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

Fluorine ChemistryFluorine Chemistry

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

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

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

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)

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



★< 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 !!!

Montreal : 0,15 mg/lMontreal : 0,15 mg/l

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

“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

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.

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

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

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.

“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

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

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.


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


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

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

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

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

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.

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

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

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%

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

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

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


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%

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.

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.

Activation by a proximal carbocationActivation by a proximal carbocation

FF

F

F

O

F

FF

COOEtF

Et2OHCO3

- C6F6HCO3

-


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


R = CR = C1010HH2121

R= CR= C66HH55CFCF22

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

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.

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

α Activationα Activation


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...

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

+


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


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%

Cross coupling using C-F bondCross coupling using C-F bond


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

C-C bond Formation using C-F bondC-C bond Formation using C-F bond


Ph

Ph

F + nPr MgBr

NiCl2, 1,3-butadiene (100mol%)72%

CuCl2, 1,3-butadiene (10mol%)98%

Ph

Ph

n-Pr



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


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...

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

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

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