Chem. Rev. 1996, (SelectFluor)

23 Electrophilic aromatic substitution Various compounds were fluorinated by electrophilic aromatic substitution. Pb: Need activated fluorinating agent, if too activated: polyfluorination Chem. Rev. 1996, 1737.

24 Fluorination of carbanion Easy access to mono or difluoro-olefins Chem. Rev. 1996, 1737.

25 Fluorination: Organocatalysis Angew. Chem. Int. Ed. 2005, 3706.

26 Fluorination: Organocatalysis (in presence of 6 equiv of an alkaloid) Org. Lett. 2002, 545. Angew ASAP

27 Fluorination: Metal-catalysed Angew. Chem. Int. Ed 2005, Angew. Chem. Int. Ed 2005, 4204.

28 J. Am. Chem. Soc. 2006, Metal induced Formation of C-F bonds Fluorination of organometallic compounds Metal catalysed fluorination

29 Fluorination organometallic compounds Chem. Rev. 1996, Perkin, Trans. 1, 1992, 1891 Organometallic = nucleophile, F = electrophile lot of examples with differents metals: organolithium, stannanes... syn product

30 J. Am. Chem. Soc. 2006, Palladium catalysed Fluorination of C-H bonds

31 C-F Bond cleavage Fluorocarbon really stable (cf. ozone layer problem), resistant to chemical attack, high thermal stability, reluctant to coordinate to metal centers but fluorocarbon-transition metal complexes are extremely robust compared to hydrocarbon-transition metal complexes C-F activation bond challenge compared to C-H activation bond one. C-F bond: 107 kcal/mol  -donnor,  -acceptor interactions between lone pair of fluorine and  orbitals of adjacent unsaturated carbon: had rather to form bonds with sp 3 than with sp 2 carbon centers. Fluorocarbon really stable (cf. ozone layer problem), resistant to chemical attack, high thermal stability, reluctant to coordinate to metal centers but fluorocarbon-transition metal complexes are extremely robust compared to hydrocarbon-transition metal complexes C-F activation bond challenge compared to C-H activation bond one. C-F bond: 107 kcal/mol  -donnor,  -acceptor interactions between lone pair of fluorine and  orbitals of adjacent unsaturated carbon: had rather to form bonds with sp 3 than with sp 2 carbon centers.

32 Unsaturated Fluorinated compounds  -framework subject to nucleophilic attack and fluorine is a good leaving group... depending on the solvent... Kinectic isotope effect ± in THF ± in Acetonitrile ± in Acetonitrile J. Am.Chem. Soc, 1996, 118, 20.

33 Activation by a proximal carbocation J. Am. Chem. Soc. 1997, 4319.

34 C-F Activation by a Metalloid J. Am. Chem. Soc. 2006, R = C 10 H 21 R= C 6 H 5 CF 2

35 C-F Bond Cleavage Activated by a Metal Fluorocarbon are reluctant to coordinate metal centers ★ Need an activation But fluorocarbon-transition-metal complexes are extremely robust compared to hydrocarbon-transition-metal complexes. ★ Will be problematic for catalytic systems Fluorocarbon are reluctant to coordinate metal centers ★ Need an activation But fluorocarbon-transition-metal complexes are extremely robust compared to hydrocarbon-transition-metal complexes. ★ Will be problematic for catalytic systems

36 Insertion of alkali in C-F bond Intrinsic difficulty to insert Mg or Li in C-F bonds (longer reaction time) and can trigger explosive decomposition of the metalation product via  or  elimination J. Chem. Soc., Chem. Commun. 1973, 7179.

37 Nucleophilic attack Organometallics, 1990, 9, Achieved by numerous electron rich metals but used almost only for stoechiometric dehalogenation

38  Activation J. Am. Chem. Soc. 2001, Activation of the C-F in  of the metal center is observed in many case (elongation of the C-F bond) However mecanism of activation is not well known...

39 Attempt with less activated substrates J. Am. Chem. Soc. 2001,

40 Further Activation with Pt J. Am. Chem. Soc. 1989, 3101.

41 Activation with Pt Organometallics, 1993, Org. Lett. 2007, 5629.

42 Cross coupling using C-F bond J. Am. Chem. Soc. 2003, 1696.

43 C-C bond Formation using C-F bond J. Am. Chem. Soc. 2003, 5646.

44 C-C bond Formation using C-F bond J. Am. Chem. Soc. 2003, 5646.

45 C-C bond Formation using C-F bond Angew. Chem., Int. Ed. 2001, R1=R1=Aryield 4-CF 3 Ph95 4-MePh82 2-MePh38 4-CF 3 4-tBuC 6 H 4 95 H4-tBuC 6 H 4 83 According to the authors, kinetics study suggest oxidative insertion...

46 Conclusion Do not swallow your toothpaste !! Usefull reagents have been developped to achieve the regio-, stereo- and enantioselective formation of C-F bonds. Mild conditions has been developped to activate C-F bonds Reactivity of perfluoroalkanes is still problematic


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