Fluorine Chemistry How to make and to break C-F bonds?
-
Upload
melany-adwell -
Category
Documents
-
view
233 -
download
5
Transcript of Fluorine Chemistry How to make and to break C-F bonds?
![Page 1: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/1.jpg)
![Page 2: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/2.jpg)
Fluorine ChemistryFluorine Chemistry
How to make and to break C-F bonds?How to make and to break C-F bonds?
![Page 3: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/3.jpg)
Fluorine HistoryFluorine History
• F2 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 KHF2 to increase the conductivity of the bath(HF too weak electrical conductivity)Platinium electrolyser, lower reaction temperature of the electrolyte bath (HF/KHF2) to avoid corrosion: observation of gaz emission at the anode
• Moissan solved a major issue of the mineral chemistry at this time
• F2 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 KHF2 to increase the conductivity of the bath(HF too weak electrical conductivity)Platinium electrolyser, lower reaction temperature of the electrolyte bath (HF/KHF2) to avoid corrosion: observation of gaz emission at the anode
• Moissan solved a major issue of the mineral chemistry at this time
![Page 4: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/4.jpg)
Modifications Introduce by a Fluorine in Organic Compounds
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
![Page 5: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/5.jpg)
Common Uses of FluorineCommon 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)
![Page 6: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/6.jpg)
Fluoride “this friend who wants you evil”
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
![Page 7: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/7.jpg)
Fluoride “this friend who wants you evil”
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 !!!
![Page 8: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/8.jpg)
Montreal : 0,15 mg/lMontreal : 0,15 mg/l
![Page 9: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/9.jpg)
C-F Bond FormationC-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
![Page 10: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/10.jpg)
“F” as a Nucleophile“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
![Page 11: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/11.jpg)
Metal FluorideMetal Fluoride
• KF, CsF, AgF, CuF2...
• boiling and anhydrous polar solvents
• crown ethers are used to make ionic fluoride soluble in non polar solvents.
• KF, CsF, AgF, CuF2...
• boiling and anhydrous polar solvents
• crown ethers are used to make ionic fluoride soluble in non polar solvents.
O OMe
OBnBnOOBn
TsOO OMe
OBnBnO
OBn
FKF / polyethylene glycol 400
44hrs, 70°C
63%
Chem. Rev. Chem. Rev. 19921992, 505., 505.
![Page 12: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/12.jpg)
Metal Fluoride Utilisation Example:Halex Reaction
Metal Fluoride Utilisation Example:Halex Reaction
Angew. Chem. Int. Ed.Angew. Chem. Int. Ed.,, 2006 2006, , 4949, 2720., 2720.
Using TBAF in DMSO at rt :Using TBAF in DMSO at rt :
conversionconversion between 80 and >95% (mainly > 90%) between 80 and >95% (mainly > 90%)
activating groupementactivating groupement : NO : NO2,2, CF CF3,3, Cl, CN, N intra cyclic, ketone Cl, CN, N intra cyclic, ketone must be in ortho or para position except for NOmust be in ortho or para position except for NO22
leaving group: -leaving group: -NONO22, -Cl, -Cl
reaction timereaction time from 20 min to 14 days from 20 min to 14 days
from 1.3 to 4 equiv. of TBAFfrom 1.3 to 4 equiv. of TBAF
Cl
CN
spray-dried KFPh4PBr
1,1-dimethyl-2-imidazolidinone
290°C
C
N
Cl F F
CN
+ KCl
N
F
![Page 13: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/13.jpg)
TASF: Ley’s synthesis of fluoroinositolTASF: Ley’s synthesis of fluoroinositol
TASF, THF, reflux
4 days
BnO
O
O
O
OBnBnO
O
O
OBn
OH
F
74%
tris(dimethylamino)sulfonium difluorotrimethylsilicatetris(dimethylamino)sulfonium difluorotrimethylsilicatewhite solidwhite solid
Middelton 1976Middelton 1976
S
N
NNSi
F
F
BnOOCOPh
OHBnOBnO
BnO
BnOOCOPh
BnOBnO
BnO F
DAST / Toluene80°C
(−)-1L-1-desoxy-1-fluoro-myo-inositol
NS
F
F
F
DAST:diethylaminosulfur trifluoride
1. 1. Tet. Lett. Tet. Lett. 19891989,, 30 30, 3557, 3557..2.2. J. Chem. Soc., Chem. Commun. J. Chem. Soc., Chem. Commun. 19881988, 1301, 1301
![Page 14: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/14.jpg)
Baltz Schiemann ReactionExample of Metalloid Fluoride:
Baltz Schiemann ReactionExample of Metalloid Fluoride:
NN
BF4
NH2
diazotisationreaction Δ
F BF3
F
BF3
OMe
MeO NH2
COOEt
H3COCHN
COOEt
OMe
MeO NO2
OH
nitro-vanillin
1. NaNO2 / 5N HCl -5°C to 0°C
2. HBF4, Et2O 85%
OMe
MeO N
COOEt
H3COCHN
COOEt
N
BF4
xylene, reflux, 2h26%
OMe
MeO
COOEt
H3COCHN
COOEt
F
48% HBrreflux85%
OH
HO
COOH
H3N
F
Br
5-fluoro-D/L-dopa hydrobromideJ. Fluorine ChemJ. Fluorine Chem 19941994,, 68 68, 141., 141.
![Page 15: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/15.jpg)
“F” as an Electrophile“F” as an Electrophile
Not easily achieved at a first glance because ‘F’ is the most electronegative element.
F2
N-O reagents
N-F reagents
Not easily achieved at a first glance because ‘F’ is the most electronegative element.
F2
N-O reagents
N-F reagents
![Page 16: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/16.jpg)
F2 itself F2 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 β-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 β-fluorocarbocation
• mainly used to synthesize O-F and N-F reagents
![Page 17: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/17.jpg)
O-F ReagentsO-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 Rdepending on Ryields from 37-60%yields from 37-60%
NR
H
NR
HO
F
CF3
NR
HHF
OCF3
F
NRH
F2CO HF
F3CO F
CO + F2 + CsF CF3OCsF2
CF3O• + F• + CsF
Chem. Rev.Chem. Rev. 19961996, 1717., 1717.
![Page 18: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/18.jpg)
O-F ReagentsO-F Reagents
In the case of concentrated reaction or neat olefin (usually electron-depleted) the radical In the case of concentrated reaction or neat olefin (usually electron-depleted) the radical pathway is observed : less regioselective reaction.pathway is observed : less regioselective reaction.
Can be overcome with a radical inhibitorCan be overcome with a radical inhibitor
Chem. Rev.Chem. Rev. 19961996, 1717., 1717.
H
Ph
Ph
HCF3OF
H
F
Ph
HPh
CF3O H
F PhOCF3
HPh
H
F
Ph
HPh
CF2O F H
F PhF
HPh
![Page 19: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/19.jpg)
O-F ReagentsO-F Reagents
Chem. Rev.Chem. Rev. 19961996, 1717., 1717.
CH3COONa ROH
R = H, Ac
F2CFCl3 (-78°C)
CH3COOF
AcOF
half life of 2h at rthalf life of 2h at rt
OOR
OR
RO
AcO18F OOR
OR
RO
18FOAc
deprotection OOH
OH
HO
18FOH
[18F]-fluorodeoxyglucose
![Page 20: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/20.jpg)
N-F ReagentsN-F Reagents
• said to be safer, easier to handle, selective source of electrophilic fluorine.
• Can be R2NF or R3N+FA- where A- is a non-nucleophilic anion.
• said to be safer, easier to handle, selective source of electrophilic fluorine.
• Can be R2NF or R3N+FA- where A- is a non-nucleophilic anion.
Chem. Rev.Chem. Rev. 19961996, 1737., 1737.
R3N F + Nu- R3N F Nu R3N F-Nu
![Page 21: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/21.jpg)
N-F ReagentsN-F Reagents
Chem. Rev.Chem. Rev. 19961996, 1737., 1737.
N
F
N
F
CF3COO
N
F
Tf
NN
F BF4
Cl
BF4
UmemotoBanks
F NS
OO
NSO2PhPhO2S
F NFSO2
N-fluorobenzenesulfonimide"NFSI"
Selectfluor
F
FF
FF
F
F
F
F
F
chiral N-Fluorosultams
![Page 22: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/22.jpg)
N-F Reagents: How They Are MadeN-F Reagents: How They Are Made
Chem. Rev.Chem. Rev. 19961996, 1737., 1737.
(SelectFluor)(SelectFluor)
NSO2PhPhO2S
H
F2, RT, 1570 TorrN
SO2PhPhO2S
F
"NFSI"
N
F
Tf
N
+ 10% F2 + Na+Tf-- 40°C, MeCN
N
F
F
F
F
FF
F
FF
F
F
N
CoF3 fluorination
HF anhydrousSimmons Cellelectrochemical
![Page 23: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/23.jpg)
Electrophilic aromatic substitutionElectrophilic aromatic substitution
Various compounds were fluorinated by electrophilic aromatic substitution. Various compounds were fluorinated by electrophilic aromatic substitution. Pb: Need activated fluorinating agent, if too activated: polyfluorinationPb: Need activated fluorinating agent, if too activated: polyfluorination
Me
MeMe
Me
F
Me
Me
F
MeF
Me
Me
Me
Me
MeF
Me
Me
Me
Me
Me
Me
F
FF
SelectFluor
SelectFluor
SelectFluor
Chem. Rev.Chem. Rev. 19961996, 1737., 1737.
![Page 24: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/24.jpg)
Fluorination of carbanionFluorination of carbanion
Easy access to mono or difluoro-olefinsEasy access to mono or difluoro-olefins
Chem. Rev.Chem. Rev. 19961996, 1737., 1737.
SO2PhPEtO
OEtO
OMet
R3
R2
R1OSiX3
R3
R2
R1O
R3
R2
R1 R1
R3
R2
NR2
R1
O
R2
O
R3 R1
O
R2
OMet
R3
![Page 25: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/25.jpg)
Fluorination: OrganocatalysisFluorination: Organocatalysis
Angew. Chem. Int. Ed.Angew. Chem. Int. Ed. 20052005, 3706., 3706.
HR1
R2
O
+ R1
FR2
H
O30mol%
0.5M in DMF4°C, 4h
NH
OH
O
very good yieldbut ee ~ 50%
NFSI
HR1
O
+ R1
F
H
O
NH
NO
Ph30mol%
0.5M in DMF4°C, 4h
8 examplesfrom 40 to 94% yieldfrom 86 to 96% ee
NFSI
![Page 26: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/26.jpg)
Fluorination: Organocatalysis(in presence of 6 equiv of an alkaloid)
Fluorination: Organocatalysis(in presence of 6 equiv of an alkaloid)
Org. Lett.Org. Lett. 20022002, 545., 545.Angew.Angew. 20082008 ASAP ASAP
OR3R1
O
R2
O
NtBu
tBuOMe
HO
N
Br
10mol%
NFSI (100mol%)base (600mol%)
toluene, rt
OR3R1
O
R2
O
F
5 examples74-94% yield
40-69% ee
(CH2)nR
X SiMe3
n = 1,2
X = O, CH2
NFSI (1.2 equiv.)bis-cinchona alkaloïd(10mol%)
K2CO3 (6 equiv.)CH3CN (CH2)n
X
RF
20 examplesyieds between 58% and 95%
X = CH2 ee up to 95%X = O ee up to 86%
![Page 27: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/27.jpg)
Fluorination: Metal-catalysedFluorination: Metal-catalysed
Angew. Chem. Int. EdAngew. Chem. Int. Ed 20052005, 4276., 4276.Angew. Chem. Int. EdAngew. Chem. Int. Ed 20052005, 4204., 4204.
COOR
O
OO
N NO
Ph Ph
NiOH2
2 ClO4
2 +
10 mol%
NSFI (120mol%)CH2Cl2, 4Å MS, RT
n
n = 1, 2
COOR
O
n
n = 1, 2
F 6 examples66-84% yield93-99% ee
![Page 28: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/28.jpg)
J. Am. Chem. Soc.J. Am. Chem. Soc. 20062006, 7134., 7134.
Metal induced Formation of C-F bondsMetal induced Formation of C-F bonds
Fluorination of organometallic compoundsFluorination of organometallic compounds
Metal catalysed fluorinationMetal catalysed fluorination
![Page 29: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/29.jpg)
Fluorination organometallic compoundsFluorination organometallic compounds
Chem. Rev.Chem. Rev. 19961996, 1743., 1743.Perkin, Trans. 1Perkin, Trans. 1, , 19921992, 1891, 1891
Organometallic = nucleophile, F = electrophileOrganometallic = nucleophile, F = electrophilelot of examples with differents metals: organolithium, stannanes...lot of examples with differents metals: organolithium, stannanes...
Tl
SelectFluor , 0°C to rt
dimethylacetylenedicarboxylate
HF
COOMe
COOMe52%
F
Poorly stable
Diels Alder
synsyn product product
![Page 30: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/30.jpg)
J. Am. Chem. Soc.J. Am. Chem. Soc. 20062006, 7134., 7134.
Palladium catalysed Fluorination of C-H bondsPalladium catalysed Fluorination of C-H bonds
N
H
10mol% Pd(OAc)2
1.5 equiv.
MW, 110°C, 1h, 200W, benzene
NF
BF4
N
F
N
Ph
N
OAc
97% conv.75% yield of 1
1 2 3
N
F
N
F
F57% 49%
N
Br
F53%
N
F
F
62%69%
from mono-fluorated
N
F
N
F
OMe
N
F
Cl
N
F
CF3
50% 59%33%52%
N
F
CF3 N
F
COOEt
N
O
F
N
F
F
MeO
52%
60%54%75%
![Page 31: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/31.jpg)
C-F Bond cleavageC-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
• π-donnor, σ-acceptor
• interactions between lone pair of fluorine and π orbitals of adjacent unsaturated carbon: had rather to form bonds with sp3 than with sp2 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
• π-donnor, σ-acceptor
• interactions between lone pair of fluorine and π orbitals of adjacent unsaturated carbon: had rather to form bonds with sp3 than with sp2 carbon centers.
![Page 32: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/32.jpg)
Unsaturated Fluorinated compoundsUnsaturated Fluorinated compounds
• π-framework subject to nucleophilic attack and fluorine is a good leaving group... depending on the solvent...
• π-framework subject to nucleophilic attack and fluorine is a good leaving group... depending on the solvent...
NO2
O2N
FHN 22°C, THF
N
NO2O2N
+ HF
Kinectic isotope effect 1.0262 ± 0.0007 in THF Kinectic isotope effect 1.0262 ± 0.0007 in THF 0.9982 ± 0.0004 in Acetonitrile0.9982 ± 0.0004 in Acetonitrile
J. Am.Chem. SocJ. Am.Chem. Soc, , 19961996, , 118118, , 20.20.
![Page 33: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/33.jpg)
Activation by a proximal carbocationActivation by a proximal carbocation
FF
F
F
O
F
FF
COOEtF
Et2OHCO3
- C6F6HCO3
-
J. Am. Chem. Soc.J. Am. Chem. Soc. 19971997, 4319., 4319.
![Page 34: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/34.jpg)
C-F Activation by a MetalloidC-F Activation by a Metalloid
Me2Si SiMe2F
Me2Si SiHMe2F
R3Si-H
R3Si
R3SiF
Me2Si SiMe2H
Me2Si SiHMe2F
RH
R-F
R
J. Am. Chem. Soc.J. Am. Chem. Soc. 20062006, 9676., 9676.
R = CR = C1010HH2121
R= CR= C66HH55CFCF22
![Page 35: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/35.jpg)
C-F Bond Cleavage Activated by a MetalC-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
![Page 36: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/36.jpg)
Insertion of alkali in C-F bondInsertion 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 α or β elimination
• Intrinsic difficulty to insert Mg or Li in C-F bonds (longer reaction time) and can trigger explosive decomposition of the metalation product via α or β elimination
F
1. KI - MgCl2-K-THF, reflux THF, 1h
2. CO2
COOH
65%
J. Chem. Soc., Chem. Commun.J. Chem. Soc., Chem. Commun. 19731973, , 7179.7179.
![Page 37: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/37.jpg)
Nucleophilic attackNucleophilic attack
FF
F
F
F F
F
FMn(CO)5
-THF
RT
F F
Mn(CO)5
F
F
FF
FF
F
F
F
FF F
Mn(CO)5
OrganometallicsOrganometallics, , 19901990, , 99, 2732., 2732.
Achieved by numerous electron rich metals but Achieved by numerous electron rich metals but used almost only for stoechiometric dehalogenationused almost only for stoechiometric dehalogenation
![Page 38: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/38.jpg)
α Activationα Activation
J. Am. Chem. Soc.J. Am. Chem. Soc. 20012001, 10973., 10973.
F
ZrCp*2
H
HgF
F
Cp*2ZrH2
- Hg0, - H2
Cp*2Zr
H
FZrCp*2
FΔ
Activation of the C-F in Activation of the C-F in αα of the metal center is observed in many case of the metal center is observed in many case (elongation of the C-F bond)(elongation of the C-F bond)
However mecanism of activation is not well known...However mecanism of activation is not well known...
![Page 39: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/39.jpg)
Attempt with less activated substratesAttempt with less activated substrates
F HCp*2ZrH2 + Cp*2ZrHF +C6D12, rt, 2d
F
HCp*2ZrF2 + 2
10 days
Cp*2ZrH2 + Cp*2ZrBuHC6D12, 30°C, 15min
Cp*2ZrHFF
+
J. Am. Chem. Soc.J. Am. Chem. Soc. 20012001, 10973., 10973.
![Page 40: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/40.jpg)
Further Activation with PtFurther Activation with Pt
F
F
F
F
F
Ph2P Ph2P
F
F
F
F
OH
F
Ph2P
F
F
F
F
F
Ph2P
O
F
F
F
Pt
Pt
Pt Pt
PC6F5Ph2
H3C
PC6F5Ph2
FH3C
PC6F5Ph2
H3C
Pt THFH3C
PC6F5Ph2
PC6F5Ph2
OH-
OH-
PC6F5Ph2
H3C OH
- HF
- HF
J. Am. Chem. Soc.J. Am. Chem. Soc. 19891989, 3101., 3101.
![Page 41: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/41.jpg)
Activation with PtActivation with Pt
Organometallics,Organometallics, 19931993, 4297., 4297.Org. Lett.Org. Lett. 20072007, 5629., 5629.
F
Cl
N Ph
F
99%
F
F
N Ph
Br
85%
F
F
N Ph
Pt
N
F
F
SMe2Me
MePh
Pt
Me2SMe
Me SMe2
PtMe
Me
F
F
F
N Ph
[Me2Pt(μ-SMe2)]25mol%Me2Zn 0.6 equiv.CH3CN, 35°C, 24h
F
F
CH3
N Ph
95%
![Page 42: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/42.jpg)
Cross coupling using C-F bondCross coupling using C-F bond
J. Am. Chem. Soc.J. Am. Chem. Soc. 20032003, 1696., 1696.
NH2+
F
NO2
Pd(PPh3)4 (10mol%)Cs2CO3,
DMF, 65°C
HN
NO2
65%
B(OH)2
+
R1
F
NO2
Pd(PPh3)4 10mol%Cs2CO3
DMF, 80°C
NO2R1
R1 = CN, 64%R1 = CHO, 86%
(nBu)3SnR1
F
NO2
R2Pd(PPh3)4, 10mol%
DMF, 65°C
R1
NO2
R2 R1 = phenyl, R2 = CN, 56%R1 = phenyl, R2 = CHO, 65%R1=vinyl, R2 = CN, 28%R1=vinyl, R2 = CHO, 45%
Pd PPh3Ph3P
NO O
R
F SNAr
NO O
R
F
Pd
PPh3
Ph3PPd
Ph3P
PPh3
FNO2
RR = CHO, CN
![Page 43: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/43.jpg)
C-C bond Formation using C-F bondC-C bond Formation using C-F bond
J. Am. Chem. Soc.J. Am. Chem. Soc. 20032003, 5646., 5646.
Ph
Ph
F + nPr MgBr
NiCl2, 1,3-butadiene (100mol%)72%
CuCl2, 1,3-butadiene (10mol%)98%
Ph
Ph
n-Pr
![Page 44: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/44.jpg)
C-C bond Formation using C-F bondC-C bond Formation using C-F bond
J. Am. Chem. Soc.J. Am. Chem. Soc. 20032003, 5646., 5646.
nC5H11-MgBr + nC9H19-F (1.5 equiv.)
nC8H17-Cl (1.5 equiv.)
nC10H21-Br (1.5 equiv.)
cat 3mol%THF, 25°C, 30min NiCl2, (100mol%) 8% 0% 39%
CuCl2, (10mol%) 16% 0% 40%
nC13H28nC14H30 nC15H32
Ph-MgBr + nC9H19-F (1.5 equiv.)
nC8H17-Cl (1.5 equiv.)
nC10H21-Br (1.5 equiv.)
CuCl2 3mol%THF, 25°C, 30min
Ph-nC8H17 0% <1%
Ph-nC9H19 8% 44%
Ph-nC10H21 2% 17%
25°C reflux
![Page 45: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/45.jpg)
C-C bond Formation using C-F bondC-C bond Formation using C-F bond
Angew. Chem., Int. Ed.Angew. Chem., Int. Ed. 20012001, 3387., 3387.
N
N
iPr
iPr
iPr
iPr
Ni
2
F+ BrMg Ar
5mol% [Ni]THF, RT, 18h
ArR1
R1
R1= Ar yield
4-CF3 Ph 95
4-Me Ph 82
2-Me Ph 38
4-CF3 4-tBuC6H4 95
H 4-tBuC6H4 83
According to the authors, kinetics study suggest oxidative insertion...According to the authors, kinetics study suggest oxidative insertion...
![Page 46: Fluorine Chemistry How to make and to break C-F bonds?](https://reader035.fdocuments.net/reader035/viewer/2022062312/551b3c17550346d41a8b547d/html5/thumbnails/46.jpg)
ConclusionConclusion
Do not swallow your toothpaste !!Do not swallow your toothpaste !!
Usefull reagents have been developped to achieve the regio-, stereo- and Usefull reagents have been developped to achieve the regio-, stereo- and enantioselective formation of C-F bonds.enantioselective formation of C-F bonds.
Mild conditions has been developped to activate C-F bondsMild conditions has been developped to activate C-F bonds
Reactivity of perfluoroalkanes is still problematicReactivity of perfluoroalkanes is still problematic