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
1
Sources of Fluorine
CaF2
HF (anhydrous)
F2 (gas)
(Fluorspar)
Metal Fluorides
Transition Metal
Complexes
2
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.
3
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.
4
A few years ago:
5
Typically reaction with elemental fluorine is an exothermic, free radical chain process.
CH4
F
CH3 +
H-F
F2
CH3F + F
Further fluorination becomes progressively
more difficult
CF4
(difficult to proceed
this far along)
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-F
+
C-H
+
F2
weak bond
Compare this to
C-H
+
Cl2
H-F
ΔH = -99kcal/mol
H-Cl
ΔH = -23 kcal/mol
strong bond
→
C-Cl
+
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).
6
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
→
weak bond
CF-CF
ΔH = -104kcal/mol
strong bonds
(For Cl2 ΔH = -31kcal/mol)
Again sufficient to smash C-C bonds when using elemental fluorine.
7
Fluorination of Hydrocarbon Surfaces
In principle,
H2
C
F2/N2
(1-3% dil.)
C n
H2
F2
C
+ H-F
C n
F2
Substn
Previous example of petrol tank.
Also anthracene and graphite
F2/He
(5% dil.)
Graphite
F2/He
(5% dil.)
F
F
C1F1
n
F
white powder
Addn
Addn
8
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.
O
Eg.
CF2CFHCF3
F2 / N2
O
F
CF2CF2CF3
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).
9
Fluorine Generation
Fluorine 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.
10
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
11
gas.
Alternatives to using Elemental Fluorine
2) Transition Metal Fluorides
Oxidative Fluorination
C H
C F
is a formal oxidation on the carbon
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.
12
Cobalt trifluoride is generated by reaction of Cobalt Difluoride with elemental Fluorine.
Co II
Co III
2 CoF2 + F2
2 CoF3 +
= OXIDATION
2 CoF3
C H
C F
+ H-F + 2 CoF2
Co III
Co II = reduction
The organic is getting oxidized
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.
13
Saturated Systems
Radical cation
C H
-1e
C H
Co(III)
-H+
Co(II)
C
Radical
Co(III)
-1e
Co(II)
etc.
FC+
C F
Recall 2CoF3
+ C-H
C-F
Cation
+ H-F + 2 CoF2
14
Unsaturated Systems
Radical cation
- 1e-
+
F-
F
Radical
- 1e-
F
F
F-
+
F
Cation
15
Examples
CoF3
nC4H10
Substn
nC4F10
CH3
CF3
CoF3
High Temp.
F
F
Addn
and
Substn
16
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.
17
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.
18
Examples
O
H3C C Cl
E.C.F.
O
F3C C F
O
H3C S Cl
O
E.C.F.
O
F3C S F
O
N(CH3)3
E.C.F.
N(CF3)3
H2O
H2O
O
F3C C OH
O
F3C S OH
O
trifilic acid - a very strong
organic acid
shows no significant basic character - is
used as an inert fluid
Such a method is very easy to conduct industrially, and the products are widely
commercially available.
19
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.
K2NiF6
+
2 BF3
aH-F
< -20oC
NiF4 + 2 KBF4
0oC
NiF3 + 1/2 F2
Actually NiF3 was later shown to be NiIVNiIIF6
20
Examples
CF3CHFCF2
O
CF2CFHCF3
NiF3, HF
CF3CF2CF2
O
F
CF2CF2CF3
CF3CF2CF2
F
CF2CF2CF3
K2NiF6, BF3
-20oC
CF3CF=CF
CF=CFCF3
K2NiF6
0 oC
H
F
CF3CF2CF2
CF2CF2CF3
H
Tertiary positions bearing an RF are resistant
to oxidation by K2NiF6
21
ii) Other Oxidative Fluorinations in HF
Again C-H → C-F using an oxidizing agent (e.g. Pb(OAc)4)
Ph-CH3
Pb(OAc)4
Ph-CH3
-H+
-1 e-
etc
Ph-CH2
Pb(OAc)4
-1 e-
Ph-CH2F
H-F
+
Ph-CH2
Again it becomes increasingly difficult to oxidize as the degree of fluorination increases.
22
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-CCl3
H-F
o
Ph-CF3
40 C
Ph3CCl
H-F
Ph3CF
Easier cation formation = lower temp
R.T.
23
The Swarts Reaction
This reaction is industrially important in the manufacture of Refrigerants (i.e. CFC’s /
Freons).
CCl4
HF, SbF5
100oC
CCl3F + CCl2F2 + CClF3
9%
90%
trace
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.
24
There is also a decrease in steric assistance to ionization as each larger chlorine is
replaced by a smaller fluorine.
+
109.5o
120o
Bulky Cl’s encourage increase in bond angle – i.e. ionization
General Mechanistic Process:
R Cl
+
SbF 5
+
R Cl
_
SbF5
(ionic)
R+
(SbF5Cl)-
H-F
(concerted)
H-F
Cl
R
R-F +
H+(SbF5Cl)-
SbF4
F
H-F
H-Cl +
H+(SbF6)-
25
General Mechanistic Process:
E.g. the following is only consistent with an ionic process:
Ph-CCl2-CCl3
HF, SbF5
Ph-CF2-CCl3
Only exchange at Benzylic position
Industrial Use
The Baeyer Company developed a one-pot synthesis of trifluorotoluene from benzene
based on this type of reaction.
C6H6 + CCl4
HF, SbF5
C6H5-CF3
26
Mechanism
CCl3 Cl
L.A.
+
(HF or SbF5)
H
CCl3
etc.
L.A.-Cl-
-H+
HF, SbF5
CF3
CCl3
27
Freon Nomenclature
Typically 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 113
CF2Cl2 is Freon 012
CF2HCl is Freon 022
C4F8 (Perfluorocyclobutane) is Freon C318
28
Despite their physical properties which make them useful as refrigerants / airconditioning 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.
29
In the stratosphere:
O2
O•
+
O2
CF2Cl2
Cl•
ClO•
→
2 O•
→
O3
→
•CF2Cl +
•Cl
+
O3
→
ClO•
+
O2
+
O3
→
Cl•
+
2 O2
The Cl• generated perpetuates the chain process.
Overall:
2 O3 → 3 O2
Catalysed by Cl•
30
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.
31
4) The use of Alkali Metal Fluorides for Creating C-F bonds
Typically:
F-
C X
F C
X-
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.
32
Common Aprotic Solvents include:
O
H3C
O
O
n
CH3
"glymes"
n=2 diglyme
n=3 triglyme
n=4 tetraglyme
CH3
N
O
N.M.P.
S
O
sulpholane
(sulfolan)
O
H3 C N C H
CH3
D.M.F.
O
H3C N C CH3
CH3
D.M.A.
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)
33
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 energy
Or 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
18-Crown-6
O
O
O
K+
O
FO
O
"naked' Fluoride ion
34
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 systems
For saturated systems, the reactivity order is:
C Cl
>
C Cl
Cl
>
Cl
C Cl
Cl
>
Cl
Cl C Cl
Cl
more reactive toward Fluoride substitution
35
Typically, saturated per-halo systems are not that reactive.
Eg.
KF
CCl4
X
CCl3F
(could use HF/SbF5)
Unsaturated Systems
Cl
F-
F
Cl-
These can be very active if sufficiently activated.
36
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 elimination
processes where the leaving group is expelled in a subsequent exothermic step.
(So this is NOT SN2)
Eg.
Cl
KF
F
autoclave
Cl
N
KF
autoclave
Cl
Cl
F
N
major product
with Cl meta
to N remaining
+
F
N
hard to force it
to this product
37
Perfluorocyclopentene
This compound is produced via the reaction of fluoride ion with perchlorocyclopentene.
KF
Cl
F
o
NMP, 180 C
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.
Cl
Cl Cl
F-
Cl
Cl
F-
Cl
F
Cl
F
Cl
F
Cl
Cl
Cl Cl
F-
F
F
Cl
Cl
F
Cl
F
F
Cl
F
Cl
-
F
Cl
Cl
F
Cl
F
38
(Educational Aside:
This is a good example of an SN2’ reaction.
The SN2’ reaction
R'
-
Y
Rγ
β
R Z
R'
α
X
Y
Z
R R Z
Z
X-
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.
39
R'
R
R Z
when
Generally:
Z=H
Z = CH3
X
Z
SN2
SN2’
larger nucleophiles favour SN2’ over SN2
Many examples in Propargyl systems:
OTos CH3MgBr, CuBr
Ph C C CH2
Aside Ends).
Ph
H3 C
C CH2
40
Heptafluorobutene (Unusual products and the use of Hydrogen atom free solvents)
Formation of heptafluorobut-2-ene from hexachlorobutadiene with KF.
Cl
Cl
Cl
Cl
Cl
Cl
KF
Sulpholane, 180 oC
F 3C
H
F
CF3
What is the mechanism and where does the Hydrogen come from?
41
Cl
Cl
F
Cl
Cl
Cl
Cl
_
-
Cl
F Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
Cl
Cl
Cl
x5
F3C
F
_
F
CF3
-
F
F
C
F 3C
F
F
F
-
F
F
F
F
F
R-H
F3C
F
H
CF3
42
Therefore what about if we do the reaction without the source of Hydrogens?
F3C
F
_
F3C
CF3
CF3
R-H
F3C
F
H
CF3
We can replace almost all the solvent with a perfluorocarbon, and the product obtained
then becomes hexafluorobutyne.
43
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
44
also).
Typical results with aromatics are shown:
Activated
and
deactivated
Systems
Normal EAS directing effects apply
H2SO4 = solvent and L.A.
Partial hydrolysis of Nitrile
to Primary Amide
45
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
Nuc
F L
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.
46
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”.
47
Typical nucleophiles to be reacted include:
(Activated) aromatics
Benzene resists fluorination under reasonable conditions, but activated aromatics do
undergo mono and difluorination.
Notice anything strange ?
48
Nucleosides and Nucleoside Bases
The value of biologically active
compounds containing F has
already been highlighted.
regiochem ?
5FU
5FU is a potent
anticancer agent.
49
Carbon-Metal Bonds
Fluorodemetallation is can be easily achieved.
The last example provides a nice route into a 5-fluorocyclopentadiene generation
(anti viral research), via a retro DA.
50
Stabilized Anions
Stabilized anions (typically generated by action of NaH or KH on the parent compound)
are readily fluorinated by Selectfluor.
51
1,3 Dicarbonyls
Mono and difluorination can be controlled by the ratio of NF reagent.
52
Alkenes/Alkynes
Solvent systems can trap the carbocationic intermediates formed in reaction with carbon
- carbon multiple bonds.
via the enol
regiochem ?
53
Chiral N-F compounds
Enantioselective fluorination is possible if a chiral N-F reagent is used.
Notice that the yields and ee’s are not brilliant.
54
70% e.e
= 85:15
LDA is lithium
di isopropyl amide
= good base
but poor nuc
(Chiral bases and achiral N-F’s also work).
55
6) Sulfur Tetrafluoride and Safer Equivalents
Sulfur Tetrafluoride is best known for its fluorodeoxygenation ability.
That is:
R OH
R F
O
R
R'
R CO2H
R CF2-R'
R CF3
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.
56
Reaction of Alcohols
The mechanism of R-OH → R-F can be represented by the following:
57
E.g.
amide has reduced N nucleophilicity
If the nitrogen is left unprotected…
1
2
3
4
3
4
5
5
1
2
58
Reactions with Carbonyls
Aldehydes and ketones are readily transformed in difluoromethyl/methylene
functionalities using SF4/lewis acid.
59
LA
Notice the ketone selectivity
The mechanism of this transformation involves one or both of:
And/or
60
Reaction of Carboxylic Acids
The 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.
61
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 Alternatives
Recently, “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
62
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.
63
(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.
64
For example, pivaldehyde is a classic acid sensitive aldehyde:
+ HF
DAST
Carbocation
rearrangement
CATION
trap with F-
- H+
trap
with F-
REARR
and ELIM
NORMAL
REARR
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Normal
Rearr/Elim
Rearr/Subs
Non-polar and non-basic solvents are best for “normal” reactions
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.
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BAST is thermally more stable and decomposes less exothermically and with less
gaseous byproducts.
TAS Fluorides
As a side note: modification of the dast preparation can lead to a useful alternate
product:
SF4 +
(CH3CH2)2NSi(CH3)3
→
DAST
→
((CH3)2N)3S+ (CH3)3SiF2-
But
SF4 + 3 (CH3)2NSi(CH3)3
TAS
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+
SALT
+ (CH3)3SiF (gas)
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.)
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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 Trifluoromethylation
Trifluoromethyl radicals can be generated by various means:
•
•
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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)
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Electrophilic Trifluoromethylation
The only example of this is some interesting salts made by Umemoto.
(Not free +CF3, but attack on CF3-SuperLG)
1
2
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In 1990 these were the first examples of trifluoromethylation of carbanions.
Nucleophilic displacement does not occur readily at a CF3-X. (See later).
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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 Trifluoromethylation
Due 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.
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Many old methods are based on the formation of “CuCF3” as a source of CF3trifluoromethyl anion.
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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).
-CF
3
→ :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.
O
F3C
H
Fluoral
HO
R
OR
H
Hemiacetal
HO
R
NR2
H
Hemiaminal
R2N
R
NR2
H
Aminal
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.
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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 Future
It 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 nonozone depleting).
8) Building Blocks
The 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:
F3 C
CF3
O
retro
(4+2)
O
CF3 (4+2)
O
CF3
F3C
CF3
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.
2
1
5
3
1
HO H
HO
4
5
CO2Et
4
2 3
F
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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.
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