Activation of nucleophilic fluorination by salts in ionic liquids and in sulfolane

Article abstract of DOI:10.1002/adsc.200606086

The nucleophilic substitution of PhCCl₃ by KF in imidazolium-type RTILs is faster than in classical organic solvents but it is strongly dependent upon the nature of the counteranion. The addition of bromide salts in substoichoimetric amounts to the [bmim][PF₆] solvent strongly accelerates this reaction. Furthermore, it has been discovered that addition of KPF₆ to the reaction mixtures strongly activates the nucleophilic fluorination by KF, not only in the [bmim][NTf₂] or [bmim][PF₆] ionic liquids but also for the reactions performed in sulfolane.

Full text of DOI:10.1002/adsc.200606086

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DOI: 10.1002/adsc.200606086
Activation of Nucleophilic Fluorination bySalts in Ionic Liquids
and in Sulfolane
StØphane Anguille,a Maxime Garayt,a Vincent Schanen,b and RenØ GrØea, c,*
a
ENSCR, Laboratoire de Synth›se et Activation de BiomolØcules, CNRS UMR 6052, Avenue du GØnØral Leclerc,
35700 Rennes Beaulieu, France
Rhodia Recherches et Technologies, Centre de Recherche de Saint Fons, 85 Avenue des Fr›res Perret, BP 62, 69192
b
Saint-Fons Cedex, France
UniversitØ de Rennes 1, Laboratoire de Synth›se et Electrosynth›se Organiques, CNRS UMR 6510,
c
Avenue du GØnØral Leclerc, 35042 Rennes Cedex, France
Fax : (+33)-(0)2-23-23-69-78; e-mail: rene.gree@univ-rennes1.fr
Received: March 8, 2006; Accepted: May 9, 2006
Abstract: The nucleophilic substitution of PhCCl3
by KF in imidazolium-type RTILs is faster than in
classical organic solvents but it is strongly depen-
dent upon the nature of the counteranion. The ad-
dition of bromide salts in substoichoimetric
ethers,[7] or the formation of carbonates.[8] Recently,
it has been demonstrated that nucleophilic fluorina-
tion on aliphatic systems can be successfully per-
formed in ionic liquids, or with polymer-supported
ionic liquids.[9] Examples of aromatic nucleophilic flu-
orinations have also been described in the litera-
ture.[10] However, it must be mentioned that various
nucleophiles, including the basic fluoride anion, can
decompose the imidazolium salts which are often
used as RTILs.[11] Using a,a,a-trichlorotoluene as a
model substrate, we have established previously that
ionic liquids offer significant improvements in terms
of reactivity and selectivity during the nucleophilic
fluorination with KF, as compared to classical organic
solvents such as sulfolane or DMSO, for instance.[12]
The purposes of this paper are (1) to report a system-
atic study of the reaction of KF with trichlorotoluene
in different imidazolium-derived ionic liquids and to
demonstrate the key role of the nature of the RTIL
anion in this process, (2) to establish that various bro-
amounts to the [bmim][PF6] solvent strongly accel-
N
erates this reaction. Furthermore, it has been dis-
covered that addition of KPF6 to the reaction mix-
tures strongly activates the nucleophilic fluorination
by KF, not only in the [bmim]
N
N
ionic liquids but also for the reactions performed in
sulfolane.
Keywords: fluorides; fluorination; halogen ex-
change; ionic liquids; nucleophilic substitution; salt
effect
The room temperature ionic liquids (RTILs) are at- mide salts, added in substoichiometric amounts,
tractive new reaction media, due to their unique phys- strongly activate the nucleophilic fluorination in
ical and chemical properties.[1] Many types of organic [bmim]
[PF6], and (3) to demonstrate that KPF6 is
U
and organometallic reactions, as well as biotransfor- also a potent activator of the nucleophilic fluorina-
mations, have already been performed in these sol- tion, not only in ionic liquids but also in sulfolane.
vents and in some cases the RTILs offer distinctive
The trichlorotoluene 1 has been selected as the
advantages in terms of reactivity and selectivity. In model compound in our studies.[13] It will allow us to
addition, these RTILs can be very often recycled and study the selectivity of the reaction since it could
reused.[2] Furthermore, they can be employed to im- afford not only the monofluorinated compound 2 but
mobilize the reagents and/or the catalysts as task spe- also the difluorinated derivative 3 or the trifluorinat-
cific ionic liquids (TSILs).[3]
ed derivative 4 (Scheme 1). Furthermore, since all
Various aspects of the nucleophilic substitution re- these derivatives hydrolyse very quickly into the
actions have already been studied in RTILs. The benzoyl fluoride (PhCOF, 5), the presence of water
halide nucleophilicity in ionic liquids has been estab- will be easily detected in these fluorinations. In all
lished on the basis of kinetic data.[4] Different types reactions we used high quality potassium fluoride
of nucleophilic substitutions have been performed, for (spray-dried KF) as nucleophilic fluorinating agent.
instance, with cyanide or azide anions.[5] The hydroly- The different butylmethylimidazolium salts have been
sis of halogen derivatives has also been reported in prepared, and dried, following literature proce-
ionic liquids,[6] as well as cleavage reactions of dures.[14]
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StØphane Anguille et al.
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ty is excellent since the amount of 3 is very low (less
than 5%) and both the trifluoro derivative 4 and the
benzoyl fluoride 5 are not detected. A comparison of
the halide-derived ionic liquids leads to some interest-
ing observations. The fluorination occurs also in
[bmim]Cl but the reaction remains relatively slow and
the yield in 2 is only 30% after 5 h. The use of
[bmim]Br led to an unusual behaviour in comparison
with the other solvents: in this ionic liquid the rate is
faster but the yield is quickly stabilised at around
60%, while all the trichlorotoluene is consumed.
These results demonstrate that bromide salts can
Scheme 1. Fluorination of trichlorotoluene.
In a first set of experiments, performed at 1508C strongly activate the nucleophilic fluorination of 1.[15]
with 2 equivalents of KF at a 0.25 molar concentra- Therefore we checked if [bmim]Br, in substoichiomet-
tion in the solvent, we compared the fluorination re- ric amounts, could also improve the fluorination in
actions in three different ionic liquids and in sulfo- the [bmim]
lane. The results are given in Figure 1 (for the conver- Figure 3 and, indeed, under the same reaction condi-
sion of 1) and in Figure 2 (for the yield in 2). tions, with only 0.2 equivalents of [bmim]Br, a 20%
[PF6] solvent. The results are given in
Under these conditions, the reaction is extremely increase in the yield of 2 (to 88%) was observed after
slow in sulfolane, affording the compound 2 in only 2 h. Furthermore, the selectivity remained good since
3% yield after 5 h. On the contrary, the fluorination 3 was obtained only in 6% yield without any traces of
is easily performed in [bmim][PF6], affording a good 4 or 5.
G
yield in 2 (87%) after 5 h. Furthermore, the selectivi-
This activation is also observed, as expected, by
using tetramethylammonium and tetramethylphos-
phonium bromides (Table 1). In all cases and under
the same reaction conditions, improvements in yields
(up to 40%), are observed. However the use of less
hygroscopic phosphonium salts is recommended since,
Figure 1. Fluorination in three ionic liquids and sulfolane
(conversion of 1, GC analysis).
Figure 3. Activation of the fluorination by using various
amounts of [bmim]Br (GC analysis).
Table 1. Activation by ammonium and phosphonium bro-
mides in [bmim]
A
KF, GC analysis).
2 (%)
3 (%)
4 (%)
5 (%)
A
[PF6]
40
75
50
67
71
80
69
/
10
traces
traces
12
/
/
2
Me4NBr (2.0 equivs.)
Me4NBr (1.0 equivs.)
Me4NBr (0.1 equivs.)
Me4PBr (2.0 equivs.)
Me4PBr (1.0 equivs.)
Me4PBr (0.2 equivs.)
traces
/
/
/
/
/
15
traces
/
/
/
5
1
Figure 2. Fluorination in three ionic liquids and sulfolane
(formation of 2, GC analysis).
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Nucleophilic Fluorination by Salts in Ionic Liquids and in Sulfolane
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under these conditions, they do not afford any benzo-
yl fluoride 5.[16]
It is known that quaternary ammonium salts cata-
lyse the fluorination reactions performed under
phase-transfer catalysis and, in that case, it is strongly
dependent upon the water content.[17] Such a phe-
nomenon could explain, at least in part, the results
obtained here in the RTILs. However, another possi-
ble explanation for the activation observed in the
presence of bromide ions is given in Scheme 2.
A first nucleophilic substitution by BrÀ affords the
bromodichlorotoluene 6 as a reactive intermediate
which can be trapped by FÀ to give the fluorinated
product 2. In the presence of larger quantities of BrÀ,
Figure 4. Activation of fluorination by KPF6 in ionic liquids
and sulfolane (GC analysis).
further substitution reactions on compound 2 (and/or
6) can occur in the same way, leading ultimately to
the difluoro derivative 3 and to the trifluorotoluene 4.
In agreement with that hypothesis, the reactions per- finished in less than 2 h, affording an excellent yield
formed in pure [bmim]Br afforded larger quantities in 2 (Figure 5).
of these two compounds. Furthermore, a GC-MS
Finally, we have found that by using only 0.2 or 0.5
analysis of the reaction mixture obtained during the equivalents of KPF6 in sulfolane at high concentra-
fluorination reaction in pure [bmim]Br allowed the tions, excellent results are obtained in the monofluori-
characterisation of a [PhCBrCl]+ ion, in agreement nation of 1 (Figure 6). Under the optimised reaction
with the intermediacy of compound 6.
conditions (1.1 equivalents of KF with 0.5 equivalents
The higher reactivity observed in [bmim][PF6] as
A
compared to other ionic liquids, such as [bmim]-
[NTf2], led us to study the effect of the PF6 counter-
anion on the fluorination of 1 (Figure 4). The addition
of 4 equivalents of KPF6 to the reaction mixture in
[bmim]
slight increase (8%) in the yield of 2. On the contrary,
in [bmim][NTf2], a significant increase in the yield
[PF6] afforded little change in reactivity with a
ACHTREUNG
(up to 25%) was observed. More surprisingly in sulfo-
lane, a very important change occurred with a 65%
increase to give a 68% yield in 2!
Furthermore, an increase of the concentration of
KPF6 in the ionic liquid (while keeping the substrate
1 at a constant 0.125M concentration) induced a fur-
ther increase in the rate of the formation of com-
Figure 5. Effect of the amount of KPF6 on the fluorination
pound 2. With 8.2 equivalents of KPF6 the reaction is by KF in sulfolane (GC analysis).
Scheme 2. Activation by BrÀ during the fluorination of tri-
chlorotoluene.
Figure 6. Effect of the concentration of KPF6 in sulfolane,
on the fluorination by KF (GC analysis).
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StØphane Anguille et al.
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red during 12 h under vacuum at 608C. After the transfer of
argon to the reaction flask, the temperature was increased
to 1508C and the trichlorotoluene 1 was added via a syringe.
After the appropriate reaction time, the samples were re-
moved from the reaction mixture via a syringe and extracted
with diethyl ether. The contents of the organic phases were
analysed by GC (HP 5890 A, SE-30 capillary column) using
authentic samples of compounds 1 to 5 as references.
of KPF6 at a 3.6M concentration in sulfolane), the
monofluorinated derivative 2 is obtained in over 85%
yield after only 3 h at 1508C. Excellent results are
also obtained in 5 h with 0.2 equivalents of KPF6 at
5.5M in sulfolane.
This new method for nucleophilic fluorination ap-
pears very attractive from the synthetic point of view
but the reasons leading to this unusual activation by
KPF6 are not clear at this stage. Further studies and,
in particular, in depth physicochemical experiments
dealing with the structure and properties of the ionic
species in solution, will be necessary before suggesting
a rationale for this process. Finally, a very unusual ac-
tivation of the fluorination by KF has been demon-
strated both in ionic liquids and in sulfolane.
Acknowledgements
We thank CNRS and RHODIA for the support of this re-
search programme.
This study confirms that the nucleophilic fluorina-
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Experimental Section
The butylmethylimidazolium salts were prepared and dried
following literature procedures.[13] The ionic liquids were
dried under vacuum (ꢀ 3 mm Hg) at 708C during 24 h
before their use; the sulfolane was also kept under vacuum
(ꢀ 3 mm Hg) at 608C during 24 h before being used. Spray-
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Representative Procedure for the Fluorination
Reactions Performed in Ionic Liquids
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