1

Synthesis of Organofluorine Compounds

General Methods:

1) Fluorine Gas

2) Transition Metal Fluorides

3) Hydrogen Fluoride

4) Alkali Metal Fluorides

5) Electrophilic Fluorination

6) Sulfur Tetrafluoride and Safer Equivalents

7) Trifluoromethylating Agents

8) Building Blocks

2

Sources of Fluorine

CaF2 HF (anhydrous)

Metal Fluorides

F2 (gas)

Transition MetalComplexes

(Fluorspar)

3

1) Direct Fluorination using Fluorine Gas

Fluorine, F2, is a diatomic molecule existing as a pale yellow gas.

It liquefies at –188oC to produce a yellowish orange liquid, and solidifies at –220oC to give a yellow solid.

Its name derives from the Latin verb “fluere” (to flow) that explains the given name to fluorite (fluorspar) since CaF2 exhibits good fluxing abilities.

Fluorine is the most reactive element, and the most powerful oxidizing element.

It readily reacts with almost all organic and inorganic materials.

4

H. Moissan and J. Dewar in J. Chem. Soc., 1897, 13, p175:

“Oil of turpentine, in the solid state, is attacked by liquid fluorine. To perform this experiment a little oil of turpentine was placed at the bottom of a glass tube surrounded with boiling liquid air. As soon as a small quantity of fluorine was liquefied on the surface of the solid, combination took place with explosive force. After each explosion, the current of fluorine gas was kept up slowly, a fresh quantity of liquid fluorine was formed, and the detonations succeeded each other at intervals of 6 – 7 minutes. Finally, after a longer interval of about 9 minutes, the quantity of fluorine formed was sufficient to cause, at the moment of reaction, the complete destruction of the apparatus. In several of these experiments a little liquid fluorine accidentally fell on the floor; the wood instantly took fire.”

Its unsurpassed electronegativity means fluorine can oxidize many other elements to high or their highest oxidation states (XeF6, SF5, IF5, etc).

The small size of Fluorine makes it easier to surround other elements with many fluorine atoms.

5

A few years ago:

6

Typically reaction with elemental fluorine is an exothermic, free radical chain process.

F• is an electrophilic radical, and therefore as we increase the fluorine content in the molecule, further fluorination becomes progressively difficult.

Consider the thermodynamics of the reaction:C-H + F2 → C-F + H-F ΔH = -99kcal/mol

Compare this toC-H + Cl2 → C-Cl + H-Cl ΔH = -23 kcal/mol

Bear in mind that a C-C bond = ~70kcal, so the heat given out is enough to break C-C bonds (i.e. destroy the molecule).

CH4 CH3 + H-F CH3F + FF F2

CF4

(difficult to proceedthis far along)

Further fluorination becomes progressively more difficult

strong bondweak bond

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So we need to control the heat evolved.

We can achieve this through dilution of the F2 in an inert gas.

1-3% F2 in N2.

This enables fluorinations to proceed in “normal’ lab settings.

Commercial Process of surface fluorination (blowmoulding) of a plastic petrol (gas) tank.

(Picture)

The surface inside gets fluorinated, and this is sufficient to stop the petrol dissolving the plastic petrol tank.

Also bear in mind that addition of F2 to double bonds is also highly exothermic.

C=C + F2 → CF-CF ΔH = -104kcal/mol

(For Cl2 ΔH = -31kcal/mol)

Again sufficient to smash C-C bonds when using elemental fluorine.

weak bond strong bonds

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Fluorination of Hydrocarbon Surfaces

In principle,

Previous example of petrol tank.

Also anthracene and graphite

F2/He (5% dil.)

GraphiteF2/He (5% dil.)

C1F1n

white powder

FFF

H2C

CH2

n

F2C

CF2

n + H-F

F2/N2(1-3% dil.)

Substn

Addn

Addn

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Moderation by Partial Fluorination

We already saw that the degree of fluorination becomes increasingly difficult, and therefore compounds that contain fluorine atoms already are of reduced reactivity to further fluorination. This means reaction with elemental fluorine is less vigorous / exothermic / dangerous.

Eg.

Since the starting material is already partially fluorinated it shows reduced reactivity –hence another way to use F2 in a controlled fashion.

(Also talk more about F2/N2 during electrophilic fluorination).

O CF2CFHCF3 F2 / N2O CF2CF2CF3F

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Fluorine GenerationFluorine gas is generated by the electrolysis of anhydrous potassium bifluoride (KHF2, or

KF.HF) in HF.

The fluoride anion is oxidized at the anode to liberate F2 gas.2F- → F2 + 2e- OILRIG

At the cathode, protons are reduced to hydrogen gas.2H+ + 2e- → H2

(Best to make sure the two compartments are kept separate!)

Anhydrous HF has a very low electrical conductivity, and so cannot be used as the electrolyte by itself. That’s why the molten fluoride salt electrolyte is used.

(In fact, rumor has it that when Moissan realized he could prepare F2 by electrolysis of HF, and most people where fairly skeptical that you could isolate fluorine gas, he invited them over to observe his work.

Since this was to be an important event, in front of the prominent scientists and doubters of his time, he did not want anything to go wrong.

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He spent time purifying the HF he was going to use in his electrolysis experiment.

Unfortunately for Moissan, he purified his HF so well that it was so pure and free from metal fluorides and anhydrous that the electrical conductivity was so low that his experiment did not work!!!!!!!

Weeks later he realized the importance of the metal fluoride salt in the electrolyte, and invited the experts back for a (successful) repeat performance.)

Essentially this is how F2 is still commercially made today – in big fluorine cells.

There are a few compounds that can release F2 when heated or reacted – but those compounds were originally made using F2.

A chemical route, which does not rely on compounds derived from F2 was reported by Karl Christe in 1986.

2 K2MnF6 + 4 SbF5 → 4 KSbF6 + 2 MnF3 + F2

The starting materials are prepared from HF, and at 150oC they react to liberate Fluorine gas.

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Alternatives to using Elemental Fluorine

2) Transition Metal Fluorides

Oxidative Fluorination

So many of these techniques are oxidative fluorination:

Some transition metal fluorides can accomplish this type of transformation, with cobalt trifluoride CoF3 being one of the most commonly used.

C H C F

is a formal oxidation on the carbon

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Cobalt trifluoride is generated by reaction of Cobalt Difluoride with elemental Fluorine.

For CH → C-F, ΔH = - 58 kcal/mol, which is much less exothermic than direct fluorination.

Mechanism of Oxidative Fluorination

Co3+ goes to Co2+, i.e. Co (III) to Co (II), which is a gain of electrons.

OILRIG – so Cobalt is reduced ⇒ the organic gets oxidized ⇒ CoF3 is an Oxidizing agent.

2 CoF2 + F2 2 CoF3

2 CoF3 + C H C F + H-F + 2 CoF2

Co III Co II = reduction

Co IICo III = OXIDATION

The organic is getting oxidized

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Saturated Systems

C H-1e

Co(III) Co(II)

C H C-H+

-1e

Co(III)

Co(II)

C+F-

C Fetc.

Recall 2CoF3 + C-H C-F + H-F + 2 CoF2

Radical

Cation

Radical cation

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Unsaturated Systems

+- 1e-F-

F

- 1e-

F+F-FF

Radical cation

Radical

Cation

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Examples

nC4H10 nC4F10

CoF3

CoF3

CH3 CF3

F FHigh Temp.

Substn

AddnandSubstn

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3) Fluorinations using Hydrogen Fluoride

These can be divided into two sections-Oxidative Fluorinations-Halogen Exchange Reactions (HALEX)

3a) Oxidative Fluorinations

i) Electrochemical Fluorination, E.C.F. (Simon’s Cell)

Using a solution of hydrogen fluoride, electrolysis is performed at a voltage lower (5-6V) than that required to generate Fluorine gas.

At the Nickel anode (oxidation occurs at the anode):

C-H → C-F

The reaction is usually performed at 0oC, and solubility in HF can be a limiting factor.

Fluorine is not generated at the anode, but hydrogen is generated at the cathode.

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Perfluorinated compounds generally are immiscible with hydrocarbons (see later for “fluorous phase”) – so the perfluorinated compounds generated separate at the bottom of the anode compartment.

(Bottom since halogenated compounds are normally denser than hydrocarbons and water.

Recall Ether/water but water/CH2Cl2)

This method is fairly tolerant to other functional groups and they are retained in the product.

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Examples

Such a method is very easy to conduct industrially, and the products are widely commercially available.

H3C CO

ClE.C.F.

F3C CO

F F3C CO

OHH2O

H3C SO

ClE.C.F.

F3C SO

F F3C SO

OHH2O

O O O

E.C.F.N(CH3)3 N(CF3)3

trifilic acid - a very strongorganic acid

shows no significant basic character - isused as an inert fluid

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The Simon’s cell process is believed to involve high valency Nickel Fluorides (NiF3 and NiF4).

Indeed workers were able to generate NiF3 and NiF4 in situ, and these were demonstrated to be powerful fluorinating agents.

Actually NiF3 was later shown to be NiIVNiIIF6

K2NiF6 + 2 BF3aH-F NiF4 + 2 KBF4

< -20oC

0oC

NiF3 + 1/2 F2

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Examples

OCF3CHFCF2 CF2CFHCF3OCF3CF2CF2 CF2CF2CF3NiF3, HFF

CF3CF=CF CF=CFCF3

CF3CF2CF2 CF2CF2CF3FK2NiF6, BF3

-20oC

H

CF3CF2CF2

CF2CF2CF3

HF

K2NiF6

0oC

Tertiary positions bearing an RF are resistant to oxidation by K2NiF6

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ii) Other Oxidative Fluorinations in HF

Again C-H → C-F using an oxidizing agent (e.g. Pb(OAc)4)

Again it becomes increasingly difficult to oxidize as the degree of fluorination increases.

Ph-CH3Pb(OAc)4

-1 e-Ph-CH3

-H+Ph-CH2

Pb(OAc)4-1 e-

Ph-CH2+H-FPh-CH2Fetc

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3b) Halogen Exchange using Hydrogen Fluoride (HALEX)

Note: C-X → C-F

is not oxidative, just a formal nucleophilic substitution.

Most commonly C-Cl → C-F

This process works best for systems able to easily form carbocations.

E.g. allylic / benzylic chlorides

Ph-CCl3H-F

40oCPh-CF3

H-F

R.T.Ph3CCl Ph3CF Easier cation formation = lower temp

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The Swarts Reaction

This reaction is industrially important in the manufacture of Refrigerants (i.e. CFC’s / Freons).

Systems that don’t easily form cations require a Lewis Acid Catalyst.

X3C-Cl:→SbF5

Since Fluorine is so electronegative and a powerful inductive electron withdrawing substituent, it makes successive Chlorines worse donors to the Lewis Acid catalyst (SbF5), hence halogen exchange becomes progressively difficult.

CCl4 CCl3F + CCl2F2 + CClF3

9% 90% trace

HF, SbF5

100oC

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There is also a decrease in steric assistance to ionization as each larger chlorine is replaced by a smaller fluorine.

General Mechanistic Process:

+

109.5o 120o

R Cl + SbF5 R Cl SbF5+ _

R+ (SbF5Cl)-

H-F

R-F + H+(SbF5Cl)-

H-F

H-Cl + H+(SbF6)-

Cl

R

F

SbF4

H-F

(concerted)

(ionic)

Bulky Cl’s encourage increase in bond angle – i.e. ionization

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General Mechanistic Process:

E.g. the following is only consistent with an ionic process:

Industrial Use

The Baeyer Company developed a one-pot synthesis of trifluorotoluene from benzene based on this type of reaction.

Ph-CCl2-CCl3 Ph-CF2-CCl3HF, SbF5

Only exchange at Benzylic position

C6H6 + CCl4HF, SbF5

C6H5-CF3

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Mechanism

CCl3 Cl L.A.

(HF or SbF5) H CCl3

etc.

-H+

+

CCl3

HF, SbF5

CF3

L.A.-Cl-

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Freon NomenclatureTypically used for CFCs (Chlorofluorocarbons)

Nomenclature was designed by engineers!

# of Carbon atoms minus 1# of Hydrogen atoms plus 1# of Fluorine atoms.

The # of chlorine atoms is not listed (but is implied)

Cyclic systems are prefixed by the letter C

E.g. CF2ClCFCl2 Freon 113CF2Cl2 is Freon 012CF2HCl is Freon 022C4F8 (Perfluorocyclobutane) is Freon C318

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Despite their physical properties which make them useful as refrigerants / air-conditioning agents, when appliances using Freons are discarded and the Freons are released into the atmosphere, environmental problems can occur.

(Freons in fridges are safe. It is when the fridge is dumped on a rubbish heap and the Freon is not removed, but is leaked into the atmosphere that creates the problem).

The environmental problem is that of Ozone Depletion.

The CFC’s cause Ozone depletion by converting ozone into oxygen:

2 O3 → 3 O2

The CFC’s released into the environment are so volatile and stable that they rise up into the stratosphere, where there react with short range UV rays.

This photochemical process breaks the weaker C-Cl bond homolytically, generating Chlorine radicals, which in turn react and destroy the ozone.

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In the stratosphere:

O2 → 2 O•

O• + O2 → O3

CF2Cl2 → •CF2Cl + •Cl

Cl• + O3 → ClO• + O2

ClO• + O3 → Cl• + 2 O2

The Cl• generated perpetuates the chain process.

Overall: 2 O3 → 3 O2 Catalysed by Cl•

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CFCs are now controlled (banned) substances and since mankind cannot live without food refrigeration or air conditioning in their homes / car / offices, there is a huge desire for CFC replacements to be found.

These replacements ideally will have similar physical properties as the CFCs, but would not be destructive to the environment.

Compounds such as HFC’s (hydrofluorocarbons) are showing large potential is this area.

E.g. HCF 134 CF3CH2F

This compound behaves like a Freon but has no Chlorine atoms, thus cannot generate Cl•, and thus does not destroy the ozone.

In fact the HFC does not even make it up into the stratosphere.

When the HFC is released into the environment, when it reaches the troposphere there are HO•, which can abstract hydrogen atoms from the HFC, and this leads to decomposition.

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4) The use of Alkali Metal Fluorides for Creating C-F bonds

Typically:

Fluoride ion is a very poor nucleophile in aqueous solution, but a very strong nucleophile in aprotic solvents.

The difference is the solvation of the fluoride ion.

If the fluoride ion is solvated it is much less accessible to perform nucleophilic attack.

C XF- CF X-

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Common Aprotic Solvents include:

These are solvents without protic hydrogens (esp. O-H, N-H, etc).

They act by solvating the metal cation.

They have a high dielectric constant. (i.e. polar)

S

N

H3CO

OCH3

OO

O

CH3

H3C NCH3

CO

H H3C NCH3

CO

CH3

n"glymes"n=2 diglymen=3 triglymen=4 tetraglyme

sulpholane(sulfolan)

N.M.P. D.M.F. D.M.A.

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Metal Fluoride Reactivity in aprotic solvents:

CsF > KF >> NaF > LiF

As the lattice energy of the solid increases the reactivity decreases.(CsF has the lowest lattice energy, whilst LiF has the larger lattice energyOr CsF has the “free-est” fluoride ion).

Potassium fluoride is the most frequently used fluoride ion source based on the combination of cost and availability versus its reactivity.

The Application of Crown-Polyethers

OO

O

OOO

K+ F-

"naked' Fluoride ion

18-Crown-6

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Crown ethers selectively solvate metal cations, leaving anion relatively unsolvated.

This “naked” fluoride ion is a superior nucleophile.

However, 18-C-6 / KF is no better than CsF in an aprotic solvent.

Saturated systemsFor saturated systems, the reactivity order is:

C Cl > C ClCl > C

ClCl

Cl > CCl

ClCl

Cl

more reactive toward Fluoride substitution

36

Typically, saturated per-halo systems are not that reactive.

Eg.

Unsaturated Systems

These can be very active if sufficiently activated.

CCl4 X CCl3FKF

(could use HF/SbF5)

ClF-

FCl-

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Recall that Cl is a fairly average nucelofuge (i.e. thing that removes two electrons / leaving group) and thus most of these processes are really addition eliminationprocesses where the leaving group is expelled in a subsequent exothermic step.

(So this is NOT SN2)

Eg.Cl KF

autoclaveF

NCl KF

autoclave NF

NF

ClCl+

major productwith Cl metato N remaining

hard to force itto this product

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Perfluorocyclopentene

This compound is produced via the reaction of fluoride ion with perchlorocyclopentene.

This is not really direct nucleophilic substitution at a saturated carbon as it may seem.

Every site is potentially vinylic and/or allylic depending on your point of view.

KF

NMP, 180oCCl F

F-Cl Cl

Cl Cl Cl

ClF

F-Cl

Cl

ClFCl

F

Cl

ClFCl

FClF

F

ClF

ClFF

Cl

ClCl

Cl

F

F-

F-

39

(Educational Aside:This is a good example of an SN2’ reaction.

The SN2’ reaction

Classically: the incoming nucleophile attacks the γ carbon, the π bond moves and displaces the leaving group.

This occurs especially when there is steric bulk around the leaving group.

X

Z Z

R

R

R'

Y- Y

RR

Z

Z

R'

X-γ αβ

40

when Z = H SN2Z = CH3 SN2’

Generally: larger nucleophiles favour SN2’ over SN2

Many examples in Propargyl systems:

Aside Ends).

X

Z Z

R

R

R'

Ph C C CH2OTos CH3MgBr, CuBr

C CH2Ph

H3C

41

Heptafluorobutene (Unusual products and the use of Hydrogen atom free solvents)

Formation of heptafluorobut-2-ene from hexachlorobutadiene with KF.

What is the mechanism and where does the Hydrogen come from?

ClCl

Cl

Cl

ClCl KF

Sulpholane, 180oC

F3C

H

F

CF3

42

ClCl

Cl

Cl

ClCl F-

ClCl

Cl

Cl

ClCl

F

_

ClF

Cl

Cl

ClCl

x 5

FF

F

F

FFF-

CF

F3C

F

F

F-F3C

F CF3

_

F3C

F CF3

H

R-H

43

Therefore what about if we do the reaction without the source of Hydrogens?

We can replace almost all the solvent with a perfluorocarbon, and the product obtained then becomes hexafluorobutyne.

F3CF3C

F CF3

_

F3C

F CF3

H

R-H

CF3

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5) Electrophilic Fluorination

Intuitively, chemists think of using fluorine as F-, however there is a need for electrophilic fluorination, fluorine as F+.

Chambers’ group in England demonstrated that fluorine gas in an acidic and high dielectric constant solvent can perform electrophilic fluorination.

Using their fluorine setup they were able to perform fluorinations using F2/N2 very safely.(New lab was 1million pounds in the 1990’s)

They found sulfuric acid or formic acid were excellent solvents to promote electrophilic (rather than radical) fluorination.

These could be used with or without other polar high dielectric solvents like CH3CN.

Formic acid gave fewer problems with some aromatic substrates (e.g. problems with competing sulfonation, hydrolysis of nitriles, etc)

(Fluorine gas is able to do all the reactions shown in this section and the N-F section also).

45

Typical results with aromatics are shown:

Activated and deactivated Systems

Normal EAS directing effects apply

H2SO4 = solvent and L.A.

Partial hydrolysis of Nitrileto Primary Amide

46

There is still a drive to get away from dealing with elemental F2, and numerous reagents have appeared over the last 50 years than can behave like a source of F+.

This involves a nucleophilic attack on F but won’t be a true F+.

More likely

These include FClO3, XeF2, CF3OF and CsSO4F.

Whilst these compounds served their purpose in the advancement of organofluorine chemistry, problems with their preparation, safety, handling and yields mean they are not widely used nowadays.

Especially since over the last 10 years, a series of stable, safe, easy to use compounds have been prepared and made commercially available for electrophilic fluorination.

F LNuc

47

These compounds all contain a nitrogen fluorine bond, and are thus often referred to as N-F compounds.

These compounds are stable, crystalline and easy to handle.

They are formed from relatively inexpensive starting materials (normally just reaction of the corresponding N-H compounds and F2).

The most common and widely commercially available is Selectfluor.

Eric Banks’ 1998 review of this compound is called

“SelectfluorTM reagent F-TEDA-BF4 in action: tamed fluorine at your service”.

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Typical nucleophiles to be reacted include:

(Activated) aromaticsBenzene resists fluorination under reasonable conditions, but activated aromatics do

undergo mono and difluorination.

Notice anything strange ?

49

Nucleosides and Nucleoside BasesThe value of biologically active compounds containing F has already been highlighted.

5FU is a potentanticancer agent.

5 F U

regiochem ?

50

Carbon-Metal BondsFluorodemetallation is can be easily achieved.

The last example provides a nice route into a 5-fluorocyclopentadiene generation (anti viral research), via a retro DA.

51

Stabilized AnionsStabilized anions (typically generated by action of NaH or KH on the parent compound)

are readily fluorinated by Selectfluor.

52

1,3 DicarbonylsMono and difluorination can be controlled by the ratio of NF reagent.

53

Alkenes/AlkynesSolvent systems can trap the carbocationic intermediates formed in reaction with carbon

- carbon multiple bonds.

via the enol

regiochem ?

54

Chiral N-F compoundsEnantioselective fluorination is possible if a chiral N-F reagent is used.Notice that the yields and ee’s are not brilliant.

55(Chiral bases and achiral N-F’s also work).

LDA is lithiumdi isopropyl amide= good base but poor nuc

70% e.e= 85:15

56

6) Sulfur Tetrafluoride and Safer Equivalents

Sulfur Tetrafluoride is best known for its fluorodeoxygenation ability.

That is:

SF4 by itself is not a fantastic fluorinating agent, but in the presence of hydrogen fluoride it is highly active.

This reagent had a massive influence on the growth of synthetic organofluorine chemistry.

R OH

R

R CO2H

OR'

R F

R CF2-R'

R CF3

57

Reaction of Alcohols

The mechanism of R-OH → R-F can be represented by the following:

58

E.g.

If the nitrogen is left unprotected…

amide has reduced N nucleophilicity

25

34

1

1

2 3 4 5

59

Reactions with Carbonyls

Aldehydes and ketones are readily transformed in difluoromethyl/methylene functionalities using SF4/lewis acid.

60

The mechanism of this transformation involves one or both of:

And/or

LA

Notice the ketone selectivity

61

Reaction of Carboxylic AcidsThe conversion of carboxylic acid to trifluoromethyl is the most demanding of the

fluorodeoxygenation transformations.

Use of high temp and plenty of HF as solvent and Lewis acid is required to perform this transformation.

This is an excellent way to make trifluoromethylated aromatics.

E.g.

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The mechanism of this transformation is as above, with the reaction proceeding from carboxylic acid → acid fluoride → trifluoromethyl.

There are some drawbacks to using sulfur tetrafluoride however:

-It is a gas-Its inhalation toxicity is comparable to that of phosgene-On exposure to moisture (air, skin) it liberates HF

-Reaction with SF4 usually requires HF as solvent / LA (which precludes use of glassware)

SF4 AlternativesRecently, “friendlier” fluorodeoxygenation reagents have become commercially

available.

These are really just substituted sulfur fluorides. The most common one being DAST (Diethylaminosulfur trifluoride).

DAST (CH3CH2)2N SF3

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DAST is a milder fluorinating agent that can convert hydroxyl to fluorine and carbonyls to CF2’s.

It cannot convert carboxylic acids to trifluoromethyls.

DAST is a liquid that is stable to distillation, and can be stored in plastic bottles, and is stable in dry conditions at room temperature or with refrigeration for long periods of time.

DAST is prepared by reaction of sulfur tetrafluoride with diethylaminotrimethylsilane at –78oC, followed by warming to room temperature, and then distillation.

64

(CH3CH2)2NSi(CH3)3 + SF4 → (CH3CH2)2NSF3 + FSi(CH3)3

DAST operates by a similar mechanism to that for sulfur tetrafluoride:

The solvents normally used for DAST reactions are non-polar and non-basic.

This is because the potential for carbocation intermediates is high, and thus polar and basic solvents encourage cation formation / rearrangement, and competing elimination, respectively.

65

For example, pivaldehyde is a classic acid sensitive aldehyde:

+ HF

trap with F-

Carbocationrearrangement

CATION

NORMAL

DAST

REARRREARRand ELIM

- H+

trap with F-

66

Whilst DAST is still the market leader of this type of reagent, safer versions of DAST are currently being marketed.

E.g. BAST = Bis(2-methoxyethyl)aminosulfur trifluoride.(CH3OCH2CH2)2NSF3

DAST will decompose at 90oC, and can explode if heated to much higher temperatures.

BAST is thermally more stable and decomposes less exothermically and with less gaseous byproducts.

Rearr/SubsRearr/ElimNormal

Non-polar and non-basic solvents are best for “normal” reactions

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TAS FluoridesAs a side note: modification of the dast preparation can lead to a useful alternate

product:

SF4 + (CH3CH2)2NSi(CH3)3 → DAST

But SF4 + 3 (CH3)2NSi(CH3)3 → ((CH3)2N)3S+ (CH3)3SiF2

-

Tris(dimethylamino)Sulphonium (TAS) salts are usually very soluble in organic solvents. The (CH3)3SiF2

- anion acts as a fluoride ion source.

E.g.

CF2=C(CF3)2 + ((CH3)2N)3S+ (CH3)3SiF2-

→ (CF3)3C- ((CH3)2N)3S+ + (CH3)3SiF (gas)SALT

Other organic soluble fluoride ions sources include the tetra alkyl ammonium fluorides.

(In more punishing applications, these counter ions can give unwanted byproducts from elimination / substitution process.)

TAS

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7) Trifluoromethylating Agents

We have already covered carboxylic acid to CF3 (SF4/HF) and CCl3 to CF3 (HF/Lewis Acid).

The following section deals with reagents that can deliver a CF3 group to a reaction center.

Radical TrifluoromethylationTrifluoromethyl radicals can be generated by various means:

••

69

The •CF3 is very electrophilic, and will add to electron rich aromatics.

Free radical Aromatic Substitution is really Addition – Elimination.

Disadvantages of this method are low yields, low stereocontrol and the inability to do poly(trifluoromethylations).

(The CF3 is a deactivator)

70

Electrophilic TrifluoromethylationThe only example of this is some interesting salts made by Umemoto.(Not free +CF3, but attack on CF3-SuperLG)

1

2

71

In 1990 these were the first examples of trifluoromethylation of carbanions.

Nucleophilic displacement does not occur readily at a CF3-X. (See later).

72

These salts are specifically designed excellent leaving groups.

However it is believed there is significant radical character to these trifluoromethylation.

I.e. the mechanism does not involve a free CF3+, nor SN2, but probably SET leading to the generation of •CF3.

The difficulty of preparing these CF3+ reagents, along with the progress of radical and nucleophilic trifluoromethylation meant these salts never became popular.

Nucleophilic TrifluoromethylationDue to the massive interest in trifluoromethylated aromatics (see later), the conversion

of Ar-I to Ar-CF3 is a very important and much studied transformation.

73

Many old methods are based on the formation of “CuCF3” as a source of CF3-

trifluoromethyl anion.

74

There are numerous ways to prepare CuCF3:

All the above reactions generate CF3- in the presence on Cu+. Usually CuI.

••

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E.g.

Many of these reactions suffer from low yields and numerous fluorinated by products, (CF3H, difluorocarbene and pentafluoroethyl products, etc).

-CF3 → :CF2 and F-

:CF2 and –CF3 →CF3CF2-

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Nucleophilic trifluoromethylation has been revolutionized by the discovery of (trifluoromethyl)trimethylsilane, CF3-TMS, CF3-Si(CH3)3 by Ruppert in 1984, and the subsequent vast application was demonstrated by Prakash.

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CF3TMS is used in conjunction with a catalytic amount fluoride ion (usually TBAF/THF),which starts the reaction going, and the reaction is autocatalytic as each oxyanion produced carries on the reaction process.

This reagent is the current reagent of choice for nucleophilic trifluoromethylation, although recently two other methodologies have appeared:

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Langlois’ hemiaminal of fluoral is a stable, crystalline compound, in the presence of base and it will do the same trifluoromethylation of electrophilic centers as CF3TMS.

E.g.

The hemiaminal, in the presence of base (usually KOtBu), is deprotonated, and CF3- is

expelled as the carbonyl C=O bond is reformed.

F3C H

O

FluoralR HHemiacetal

ORHOR HHemiaminal

NR2HOR HAminal

NR2R2N

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b) Dolbier and coworkers recently showed that the photoinduced reduction of CF3I by TDAE provided another route for nucleophilic trifluoromethylation.

TDAE is a powerful (two) electron donor:TDAE → TDAE2+ + 2e-

The mechanism is believed to involve stepwise, photoinduced SET of two electrons from TDAE to CF3-I to form a complex between TDAE2+ and the CF3

- anion. This is the presumed active Trifluoromethylating reagent.

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(Environmental Aspects of the FutureIt is worth pointing out that because of ozone issues, the industrial production of CF3Br

is currently restricted, and CF3I will probably soon go the same way.Langlois’ method derives from trifluoroacetaldehyde which is easily prepared and non-

ozone depleting).

8) Building BlocksThe use of the “building block” approach in modern organic synthesis is wide spread.

The use of fluorinated building blocks as a strategy for the construction of fluorinated organic molecules is becoming more popular and also more organized.

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For example consider 3,4-bis(trifluoromethyl)furan:

Hexafluorobut-2-yne is a building block that can be used to construct molecules with two vicinal trifluoromethyl groups.

A useful fluorinated butenolide building block was prepared via Wadsworth-Emmons reaction (like a fancy Wittig), followed by ketal removal.

O

CF3F3C OCF3

CF3

O

F3C CF3

retro(4+2) (4+2)

F

HOHO

CO2EtH

2 3

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1

1

2

4

5

5

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These are just illustrative examples of “normal” organic chemistry using fluorinated compounds.

There is currently a large drive to categorize the use of fluorinated building blocks for installing fluorinated motifs.

There is currently a large drive to categorize the use of fluorinated building blocks for installing fluorinated motifs.

The demonstration of transformation methods and their applicability continues to help the building block approach grow in popularity.