Selective fluorination of substituted trichloromethyl benzenes by HF in liquid phase: Preparation of fluorinated building blocks

Article abstract of DOI:10.1016/j.jfluchem.2010.06.013

The selective fluorination by successive Cl/F exchanges of α,α,α-trichlorotoluene, substituted or not by a chlorine atom, was studied in the presence of HF as the fluorinating agent. The influence of the presence of a catalyst or a basic solvent (such as dioxane, pyridine, tributylphosphate) in order to control the fluorination was also investigated. In mild conditions (50 °C and after 1 h of reaction), HF in excess was required in order to obtained the trifluoromethylation by Cl/F exchanges. The presence of SbCl₅ in small amount activated the Cl/F exchanges and only a stoichiometric amount of HF was required whatever the chlorinated molecules. Selective mono and difluorination could be obtained by using basic solvents.

Full text of DOI:10.1016/j.jfluchem.2010.06.013

Journal of Fluorine Chemistry 131 (2010) 1241–1246
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Selective fluorination of substituted trichloromethyl benzenes by HF in liquid
phase: Preparation of fluorinated building blocks
*
Alexandre Piou, Stephane Celerier, Sylvette Brunet
Laboratoire de Catalyse en Chimie Organique, UMR CNRS 6503, Universite´ de Poitiers, Faculte´ des Sciences Fondamentales et Applique´es 40, Avenue du Recteur Pineau,
86022 Poitiers cedex, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The selective fluorination by successive Cl/F exchanges of a,a,a-trichlorotoluene, substituted or not by a
Received 26 April 2010
Received in revised form 14 June 2010
Accepted 15 June 2010
Available online 23 June 2010
chlorine atom, was studied in the presence of HF as the fluorinating agent. The influence of the presence
of a catalyst or a basic solvent (such as dioxane, pyridine, tributylphosphate) in order to control the
fluorination was also investigated. In mild conditions (50 8C and after 1 h of reaction), HF in excess was
required in order to obtained the trifluoromethylation by Cl/F exchanges. The presence of SbCl5 in small
amount activated the Cl/F exchanges and only a stoichiometric amount of HF was required whatever the
chlorinated molecules. Selective mono and difluorination could be obtained by using basic solvents.
ß 2010 Elsevier B.V. All rights reserved.
Keywords:
Fluorination
Lewis acid
Antimony pentachloride
a,a,a-Trichlorotoluene
Chloro-trichlorotoluene
HF-base
1. Introduction
deactivation of the catalytic system (SbIII halides are inert) [14],
antimony chlorides are very powerful catalysts for fluorination
The incorporation of fluorine, especially the –CF3 group, into
organic compound results in changes in the physical, chemical and
biological properties [1–3]. These changes make them suitable for
diverse applications in the areas of material science, agrochemistry
and pharmaceuticals [4–6]. While a wide variety of methods have
been developed for introducing trifluoromethyl groups into
organic molecules [7–11], the fluorine–chlorine exchange is the
most widely used technology in industrial scale especially for the
selective synthesis of fluorinated building blocks. This reaction can
be carried out using two different sources of fluorine: alkali metal
fluorides, such as potassium fluoride (KF) [12], or anhydrous
hydrogen fluoride (HF). Although KF is more safe and cheap to use,
some organic compounds need more vigorous conditions to be
fluorinated and in this case HF is required. The reaction between
hydrofluoric acid and an organic halide can be carried out either in
vapour phase or in liquid phase. Moreover in both cases, the use of
Lewis acid as catalyst can improve the reaction. The most
commonly used in liquid phase fluorination reactions are
antimony pentachloride (SbCl5) or antimony mixed halides [13].
Even if antimony chlorides suffer from the fact that they are very
corrosive and they can be reduced from SbV to SbIII, to lead to a
reactions. That is why they are used in industrial scale reactions
[15–17]. The catalytic processes offer a lot of advantages from
classical chemistry. Indeed, the catalytic fluorination with HF as
the fluorinating agent and a catalyst such as SbCl5 for the
fluorination of chlorinated molecules such as chlorinated hydro-
carbon (to produce hydrofluorocarbon) and chlorinated aromatics
(to produce building blocks) which involved only Cl/F exchanges
lead to high degree of fluorinated molecules and only to HCl as the
by-product. Only a few examples of catalytic fluorination reactions
have been reported in the academic literature.
Previous works [17] have been carried out on the fluorination of
trichloromethoxy-benzene by liquid HF with various Lewis acids
as catalysts. Only Lewis acids with an oxidation state of +V are
efficient and SbCl5 is the most powerful. The efficiency of these
Lewis acids is due to there abilities to form nucleophilic complexes
in the presence of HF. Indeed, the presence of few amount of the
catalyst favoured the last Cl/F exchange to produce fluoro-
methoxy-benzene only in stoichiometric amount of HF and at a
temperature of 50 8C. Moreover, few works in the literature
reported selective fluorination in the presence of a solvent [18–22].
HF–pyridine is well known to be a good fluorinating agent.
This paper deals with the operating conditions for the
fluorination of chlorinated compounds and more particularly of
trichloromethyl benzene substituted or not by a chlorine atom.
Indeed the presence of chlorine atom which is an attractive atom
* Corresponding author. Tel.: +33 549453627; fax: +33 549453897.
E-mail address: sylvette.brunet@univ-poitiers.fr (S. Brunet).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.06.013

1242
A. Piou et al. / Journal of Fluorine Chemistry 131 (2010) 1241–1246
Table 1
Effect of the amount of HF in the transformation of various trichloromethyl benzenes (Pi = 10 bar, time= 1 h, T =50 8C, substrate = 0.2 mol).
Substrate
TCTd
HF/substrate molar ratio
Conversion (mol%)a
Yield (mol%)b
Selectivityc (%)
R-CCl2F
R-CClF2
R-CF3
1
2
3
4
79
99
79
95
99
89
66
3
33
84
19
4
1
13
81
96
100
100
0
0
4CTCTe
2CTCTf
1
2
3
4
87
100
100
100
68
85
87
82
70
2
29
86
71
2
2
12
28
96
1
2
1
2
3
4
71
100
100
100
66
100
84
74
3
24
96
41
2
2
1
1
58
96
82
2
TCMBg
3
100
93
0
98
2
a
Amount of substrate transformed.
b
c
d
e
f
Molar amount of fluorinated products (by-products excepted).
Amount of mono, di and trifluorinated compounds.
a,a,a-Trichlorotoluene, R = Ph.
4-Chloro- -trichlorotoluene, R = p-Cl-Ph.
a
,a,
a
2-Chloro-a,a,a-trichlorotoluene, R = o-Cl-Ph.
Trichloromethoxy-benzene.
g
(in position ortho or para) in the aromatic ring could modify the
reactivity of the –CCl3 group. Consequently, the influence of the
substitution on the aromatic ring, the amount of HF used as
fluorine source and SbCl5 used as the catalyst on the reaction has
been studied. Selective fluorinations (mono and di) were also
studied by using various HF-base systems with dioxane, tributyl-
phosphate or pyridine as base.
small amount of trifluoromethoxy-benzene (2%) was isolated from
trichloromethoxy-benzene (TCMB) under theses conditions.
When 4 equiv. of HF were added, the trifluorination was almost
total in all cases.
The results showed that the first two Cl/F exchanges were rather
fast and that the last one was the slowest. This is in accordance with
other studies onthe fluorination of aliphaticchlorinated compounds
[23]. In fact, the presence of two fluorine atoms on carbon atom
makestheruptureofthelastC–Clbondmoredifficultduetothehigh
electronegativity of the fluorine atom.
2. Results and discussion
2.1. Fluorination of trichloromethyl benzenes
The trichloromethoxy-benzene (TCMB) is less reactive than the
other chlorinated compounds. Indeed, the presence of the methoxy
group and mainly the presence of the oxygen modified the
electronegativity and consequently the C–Cl bond rupture. In this
case, the last Cl/F exchange was inhibited with 3 equiv. of HF
(Table 1). The presence of chlorine atom on benzene ring modified
the reactivity of the –C–Cl bond of the –CCl3 group and disfavoured
also the third Cl/F exchange. Indeed, the presence of the chlorine
atom on benzene ring modified the selectivity towards the
trifluoromethylation of the –CCl3 group. Morevover, the 2-
The fluorination of different chlorinated molecules (
trichlorotoluene, TCT; 4-chloro- -trichlorotoluene, 4CTCT; 2-
chloro- -trichlorotoluene, 2CTCT) was carried out for 1 h at
a,a,a-
a,a,a
a,a,a
50 8C with different amounts (from 1 to 4 equiv. from chlorine
atoms) of HF (Table 1). The conversion corresponds to the amount
of the substrate which is transformed into fluorinated products
and the yield to the sum of molar percentages of mono, di and
trifluorinated products. In all reactions, yields were good.
When 1 equiv. of HF was added to the reaction medium, the
conversion of chlorinated substrates was not total and only traces
of trifluorinated products were obtained. Whatever the trichlori-
nated compounds, the monofluorinated compound was the major
product (66–74%) but the difluorinated compound was also
present (24–33%). While the amount of HF increased to 2 equiv.,
the amount of difluorination reaction product increased from 84%
to 96% and conversions became complete. The product of
trifluorination was isolated (from 1% to 13%). The different
molecules tested had similar reactivities with 1 or 2 equiv. of
HF. The presence of the chlorine atom in 2 or 4 position on the
aromatic ring or the monofluorination of the –CCl3 group did not
change the reactivity of the substrate for the last two Cl/F
exchanges. Theses experiments confirmed that the two first Cl/F
exchanges were very fast.
chloro-
a
,
,
a
a
,
a
-trichlorotoluene was more reactive than the 4-
-trichlorotoluene. These results show that the para
chloro-
a
,a
position is more deactivated than ortho position. These observa-
tions are in accordance with the other work performing on acidity
of aromatic compounds [24,25]. It has been shown that acidities of
chloro benzoic acid and chloro phenol are more significant when
the chlorine atom is in para position than in ortho position.
Therefore the electron-withdrawing power of chlorine is increased
for the para position.
2.2. Effect of the presence of SbCl5
The effect of the presence of antimony pentachloride as catalyst
(2 mol%) was studied in the same conditions (Table 2). Whatever
the chlorinated compounds, the reaction of trifluorination was
almost complete. All yields were goods (77–92%) with three
equivalents.
With 1 equiv. of HF, the conversion was not total in all cases
(54–60%). The product obtained was the product of trifluoro-
methylation (78–82%). Small amount of mono or difluorinated
product were also isolated. The increase of the amount of HF to 2
With 3 equiv. of hydrogen fluoride (corresponding to the
stoichiometric amount for the total Cl/F exchanges for the –CCl3
group), the trichlorotoluene (TCT) appeared to be the most reactive
and 81% of trifluorotoluene (TFT) was isolated. However, for the 2-
chloro-trichlorotoluene (2CTCT), 58% of trifluorination product
was obtained and only 28% of the para compound (4CTCT). Only

A. Piou et al. / Journal of Fluorine Chemistry 131 (2010) 1241–1246
1243
Table 2
Effect of the amount of HF in the transformation of various trichloromethyl benzenes in the presence of SbCl5 (Pi = 10 bar, time = 1 h, T = 50 8C, substrate = 0.2 mol,
SbCl5 = 0.004 mol: 2 mol%).
Substrate
TCTd
HF/substrate molar ratio
Conversion. (mol%)a
Yield (mol%)b
Selectivityc (%)
R-CCl2F
R-CClF2
R-CF3
1
2
3
54
87
98
40
74
77
8
3
0
10
5
82
92
3
100
4CTCTe
2CTCTf
1
2
3
60
83
45
63
84
9
3
0
12
8
79
89
100
0
100
1
2
3
58
81
41
63
92
10
4
12
8
78
88
100
0
0
100
TCMBg
3
100
86
0
0
100
a
Amount of substrate transformed.
b
c
d
e
f
Molar amount of fluorinated products (by-products excepted).
Amount of mono, di and trifluorinated compounds.
a,a,a-Trichlorotoluene, R =Ph.
4-Chloro- -trichlorotoluene, R = p-Cl-Ph.
a,
a,
a
2-Chloro-a,a,a-trichlorotoluene, R = o-Cl-Ph.
Trichloromethoxy-benzene, R = Ph-O.
g
and 3 equiv. led to an increase to the conversion whatever the
substrate with selectivity towards the trifluoromethylation
product of 100%. No significant selectivity was observed by the
increase of the amount of HF.
to explain the last Cl/F exchange as reported for fluorination of
aliphatic chlorinated molecules [26–30].
2.3. Fluorination by HF-base system
For all molecules studied, the catalyst enabled the selective
formation of trifluoromethylated compound even if
stoichiometric amount of HF was used. With only 2% of SbCl5
and a stoichiometric amount of HF, -trichlorotoluene and
a
sub-
It could be possible to produce selectively the mono or
difluorinated compounds in the presence of HF and a basic solvent
such as dioxane, tributylphosphate (TBP) or pyridine. As reported
in the literature, pyridine was more basic than dioxane and
tributylphosphate [31]. The presence of a basic solvent in the
reaction, allowed the selective fluorination of the different
substrates and the production with good selectivity of the mono
or difluorinated products. All reactions were carried out in the
same conditions as described before (50 8C, 1 h, P = 10 bar of N2).
The change of the conversion, the yield in fluorinated products
and the selectivity towards mono and difluorination are respec-
tively reported in Table 3 with the introduction of dioxane, in
Table 4 with pyridine, and in Table 5 with tributylphosphate. The
introduction of dioxane allows the control of the fluorination
whatever the chlorinated starting materials. Whatever the amount
of HF used, no more trifluorinated products were produced. With a
a,a,a
trichloromethoxy-benzene had the same reactivity. The conver-
sion was complete for both molecules. Trifluorotoluene and
trifluoromethoxy-benzene were isolated with good selectivity
(100%). Moreover, the presence of the catalyst inhibited effects of
substitution. Whatever the substituent position on the aromatic
ring, all molecules tested showed the same reactivity to the
trifluorination reaction. The trifluoromethylated product was
always the major product. With SbCl5, a stoichiometric amount
of HF was enough to obtain a selectivity of 100% of trifluorinated
products with good to excellent yields (77–92%).
For each substrate, no secondary product corresponding to the
Friedel–Craft products was observed. Moreover, there was no
product of substitution of the chlorine atom on aromatic ring by a
fluorine atom. Only chlorine atoms on the methyl group were
exchanged by fluorine atom, even if SbCl5 was used.
These results confirm that SbCl5 is effective to activate the last
Cl/F exchange. This is in accordance with other works performed
on fluorination of trichloromethoxy-benzene [19] or other
substrates [28–32]. The activity of antimony pentachloride is
related to its ability to form mixed halides and to its strong Lewis
acidity. In the presence of HF, SbCl5 can form species such as
SbClxF5Àx which could give protons and very reactive nucleophilic
species (Scheme 1). A SN2 concerted mechanism can be proposed
HF/dioxane ratio of 3.5, the conversion of
was around 57% and the monofluorinated products was isolated
with a selectivity of 94%. For the 4-chloro- -trichlorotoluene
and the 4-chloro- -trichlorotoluene, the monofluorinated
a,a,a-trichlorotoluene
a,a,a
a,a,a
product could be isolated with a selectivity of 82% and 94% with
respectively an HF/dioxane ratio of 4 or 6 (Table 3). Increasing the
HF/dioxane ratio to 5 for the
4-chloro- -trichlorotoluene, the conversion of the substrate
increased respectively to 95% and 97%. Moreover the difluorinated
a,a,a-trichlorotoluene and 6 for the
a,a,a
product was isolated with a selectivity of 84% for the
a,a,a-
[(Scheme_1)TD$FIG]
Scheme 1. Formation of mixed halides of antimony and mechanism of Cl/F exchange by nucleophilic substitution.

1244
A. Piou et al. / Journal of Fluorine Chemistry 131 (2010) 1241–1246
Table 3
Effect of the amount of HF/dioxane in the transformation of various trichloromethyl benzenes (Pi = 10 bar, time = 1 h, T = 50 8C, substrate = 0.2 mol).
Substrate
TCTd
HF/diox
HF/substrate
Conversion (mol%)a
Yield (mol%)b
Selectivityc (%)
R-CCl2F (%)
R-CClF2 (%)
R-CF3 (%)
–
4
6
9
100
57
89
51
87
–
94
12
4
6
96
–
3.5
5
95
84
4
4CTCTe
–
4
6
4
7
100
56
82
50
76
2
82
18
2
18
78
96
–
11
97
4
2CTCTf
–
6
4
100
62
82
35
2
2
6
96
–
11
94
a
Amount of substrate transformed.
b
c
d
e
f
Molar amount of fluorinated products (by-products excepted).
Amount of mono, di and trifluorinated compounds.
a,a,a-Trichlorotoluene, R = Ph.
4-Chloro- -trichlorotoluene, R = p-Cl-Ph.
a
,a,
a
2-Chloro-a,a,a-trichlorotoluene, R = o-Cl-Ph.
Table 4
Effect of the amount of HF/pyridine in the fluorination of various trichloromethyl benzenes in the presence of SbCl5 (Pi = 10 bar, time= 1 h, T = 50 8C, substrate = 0.2 mol).
Substrate
HF/pyridine
HF/substrate
Conversion (mol%)a
Yield (mol%)b
Selectivityc (%)
R-CCl2F (%)
R-CClF2 (%)
R-CF3 (%)
TCTd
–
5
7
4
10
14
100
43
89
33
83
–
80
13
4
20
78
96
–
97
9
4CTCTe
–
7
4
100
41
82
35
2
2
96
–
14
88
12
2CTCTf
–
7
4
100
10
82
10
2
2
–
96
–
14
100
a
Amount of substrate transformed.
b
c
d
e
f
Molar amount of fluorinated products (by-products excepted).
Amount of mono, di and trifluorinated compounds.
a,a,a-Trichlorotoluene, R = Ph.
4-Chloro- -trichlorotoluene, R = p-Cl-Ph.
a
,a,
a
2-Chloro-a,a,a-trichlorotoluene, R = o-Cl-Ph.
Table 5
Effect of the amount of HF/tributylphosphate (TBP) in the transformation of various trichloromethyl benzenes (Pi = 10 bar, time= 1 h, T = 50 8C, substrate = 0.2 mol).
Substrate
HF/TBP
HF/substrate
Conversion (mol%)a
Yield (mol%)b
Selectivityc (%)
R-CCl2F (%)
R-CClF2 (%)
R-CF3 (%)
TCTd
–
5
7
3
3
4
100
58
99
51
75
–
90
47
19
10
52
81
–
92
1
4CTCTe
–
6
3
100
83
87
74
1
71
23
28
–
3.5
77
2CTCTf
–
6
3
100
51
84
41
1
41
1
58
–
3.5
99
a
Amount of substrate transformed.
b
c
d
e
f
Molar amount of fluorinated products (by-products excepted).
Amount of mono, di and trifluorinated compounds.
a,a,a-Trichlorotoluene, R = Ph.
4-Chloro- -trichlorotoluene, R = p-Cl-Ph.
a
,a,
a
2-Chloro-a,a,a-trichlorotoluene, R = o-Cl-Ph.
trichlorotoluene and 78% for the 4-chloro-
a
,
a
,
a
-trichlorotoluene.
7, led to an increase of the conversion from 43% to 97%. The
selectivity depends on the amount of HF used. With HF/
pyridine = 5, monofluorinated was formed with a selectivity of
80%. The increase of the HF/pyridine ratio to 7 allowed the
formation of the difluorinated product with 78% of selectivity. In
For the 2-chloro- -trichlorotoluene, no difluorinated product
a,a,a
could be isolated with good selectivity even increasing the amount
of HF.
As with dioxane, the presence of pyridine slowed down the
reaction and no trifluorinated product was formed whatever the
the case of the 4-chloro-a,a,a-trichlorotoluene, the conversion
amount of HF introduced (Table 4). For the
an increase of the amount of HF, from a HF/pyridine ratio from 5 to
a
,
a
,
a
-trichlorotoluene,
was 41% with a HF/pyridine ratio of 7 and only the monofluori-
nated product could be isolated with a good selectivity (88%). The

A. Piou et al. / Journal of Fluorine Chemistry 131 (2010) 1241–1246
1245
Table 6
Effect of the presence of SbCl5 in the transfomation of
a,a,a-trichlorotoluene (TCT) (Pi = 10 bar, time = 1 h, T = 50 8C, substrate = 0.2 mol, SbCl5 = 0.004 mol: 2 mol%).
Solvent
Catalyst
HF/TCTa
Conversion. (mol%)b
Yield (mol%)c
Selectivityd (%)
R-CCl2F (%)
R-CClF2 (%)
R-CF3(%)
Dioxane (HF/diox = 2)
Pyridine (HF/py = 4)
–
3.5
3.5
5
5
100
90
0
0
0
SbCl5
44
33
10
–
8
8
23
34
20
17
99
77
1
0
6
SbCl5
17
TBPe (HF/TBP =7)
–
4
4
92
97
75
79
47
15
52
82
<1
SbCl5
3
a
a
,
a
,
a
-Trichlorotoluene, R = Ph.
b
c
Amount of substrate transformed.
Molar amount of fluorinated products (by-products excepted).
Amount of mono, di and trifluorinated compounds.
Tributylphosphate.
d
e
2-chloro-
a
,
a
,
a
-trichlorotoluene was the less reactive substrate
between HF and the basic compound was chosen in order to show
the influence on the conversion and the selectivities. Consequently,
the different ratios were 2 for HF/dioxane, 4 for HF/pyridine and 7
for HF/tributylphosphate. With HF–dioxane system (HF/diox-
ane = 2), the presence of 2% of SbCl5 allowed an increase of the
conversion from 5% to 44% and in the same time, the selectivity
waited in favour of the monofluorinated product (90%). In the case
of the HF–pyridine system (HF/pyridine = 4), the increase of
conversion was quite low (from 23% to 34%) and the addition of
catalyst led to decrease the selectivity of monofluorinated product
(from 99% to 77%) and the formation of the difluorinated and
trifluorinated products appeared. The transformation in the
presence of tributylphosphate (HF/tributylphosphate = 7) and
SbCl5 (2%) led to the selective formation of the difluorinated
product with a selectivity of 82%. In this case, the presence of the
catalyst allowed the increase of the selectivity from 52% to 82%.
The conversion in both cases was around 100%.
and in the same conditions as for the 4-chloro-
otoluene, the conversion was only 10%.
The introduction of tributylphosphate (TBP) during the reaction
was less selective than dioxane or pyridine (Table 5). For the
trichlorotoluene, without tributylphosphate and with 3 equiv. of
HF with respect of the substrate, the conversion was 100% and the
major product was the trifluorinated compound (81% of selectivi-
ty). The introduction of tributylphospate (HF/tributylpho-
sphate = 5) led to a decrease of the conversion to 58% and under
these conditions the monofluorinated product was formed with a
selectivity of 90%. The selectivity of the difluorinated product
increased to 52% when the ratio HF/tributylphosphate raised to 7.
a,a,a-trichlor-
a,a,a-
In the case of a substituted molecules (4-chloro-
otoluene and 2-chloro- -trichlorotoluene), the introduction
of tributylphosphate (HF/tributylphosphate = 6) in the reaction
medium led to the formation of the monofluorinated products with
a,a,a-trichlor-
a,a,a
a selectivity of 77% for the 4-chloro-
a
,
a
,
a
-trichlorotoluene and
These results show that with the HF–dioxane system, the
presence of SbCl5 could activate the C–Cl bond and favour the Cl/F
exchange without modification of the selectivity. This could also
correspond to the formation of a complex between HF and the
Lewis acid as reported previously in different works [19,28–32].
This system could have an increased nucleophilicity compared to
HF-base alone (Scheme 1). With dioxane, in conditions which
disfavour the fluorination reaction, the formation of a mixed halide
99% for the 2-chloro- -trichlorotoluene.
a,a,a
These results show that the introduction of a basic solvent
slows down the reaction of halogen exchange which allows the
selective formation of mono or difluorinated products. On the
other hand, as reported previously, the presence of a chlorine atom,
on the aromatic ring, deactivated the Cl/F exchanges. A higher
amount of HF was required to obtain good conversions of
substrates. Moreover, it is well known that HF molecules form
polymers and decrease the nucleophilicity in anhydrous condi-
tions [32]. The basic solvent could complex a part of this polymer
and decreases the acidity of the medium and the nucleophilic of
the fluoride atom as reported in the literature for pyridine [20].
Two sources of nucleophilic fluoride could be present, one from
free HF and the other from the complex HF-base. The formation of
the mono and difluorinated products depends on the amount of
these two fluorine sources. If all HF was complexed with the
heteroatom of the basic solvent (oxygen or nitrogen atoms),
mainly the mono fluorination was observed whatever the
chlorinated substrates. If the amount of HF was too high, the
fluorination of the chlorinated molecules involved two sources of
nucleophilic fluoride and the reaction was less selective. Indeed, a
mixture of mono and difluorinated products was observed as
allows the transformation of the
a,a,a-trichlorotoluene and the
formation of the monofluorinated product. In the case of
tributylphosphate which is less basic than dioxane, the formation
of a mixed halide promotes the halogen exchange and the selective
formation of the difluorinated product. The effect of the catalyst is
very low in the presence of pyridine as the basic solvent due to the
high basicity of pyridine.
3. Conclusion
Based on our finding, we can conclude that the selective
trifluoromethylation of the corresponding chlorinated compounds
was obtained by successive Cl/F exchanges under mild conditions
with antimony pentachloride as catalyst and HF in stoichiometric
amount as fluoride source. At 50 8C with 2% of SbCl5 and a
stoichiometric amount of HF the conversion of trichlorinated
substrates is complete and the selectivity towards the trifluor-
omethylation is close to 100%. Moreover the presence of the
catalyst inhibits the effects of substituents on benzene ring. On the
other hand, the introduction of basic solvent (dioxane, pyridine or
tributylphosphate) allows the selective formation of the mono or
difluorinated products depending on the HF-base amount that
modulates the nucleophilicity of the fluoride source. Finally, the
introduction of a catalyst with the HF-base system can increase
reported for the transformation of
a,a,a-trichlorotoluene. These
results show that it could be possible to adapt the amount of HF
and the basic solvent to the reactivity of the chlorinated starting
molecule in order to produce selectively the mono or difluorinated
compound.
The impact of the presence of SbCl5 (2 mol%) as the catalyst was
studied on the fluorination reaction of
a,a,a-trichlorotoluene by
HF-base system (Table 6) in order to enhance the conversion and/
or the selectivity of mono and difluorinated products. The ratio

1246
A. Piou et al. / Journal of Fluorine Chemistry 131 (2010) 1241–1246
either the conversion or selectivity of mono or difluorinated
products. Depending of the fluorinating system, it could be
possible to adapt the operating conditions in order to prepare
selectively the mono, di or trichlorinated compound with a good
conversion of the starting materials.
fluorinated compounds. The difference between conversion and
yield corresponds to non-identified by-products and the discrep-
ancy of the experiment.
The chromatograph was a Varian 3380 equipped with 30 m VF-
5ms (Varian) capillary column (inside diameter: 0.25 mm; film
thickness: 1
mm) with a temperature program from 80 8C to 200 8C
4. Experimental
(5 8C/min) and then from 200 8C to 300 8C (10 8C/min).
4.1. Chemical products
References
All commercially available reagents were used without further
purification. Hydrogen fluoride was purchased from Air Liquid;
[1] B.E. Smart, J. Fluorine Chem. 109 (2001) 3–11.
[2] K. Mikami, Y. Itoh, M. Yamanaka, Chem. Rev. 104 (2004) 1–16.
[3] J.T. Welch, Tetrahedron 43 (1987) 3123–3197.
SbCl5 from VWR; -trichlorotoluene, 2-chloro-a,a,a-trichlor-
a
,a
,
a
[4] M.D.I. Fyaz, J. Fluorine Chem. 118 (2002) 27–33.
otoluene, 4-chloro-a,a,a-trichlorotoluene, dioxane, pyridine and
tributylphosphate from Aldrich and C6H5OCCl3 was kindly
provided by Rhodia.
[5] F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 105 (2005) 827–856.
[6] G. Foulard, T. Brigaud, C. Portella, J. Fluorine Chem. 91 (1998) 179–183.
[7] D.A. McClinton, Tetrahedron 48 (1992) 6555–6666.
[8] B.R. Langlois, T. Billard, S. Roussel, J. Fluorine Chem. 126 (2005) 173–179.
[9] S. Large, N. Roques, B.R. Langlois, J. Org. Chem. 65 (2000) 8848–8856.
[10] T. Billard, B.R. Langlois, G. Blond, Tetrahedron Lett. 41 (2000) 8777–8780.
[11] F. Massicot, N. Monnier-Benoit, N. Deka, R. Plantier-Royon, C. Portella, J. Org.
Chem. 72 (2007) 1174–1180.
4.2. General experimental procedure
All reactions were performed in a 100 mL stainless steel
autoclave under an initial pressure of 10 bar. The temperature was
regulated and controlled by means of a thermocouple placed in a
thermometric well in the furnace wall. At the early stage of the
experiment, the substrate (0.125 mol) depending on the experi-
ment, the basic solvent (19 ml) and the catalyst (2.5 mmol) were
introduced in the autoclave. The difference in temperature
between an HF cylinder warmed by means of a heating cord
and the autoclave cooled in liquid nitrogen enabled the required
amount of HF to be transferred to the reaction medium. The
reaction then took place with continuous stirring, at the desired
temperature (50 8C) and under autogene pressure. At the end of the
reaction, the autoclave was cooled down and vented with dry
dinitrogen in order to eliminate the HCl and the unreacted HF. The
contents were quenched with 30 mL of water/dichloromethane
mixture (50/50), using a 316 L stainless steel tank. After extraction
with CH2Cl2, the organic phase was dried with MgSO4 and analysed
by GC. The fluorinated products and the chlorinated reactant were
quantified by gas chromatography using bromobenzene as internal
standard. The yield corresponds to the mol% of the various
chlorinated compounds transformed into the corresponding
[12] Imperial Smelting Corporation (N.S.C.) Limited, BE Patent 659239 (1965).
[13] M.Y. Elsheikh, US Patent 6074985 (2000).
[14] S. Brunet, C. Batiot, P. Moriceau, N. Thybaud, J. Mol. Catal. A: Chem. 142 (1999)
183–186.
[15] Klauke et al., US Patent 4093669 (1978).
[16] Bayer, FR patent (a) 2327978, (b) 2329626, (c) 2329625 (1976).
[17] J. Salome´, C. Mauger, S. Brunet, V. Shanen, J. Fluorine Chem. 125 (2004) 1947–
1950.
[18] G.A. Olah, J.T. Welch, Y.D. Vankar, M. Nojima, I. Kerekes, J.A. Olah, J. Org. Chem. 44
(1979) 3872–3881.
[19] C.G. Bergsrom, R.T. Nicholson, R.M. Dodson, J. Org. Chem. 28 (1963) 2633–2640.
[20] L. Saint-Jalmes, J. Fluorine Chem. 127 (2006) 85–90.
[21] L. St-Jalmes, WO 9743231, RHONE-POULENC CHIMIE.
[22] M.A. McClinton, Aldrichimica Acta 28 (1995) 31–35.
[23] S.S. Kumaran, M.C. Su, K.P. Lim, J.V. Michael, A.F. Wagner, L.B. Harding, D.A. Dixon,
J. Phys. Chem. 100 (1996) 7541–7549.
[24] T.B. MacMahon, P. Kebarle, J. Am. Chem. Soc. 99 (1977) 2222–2230.
[25] A. Pross, L. Radom, R.W. Taft, J. Org. Chem. 45 (1980) 818–826.
[26] E. Meissner, E. Milchert, J. Fluorine Chem. 119 (2003) 89–95.
[27] S. Brunet, C. Batiot, J. Barrault, M. Blanchard, J. Fluorine Chem. 59 (1992) 33–39.
[28] A.E. Feiring, J. Fluorine Chem. 14 (1979) 7–18.
[29] S. Brunet, C. Batiot, J. Barrault, M. Blanchard, J.-M. Coustard, J. Fluorine Chem. 63
(1993) 227–232.
[30] M.F.A. Dove, Md.O. Ali, J. Inorg. Nucl. Chem. 28 (Suppl. 1) (1976) 77–80.
[31] T. Kagiya, Y. Sumida, T. Inoue, Bull. Chem. Soc. Japan 41 (1968) 767–773.
[32] J.T. Lagowsky, The Chemistry of Non Aqueous Solvents, vol. II, Academic Press,
New York, 1967, p. 54.