Catalytic fluorination of dichloromethylbenzene by HF in liquid phase. Preparation of fluorinated building blocks

Article abstract of DOI:10.1016/j.jfluchem.2011.04.003

The selective fluorination by successive Cl/F exchanges of the dichloromethylbenzene, 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

Full text of DOI:10.1016/j.jfluchem.2011.04.003

Journal of Fluorine Chemistry 134 (2012) 103–106
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Catalytic fluorination of dichloromethylbenzene 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, Universit e´ de Poitiers Facult e´ des Sciences Fondamentales et Appliqu e´ 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 the dichloromethylbenzene, was studied in the
presence of HF as the fluorinating agent. The influence of the presence of a catalyst or a basic solvent
Received 7 February 2011
Received in revised form 29 March 2011
Accepted 9 April 2011
(such as dioxane, pyridine, tributylphosphate) in order to favour the fluorination was investigated. In
mild conditions, (50 8C and after 1 h of reaction), the fluorination of the dichloromethylbenzene was
observed and the polymerization reaction inhibited. The best results were obtained in the presence of
the HF-dioxane system and antimony trifluoride as catalyst.
Available online 15 April 2011
Keywords:
ß 2011 Elsevier B.V. All rights reserved.
Fluorination
Lewis acid
Antimony trifluoride
Dichloromethylbenzene
Dioxane
Pyridine
Tributylphosphate
HF
1
. Introduction
and a catalyst leads to high degree of fluorinated molecules and
only to HCl as the by-product. Only a few examples of catalytic
The incorporation of fluorine, especially the –CF
3
, –CHF
2
or –
fluorination reactions have been reported in the academic
literature.
CH
2
F groups, 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 mainly of
agrochemistry and pharmaceuticals [4–6]. While a wide variety of
methods have been developed for introducing trifluoromethyl
groups into organic molecules [7–11], the most selective process is
the fluorine–chlorine exchange used in industrial scale especially
for the selective synthesis of fluorinated building blocks. 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 presence of a Lewis acid or a metal oxide as catalyst
increases the conversion of the chlorinated starting materials. The
most catalyst commonly used in liquid phase fluorination
Previous works [15] reported the fluorination of trichloro-
methoxy-benzene by liquid HF with various Lewis acids as
catalysts. In this case, only Lewis acids with an oxidation degree
5
of +V are efficient and SbCl is the most powerful. The efficiency of
these Lewis acids is due to their abilities to formnucleophilic
complexes in the presence of HF. Indeed, the presence of few
amount of the catalyst favored the last Cl/F exchange to produce
fluoromethoxybenzene with only a stoichiometric amount of HF
and a temperature of 50 8C. In the same way, the transformation of
the bis-1,3-trichloromethylbenzene depends on the experimental
conditions (temperature, amount of HF and the presence of a Lewis
acid). In the presence of HF in excess, the hexafluorinated product
was selectively observed whatever the conditions. The 1-trichlor-
omethyl-3-trifluoromethylbenzene is selectively formed in the
presence of low amount of HF alone and a temperature higher than
150 8C. Similar results were obtained in the presence of a Lewis
acid at lower temperatures [16].
5
reactions are antimony pentachloride (SbCl ) or antimony mixed
halides [12]. They are used in industrial scale reactions [13–15].
The catalytic processes offer a lot of advantages from classical
chemistry. Indeed, the catalytic fluorination of chlorinated
molecules (such as chlorinated hydrocarbon and aromatic)
involving only Cl/F exchanges with HF as the fluorinating agent
More recently, the selective trifluoromethylation of the
corresponding chlorinated compounds was obtained by successive
Cl/F exchanges under mild conditions with antimony pentachlor-
ide as catalyst and HF in stoichiometric amount as fluoride source.
At 50 8C the conversion of trichloromethylbenzenesis total and the
*
Corresponding author. Tel.: +33 549453627; fax: +33 549453897.
E-mail address: sylvette.brunet@univ-poitiers.fr (S. Brunet).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.04.003

1
04
A. Piou et al. / Journal of Fluorine Chemistry 134 (2012) 103–106
selectivity towards the trifluoromethylation is close to 100% with
% of SbCl and a stoichiometric amount of HF. On the other hand,
the introduction of basic solvent (dioxane, pyridine or
Cl
Cl
Cl
Cl
F
Cl
2
5
a
Cl
Cl
Cl
Cl
tributylphosphate) allows the selective formation of the mono
or difluorinated products depending on the HF-base amount which
modulates the nucleophilicity of the fluoride source. The
introduction of a catalyst with the HF-base system can increase
either the conversion or the selectivity towards mono or
difluorinated products. Depending on the fluorinating system, it
could be possible to adapt the operating conditions in order to
prepare selectively the mono, di or trifluorinated compounds with
a good conversion of the starting materials [17]. Only, few works in
the literature reported selective fluorination in the presence of a
solvent [18–21] mainly HF-pyridine which is well known to be a
good fluorinating agent.
n
H+
-HCl
+
Cl
F
F
HF
-HCl
Scheme 1. Transformation of dichloromethylbenzene in the presence of Broensted
acid sites.
the acidity of the medium, this could be corresponds to the
polymerization of the substrate as reported Scheme 1. This
reaction could be inhibited and the fluorination reaction favored
when a basic solvent was added such as dioxane, pyridine or
tributylphosphate. Indeed, in the presence of this kind of
compounds, it could be possible to control the acidity of the
reaction medium and to control the fluorination reaction as
reported in a previous paper for the transformation of trichlor-
omethylbenzenes [17]. When dioxane, pyridine or tributylpho-
sphate was added, the polymerization reaction was inhibited.
Indeed, in the presence dioxane corresponding to ratios between
HF and dioxane of 2 and 3.5, the monofluorinated product is
selectively observed. (Table 1). Beyond HF/dioxane ratio of 3.5, the
polymerization reaction was again observed. This could corre-
spond to the formation of bond between the oxygen atom and HF
(as reported Scheme 2) which modulate the strength of the fluorine
nucleophily. For HF/dioxane ratios higher than 4, free HF in the
reaction medium is present. In the presence of HF/dioxane ratios of
2 or 4, the polymerization reaction disappeared, however only a
fluorination yield of 2 or 4 was noticed. When, pyridine was used as
solvent and whatever the HF:Pyridine ratios (from 3 to 10), only
the fluorination reaction was also observed (Table 2). The
fluorination yield increases with the HF/pyridine ratios. Indeed,
an increase of the yield from 2.5 to 9 mol% is observed. In all cases,
the monofluorination of the dichloromethylbenzene was the main
product. As reported for the HF/dioxane system, an interaction
between HF and the nitrogen atom explains the experimental
results (Scheme 3). However, in the presence of the HF-
tributylphosphate system, only the polymerization reaction was
2
This paper deals with the fluorination of a –CHCl group in the
presence of HF-base systems (HF-pyridine, HF-dioxane and HF-
tributylphosphate). Dichloromethylbenzene has been chosen as
the model molecule. More particularly, the operating conditions
(temperature, amount of HF, HF-base system) are studied in order
to establish the best conditions to favour the fluorination reaction
of the dichloromethylbenzene.
2
. Results and discussion
2.1. Transformation of dichloromethylbenzene (DCMB) in the
presence of the HF-base system
The transformation of dichloromethylbenzene was carried out
for 1 h at 50 8C in the presence of various amount of HF and
dioxane, pyridine or tributylphosphate as basic solvents. Various
ratios between HF and the basic solvent (from 0 to 10) were
studied. The conversion corresponds to the amount of the
substrate transformed and the yield to the sum of the mono,
difluorinated products.
Dichloromethylbenzene and trichloromethylbenzenes present
different reactivities in the same operating conditions (50 8C).
Indeed, when HF was used alone as the fluorinating agent, the
transformation of the dichloromethylbenzene leads only to a solid
into the autoclave corresponding only to the polymerization.
Under these conditions, it was difficult to identify the products
since they were not soluble in any solvent. However, considering
Table 1
Effect of the presence of dioxane in the transformation of dichloromethylbenzene (P
i
= 10 bar, time = 1 h, T = 50 8C, substrate = 0.1 mol).
a
b
c
HF/diox
HF/Substrate molar ratio
Molar balance (%)
Conv. (mol%)
Yield (mol%)
Selectivity
By-products (%mol)
PhCHFCl (%)
2
PhCHF (%)
–
2
2
2
4
8
0
92
73
0
100
14
Polymerization
100
2
4
0
0
4
2
3
7
.5
33
100
100
Polymerization
a
b
c
Conversion: amount of substrate transformed.
Yield: molar amount of fluorinated products (by-products excepted).
Selectivity: amount of mono and difluorinated compounds.
Table 2
i
Effect of the presence of pyridine in the transformation of dichloromethylbenzene (P = 10 bar, time =1 h, T = 50 8C, substrate = 0.1 mol).
a
b
c
HF/pyridine
HF/ DCMB
Molar balance (%)
Conv. (mol%)
Yield (mol%)
Selectivity
By-products (%mol)
PhCHFCl (%)
2
PhCHF (%)
–
3
2
2
4
6
0
86
98
93
100
14
Polymerization
2.5
8
60
75
67
40
25
33
1
4
4
6
0
.5
14
1
20
9
a
b
c
Conversion: amount of substrate transformed.
Yield: molar amount of fluorinated products (by-products excepted).
Selectivity: amount of mono and difluorinated compounds.

A. Piou et al. / Journal of Fluorine Chemistry 134 (2012) 103–106
105
(
HF)n
O
O
O
O
+ n HF
N
N
+
2n HF
n = 10
(HF)n
(HF)n
2
n = 3.5
Scheme 3. Formation of HF/pyridine complex.
Scheme 2. Formation of HF/dioxane complex.
O
O
C4H9O
C4H9O
C4H9O
noticed whatever the HF/tributylphosphate ratio. As reported in
the literature, pyridine was more basic than dioxane and
tributylphosphate [22]. Consequently, the various complexes form
between HF and dioxane, (Scheme 2) pyridine (Scheme 3) or
tributylphosphate (Scheme 4) have not the same fluorination and
acid properties.The fluorination yield could be increased from 4 to
P
+ n HF
P
(HF)n
O
C4H9O
OC4H9
n = 3
Scheme 4. Formation of HF/tributylphosphate complex.
1
9 mol% when the temperature rose from 50 to 150 8C (Table 3) in
the presence of the HF-dioxane system. A change of the selectivity
towards mono and di-fluorinated compounds was noticed. Indeed,
the monofluorinated compound was the main product at 50 8C and
the formation of the di-fluorinated was favored with the increase
TiCl
MoCl
3
, TiF
3 3 3 4 4 5 5 5 5 5
, FeCl or AlCl , TiF , TiCl , SbF , SbCl , TaF , NbCl , NbF
5
are evaluated. Under these experimental conditions,
whatever the catalyst, only the polymerization reaction is
observed. If the amount HF or the temperature were decreased
in the presence of these catalytic systems, the conversion of
dichloromethylbenzene was close to zero. An increase of the
conversion of dichloromethylbenzene was found in the presence of
of the temperature.
A change of conversion and yield of
fluorination products was also obtained when the DCMB/dioxane
ratio increased from 4 to 7 corresponding also to the formation
mainly to the di-fluorinated compound (Table 4). The catalytic
performances of various Lewis acid with various oxidation degrees
were measured with the HF-dioxane fluorinating system for the
transformation of dichloromethylbenzene. Lewis acid such as
SbF
3
or BF
3
(Table 5). The fluorination yield increases from 18 to
added rises from 5 to 20%. In all
48 mol% when the amount of SbF
cases, the selectivity towards the difluorinated compound was
3
Table 3
Effect of the temperature in the transformation of dichloromethylbenzene (P
i
= 10 bar, time = 1 h, substrate = 0.1 mol, HF/dioxane = 4).
a
b
c
T8 (8C)
Molar balance (%)
Conv. (mol%)
Yield (mol%)
Selectivity
By-products (%mol)
PhCHFCl (%)
2
PhCHF (%)
5
0
73
90
67
33
35
67
4
18
19
100
33
0
67
74
2
7
1
00
50
1
26
15
a
b
c
Conversion: amount of substrate transformed.
Yield: molar amount of fluorinated products (by-products excepted).
Selectivity: amount of mono and difluorinated compounds.
Table 4
i
Effect of the amount of dioxane in the transformation of dichloromethylbenzene (DCMB) (P = 10 bar, T = 50 8C, time = 1 h, substrate = 0.1 mol).
a
b
c
DCMB/dioxane
HF/dioxane
Molar balance (%)
Conv. (mol%)
Yield (mol%)
Selectivity
By-products (%mol)
PhCHFCl (%)
2
PhCHF (%)
0
1
.3
3.5
7
73
75
33
36
4
7
100
29
0
2
4
71
a
b
c
Conversion: amount of substrate transformed.
Yield: molar amount of fluorinated products (by-products excepted).
Selectivity: amount of mono and difluorinated compounds.
Table 5
Effect of the amount of catalyst (SbF
dioxane = 3.5).
3
or BF
3
) on the transformation of dichloromethylbenzene (DCMB)(P
i
= 10 bar, T = 100 8C, time = 1 h, substrate =0.1 mol, HF/DCMB = 4, HF/
a
b
c
Catalyst
%mol)
Molar balance (%)
Conv. (mol%)
Yield (mol%)
Selectivity
By-products (%mol)
(
PhCHFCl (%)
2
PhCHF (%)
SbF
3
0
5
0
0
5
0
90
93
96
99
89
0
35
48
18
31
37
48
28
33
67
71
81
88
75
7
10
12
15
13
29
1
2
54
19
64
12
BF
3
52
25
1
100
Polymerization
a
Conversion: amount of substrate transformed.
b
c
Yield: molar amount of fluorinated products (by-products excepted).
Selectivity: amount of mono and difluorinated compounds.

1
06
A. Piou et al. / Journal of Fluorine Chemistry 134 (2012) 103–106
favored. In the presence of BF
3
, an increase of the conversion was
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 took then place with continuous stirring, at
the desired temperature (between 50 8C and 150 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
also observed when 5 mol% was added. However, beyond this
value, only the polymerization reaction was noticed. The
transformation of dichloromethylbenzene which is very sensitive
to the acidity of the reaction medium leads to only of the
polymerization with the highest Lewis acidity. The best results for
the fluorination dichloromethylbenzene are obtained in the
presence of SbF
bond is activated by the presence of SbF
3
, a moderate Lewis acid. In this case, the –C–Cl
and the fluorine source
3
stainless steel tank. After extraction with CH
2 2
Cl , the organic phase
comes from the HF-dioxane system. When the Lewis acidity of
catalyst is stronger, it could favored the dissociation of HF, the
acidity of the reaction medium increases also and the reaction of
polymerization of dichloromethylbenzene become the main
reaction.
was dried with MgSO and analysed by GC. The fluorinated
4
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 fluorinated
compounds. The difference between conversion and yield corre-
sponds to non-identified by-products and the discrepancy of the
experiment.
3
. Conclusion
Based on our finding, we have determined the best conditions
The chromatograph was a Varian 3380 equipped with 30 m VF-
5ms (Varian) capillary column (inside diameter: 0.25 mm; film
to favour the fluorination of the dichloromethylbenzene using HF-
base system. Indeed, under these operating conditions, the
polymerization reaction was totally inhibited by decreasing the
acidity of the reaction medium. However, the fluorination yield is
very low in the presence of HF and dioxane or pyridine. However it
could be possible to increase this yield by increasing the
thickness: .1
mm) with a temperature program from 80 8C to
200 8C (5 8C/min) and then from 200 8C to 300 8C (10 8C/min).
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3
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