Transformations of organic molecules with F-TEDA-BF4 in ionic liquid media

Article abstract of DOI:10.3390/molecules14072394

The transformations of organic molecules with F-TEDA-BF₄ (1) were investigated in the hydrophilic ionic liquid (IL) 1-butyl-3-methyl- imidazolium tetrafluoroborate ([bmim][BF₄], 2) and the hydrophobic IL 1-butyl-3-methyl-imidazolium hexafluorophosphate ([bmim][PF₆], 3). The range of substrates included alkyl substituted phenols 4a-c, 9, 13, 1,1-diphenylethene (15), alkyl aryl ketones 19-22, aldehydes 23-25 and methoxy-substituted benzene derivatives 26-30. The evaluation of the outcome of reactions performed in IL media in comparison to those of the corresponding reactions in conventional organic solvents revealed that the transformations in IL are less efficient and selective. The effect of the presence of a nucleophile (MeOH, H₂O, MeCN) on the course of reaction was also studied.

Full text of DOI:10.3390/molecules14072394

Molecules 2009, 14, 2394-2409; doi:10.3390/molecules14072394
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Transformations of Organic Molecules with F-TEDA-BF4 in
Ionic Liquid Media
Jasminka Pavlinac 1, Marko Zupan 2 and Stojan Stavber 1,*
1
Department of Physical and Organic Chemistry, ‘Jožef Stefan’ Institute, Jamova 39, 1000
Ljubljana, Slovenia; E-mail: jasminka.pavlinac@ijs.si (J.P.)
2
Faculty for Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000
Ljubljana, Slovenia; E-mail: marko.zupan@fkkt.uni-lj.si (M.Z.)
* Author to whom correspondence should be addressed; E-mail: stojan.stavber@ijs.si;
Tel.: +386 1 477 3660; Fax: + 386 1 251 93 85
Received: 11 May 2009; in revised form: 10 June 2009 / Accepted: 3 July 2009 /
Published: 6 July 2009
Abstract: The transformations of organic molecules with F-TEDA-BF4 (1) were
investigated in the hydrophilic ionic liquid (IL) 1-butyl-3-methyl-imidazolium
tetrafluoroborate ([bmim][BF4], 2) and the hydrophobic IL 1-butyl-3-methyl-imidazolium
hexafluorophosphate ([bmim][PF6], 3). The range of substrates included alkyl substituted
phenols 4a-c, 9, 13, 1,1-diphenylethene (15), alkyl aryl ketones 19-22, aldehydes 23-25
and methoxy-substituted benzene derivatives 26-30. The evaluation of the outcome of
reactions performed in IL media in comparison to those of the corresponding reactions in
conventional organic solvents revealed that the transformations in IL are less efficient and
selective. The effect of the presence of a nucleophile (MeOH, H2O, MeCN) on the course
of reaction was also studied.
Keywords: F-TEDA-BF4; fluorination; ionic liquids; green chemistry
1. Introduction
The last decade has witnessed a rapidly growing interest in various aspects of ionic liquids (ILs),
with great emphasis being placed on their potential utility in chemical synthesis as recyclable solvents,
reagents and catalysts [1,2]. Prime features that have made ILs so attractive include their low vapour

Molecules 2009, 14
2395
pressure, high thermal and chemical stability, wide liquid-state temperature range, large
electrochemical window, favourable solvation behavior and their potential for recyclability, all of
which lead to their recognition as ‘greener’ alternative media to volatile and often toxic organic
solvents [3-6]. Additionally, their highly diverse chemical and physical properties resulting from the
infinite possibilities for combining cations and anions to form ILs are also considered promising
advantages for their various applications, e.g. in synthetic transformations, catalysis, electrochemistry,
spectroscopy, extraction and separation processes [7-10]. However, a full understanding of their
physical and chemical behavior is still lacking and data on their environmental effects have only just
started to appear [11-14], so one should be extremely careful before claiming that a certain
transformation is advantageous and environmentally friendlier if performed in ILs rather than in
conventional organic solvents.
Owing to its unique properties (e.g. small size, high electronegativity, low polarizability, strong C-F
bond), the incorporation of fluorine into organic molecules may bring about a dramatic change in their
physical, chemical and biological properties [15]. An increased demand for fluorinated compounds for
diverse applications, such as pharmaceuticals, agrochemicals, solvents, liquid crystals, dyestuffs,
polymers and novel materials, has been notable in recent decades and consequently, fluorination of
organic molecules has become a very important target in various sectors [16,17]. Although substantial
effort has been devoted to the development of methods for the selective introduction of fluorine into
target molecules, mild, selective and environmentally more acceptable fluorination procedures still
continue to remain a significant challenge to organofluorine chemists. Due to the lack of appropriate
reagents at the beginning of the 20th century, fluorination of organic compounds represented an
extremely demanding area of organic chemistry. Reactions employing molecular fluorine are, due to
the weak F-F bond and strong C-F bond formed, characterized by high exothermicity, and thus its
handling requires working at very low temperatures and pressure, using special laboratory equipment
and exceptional safety precautions. Further developments included reagents such as XeF2 and O-F
reagents, while a breakthrough was achieved with the introduction of N-F reagents. The latter have
been recognized as mild and efficient electrophilic fluorinating reagents, whose handling does not
require
special
safety
measures.
Among
them
1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), F-TEDA-BF4 (1), known under the commercial
name of Selectfluor™, has been highlighted as an efficient and selective fluorinating reagent for a
wide variety of organic compounds, in addition to possessing oxidative properties and as such being
utilized also as a mediator or a catalyst for other functionalizations [18-21]. This reagent has been
extensively studied for various transformations in conventional organic solvents, while in ILs it has
been investigated only for a limited series of compounds [22-26].
The present study aimed to investigate transformations of alkyl substituted phenols 4a-c, 9, 13,
1,1-diphenylethene (15) as a model alkene molecule, methoxy substituted alkyl aryl ketones 19-22,
aldehydes 23-25 and methoxy-substituted aromatic substrates 26-30, and to compare the results
obtained in IL media with the outcomes of the corresponding reactions in conventional organic
solvents. Especially for alkyl substituted phenols [27-30], alkenes [31-33] and aryl alkyl ketones [34],
it has been previously established that the reaction conditions may play a significant role on the course
of the transformation, while many examples display the dramatic effect of ionic liquids on the
selectivity and efficiency of reaction. This study was performed using the hydrophilic IL 1-butyl-3-

Molecules 2009, 14
2396
methyl-imidazolium tetrafluoroborate ([bmim][BF4], 2) and hydrophobic 1-butyl-3-methyl-
imidazolium hexafluorophosphate ([bmim][PF6], 3). The effect of a nucleophile on the course of
reaction was additionally investigated (Scheme 1).
Scheme 1. Effect of reaction conditions on the course of transformation of organic
molecules with F-TEDA-BF4 in the presence of a nucleophile.
Range of substrates:
Reaction conditions:
Type of transformation:
F
OH
OH
OH
But
tBu
N
-
(BF4)2
N
tBu
O
CH2Cl
9
R
13
fluorofunctionalization
R=Me (4a),
F-TEDA-BF4 (1)
i-Pr (4b), t-Bu (4c)
R1 R1 = H, Alk
R2 = H, Me
n=1,2
(19-22)
(OR2)n
nucleophile
oxidation
Ph
NuH: MeOH, H2O, MeCN (5-50 equiv.)
incorporation
Ph
ILs:
15
Me
Bu
N
Me
Bu
N
N
N
+
+
BF4
PF6
CHO
OR
OMe
[bmim][PF6] (3)
[bmim][BF4] (2)
T = 20 - 70 °C
t = 2-24 h
(OMe)n
n = 1,2
(26-30)
R=Alk, OH
(23-25)
2. Results and Discussion
First of all we performed a blank experiment by stirring solutions of 0.24 mmol of F-TEDA-BF4 in
1 mL of ILs [bmim][BF4] or [bmim][PF6] at 70oC for 24 h and established that no reaction between the
fluorinating reagent and either IL occurred. The fluorinating reagent F-TEDA-BF4 remained active,
while no transformation of [bmim][BF4] or [bmim][PF6] could be observed from NMR spectra.
The study of fluoro transformations of alkyl substituted phenols with F-TEDA-BF4 (1) in the ILs
[bmim][BF4] and [bmim][PF6] revealed that the properties of the IL have a considerable effect on the
course of transformation, as well as on its efficiency. Likewise, in conventional organic solvents,
depending upon the substrate structure and reaction conditions, the following products may be present
in the reaction mixture when employing IL media: (a) 2-fluoro-4-alkylphenols 5, as a consequence of
electrophilic substitution at the ortho position with respect to the phenolic group; (b)
difluorocyclohexadienone (6) after further fluorination of ortho-fluoro substituted phenolic product 5;
(c) 4-alkyl-4-fluoro-cyclohexa-2,5-dienone (7) after the addition-elimination process following an
attack at the para position with respect to the phenolic group, and (d) 4-fluorophenol (8) as a result of
ipso substitution after dealkylation at the para position (Scheme 2). However, their distribution in ILs
(Table 1) differs from the corresponding product distribution obtained in MeCN or in MeOH [27].
A typical experiment was performed in the following way: 0.24 mmol of F-TEDA-BF4 was
vigorously stirred in 1 mL IL until the reagent was completely dissolved. Then, 0.2 mmol of substrate
was added and the reaction mixture was continued to be stirred at temperature similar to the

Molecules 2009, 14
2397
corresponding reaction in an organic solvent. After reaction ceased, the reaction mixture was extracted
with t-BuOMe, the organic phase washed with water and after drying, filtered, concentrated in vacuo
and the crude reaction mixture analysed by TLC, 1H- and 19F-NMR.
Scheme 2. Transformation of 4-alkyl substituted phenols with F-TEDA-BF4.
(a) fluorination of
the aromatic ring
(d) ipso substitution
and dealkylation
OH
OH
OH
F
5a, R=Me
5b, R=i-Pr
5c, R=t-Bu
8
F-TEDA-BF4 (1)
media: IL (2 or 3),
MeCN, MeOH
T, t
F
R
R
O
O
F
4a, R=Me
4b, R=i-Pr
4c, R=t-Bu
F
F
R
R
7a, R=Me
7b, R=i-Pr
7c, R=t-Bu
6a, R=Me
6b, R=i-Pr
6c, R=t-Bu
(b), (c) addition
In the case of 4-methylphenol (4a), the transformation was less efficient in both studied ILs than in
MeCN or MeOH [27], since the formation of a complex reaction mixture or low transformation of
starting material was observed (entries 1-3; Table 1). Compared to 4a, 4-i-propyl phenol (4b) and 4-t-
butyl phenol (4c) were transformed more efficiently in IL media (Table 1, entries 4-6), but still less
efficiently compared to the reaction carried out in an organic solvent [27]. In a 24 h reaction between
4b and F-TEDA-BF4 carried out at 70 °C in [bmim][BF4], the substrate was 71% converted into a
mixture of fluorinated products, with 2-fluoro-4-i-propyl phenol (5b) as the major product and 2,2-
difluoro-4-i-propyl-3,5-cyclohexadienone (6b) and 4-fluorophenol (8) as minor ones. Under
comparable reaction conditions in the hydrophilic IL [bmim][PF6], only the ortho-fluoro substituted
product 5b was formed, however with a modest conversion (36%). The transformation proceeded more
efficiently in hydrophilic [bmim][BF4] than in [bmim][PF6], as was the case of 4-t-butylphenol (4c)
(Table 1, entries 5, 6). In the reaction between 4c and F-TEDA-BF4 carried out at 70 °C for 4 h in
[bmim][BF4], 69% of the substrate was converted into a mixture of 3 products, namely 2-fluoro-4-t-
butylphenol (5c, 37%), 4-fluorophenol (8, 28%) and 2,2-difluoro-4-t-butyl-3,5-cyclohexadienone (6c,
4%), while 31% of the substrate remained unchanged (Table 1, entry 5). Under the same reaction
conditions applied to the reaction between 4c and F-TEDA-BF4 in [bmim][PF6], 86% of the substrate
remained unreacted, the rest corresponding to ortho-fluoro substituted product 5c (10%) and 4-
fluorophenol (8, 4%). Prolonging the reaction time to 24 h increased to the efficiency of the
transformation (entry 6). In [bmim][PF6] 46% of 4c was converted into a 2:1 mixture of 2-fluoro-4-t-
butylphenol (5c) and 4-fluorophenol (8) (Table 1, entry 6). Comparing the outcome of reactions for
these substrates with F-TEDA-BF4 performed in organic solvents (MeCN, MeOH) or in IL media
([bmim][BF4], [bmim][PF6]), a more efficient and faster reaction was observed to take place in organic

Molecules 2009, 14
2398
solvents than in ILs, while the distribution of products were also found to be considerably
different (Figure 1).
Table 1. Transformations of 4-alkyl substituted phenols with F-TEDA-BF4 in ILs.
Products:
Substrates:
O
OH
OH
O
OH
F
F
F
4a, R=Me
4b, R=i-Pr
4c, R=t-Bu
F
R
R
5
F
8
R
6
R
7
ILa
[bmim][BF4]
Conv.b Product
distribution
(5 : 6 : 7 : 8)
complex reaction mixture
[bmim][PF6]
Conv.b Product
distribution
(5 : 6 : 7 : 8)
complex reaction mixture
0c
Entry R
T, t
1
2
3
4
Me
(4a)
70 °C, 4 h
22 °C, 22 h 10%
50 °C, 22 h
6 : 0 : 4 : 0
20%
36%
100 : 0 : 0 : 0
100 : 0 : 0 : 0d
i-Pr
70 °C, 24 h 71%
59 : 2 : 0 : 10
(4b)
t-Bu
(4c)
5
6
70 °C, 4 h
70 °C, 24 h 87%
69%
37 : 4 : 0 : 28
44 : 11 : 0 : 32
14%
46%
10 : 0 : 0 : 4
31 : 0 : 0 : 15e
a Ionic liquid; b Conversion of substrate determined by 1H- and 19F-NMR; c Unreacted substrate;
d The presence of 6b and 8 in traces; e The presence of 6c in traces.
Figure 1. Comparison of product distribution obtained in reaction of 4-i-propyl phenol
(4b) or 4-t-butyl phenol (4c) with F-TEDA-BF4 in ILs and organic solventsa.
(
)
4-i -propyl phenol 4b
(
)
4-t -butyl phenol 4c
100%
80%
60%
40%
20%
0%
substrate
100%
80%
60%
40%
20%
0%
16
32
22
13
32
16
34
17
16
8
7
6
5
39
10
31
28
54
64
86
47
11
44
4
15
31
59
52
50
37
67
36
31
4
10
Conversion:
React. time:
Media:
4h
24h
4h
24h
2h
2h
24h
24h
2h
2h
MeOH
[bmim][BF4]
[bmim][PF6]
MeCN MeOH
[bmim][BF4] [bmim][PF6]
MeCN
a Reaction conditions: in [bmim][BF4] and [bmim][PF6]: 0.2 mmol substrate, 0.24 mmol F-TEDA-
BF4, 1 mL IL, 70 °C; in organic solvent [27]: 1 mmol substrate, 1 mmol F-TEDA-BF4, 10 mL
solvent, reflux.
In the case of a sterically hindered alcohol, namely 2,4,6-tri-t-butylphenol (9, Scheme 3), the
reaction with F-TEDA-BF4 in [bmim][PF6] did not proceed at all in 5 h either at room temperature or
at 70 °C. After 2 h reaction carried out at 70 °C in [bmim][BF4], 60% of the substrate remained
unreacted, while 31% of oxidized quinone product 10 was formed along with 9% 2-fluoro-4,6-di-t-

Molecules 2009, 14
2399
butylphenol (11). This result is different from the outcome of the reaction performed in MeCN or
MeOH, where as earlier established, the polarity of the solvent and reaction temperature greatly
affected the course of reaction [28,29]. In MeCN, the substrate 9 was quantitatively transformed into
the fluoro-dealkylated product 11 at 80 °C, while a mixture of MeCN/MeOH (9/1 ratio) at 30 °C
proved to be suitable for the quantitative formation of 4-methoxy-2,4,6-tri-t-butyl-cyclohexa-2,5-
dienone (12).
Scheme 3. Effect of reaction conditions on the reaction of 2,4,6-tri-t-butyl phenol (9) with
F-TEDA-BF4.
OH
O
OH
F-TEDA-BF4
But
F
But
F
But
tBu
[bmim][BF4]
70 °C, 2 h
+
MeCN
80 °C
+
tBu
11
OH
tBu
O
(100%)[28]
But
But
tBu
10
(31%)
11
(9%)
O
MeCN/MeOH
(9/1)
[bmim][PF6]
70 °C, 5 h
tBu
30 °C
tBu
9
MeO
tBu
12 (86%)[28]
3,4,5-Trimethylphenol (13) in [bmim][BF4] was quantitatively converted into 4-fluoro-3,4,5-
trimethyl-2,5-cyclohexadienone (14) when it was reacted with F-TEDA-BF4 for 22 h at room
temperature or for 4 h at 70 °C (Scheme 4). On the contrary, the reaction carried out in [bmim][PF6] at
room temperature was inefficient, while at elevated temperature a polymeric material was formed.
Likewise for the previously discussed substrates, MeCN seems to be an advantageous solvent for this
transformation, since the product 14 was obtained efficiently in a reaction performed for 4.5 hours at
room temperature [30].
Scheme 4. Transformation of 3,4,5-trimethylphenol (13) with F-TEDA-BF4 in the
hydrophilic IL [bmim][BF4].
OH
O
F-TEDA-BF4
[bmim][BF4]
s.T, 22h or 70 °C, 4 h
F
13
14
Furthermore, we investigated the effect of a nucleophile on the transformation of 4-t-butylphenol
(4c) and the sterically more hindered 2,4,6-tri-t-butylphenol (9) in reaction with F-TEDA-BF4
performed in an IL. After F-TEDA-BF4 was completely dissolved in the IL, the substrate (4c or 9) was
added to the reaction mixture, followed by the addition of approximately 5 molar equivalents of
MeOH or MeCN and the reaction mixture continued to be stirred at an optimized reaction temperature.
In the case of 4-t-butylphenol (4c), the presence of MeOH or MeCN in [bmim][BF4] did not have a
substantial effect on the course of the reaction as transformation of the substrate, as well as the

Molecules 2009, 14
2400
distribution of products 5c, 8 and 6c, were comparable to the results of reactions performed in the
absence of the nucleophile. In the case of 2,4,6-tri-t-butylphenol (9), the substrate still prevailed (50-
66%) in the reaction mixture when the reaction with F-TEDA-BF4 was performed in [bmim][BF4] and
in the presence of 4-5 equivalents of a nucleophile (MeCN or MeOH), where 2,6-di-t-butyl-p-
benzoquinone (10, 26-45%) was formed as the major product. In addition to the quinonic product 10,
the presence of a minor amount of dealkylated methoxy substituted di-t-butylphenols (2-methoxy-4,6-
di-t-butylphenol and 4-methoxy-2,6-di-t-butylphenol) could be noticed from the NMR spectra if the
reaction was carried out at 70 °C; however, these products were present in small quantities. Since in
the mixture of MeCN/MeOH (9/1) the substrate 9 was converted with high yield into 4-methoxy-2,4,6-
tri-t-butyl-cyclohexa-2,5-dienone (12) at 30 °C in few hours, one can conclude that an organic solvent
is more advantageous for these transformations than the use of ILs (Scheme 3).
The effect of the presence of a nucleophile in IL media was further investigated for the
fluorofunctionalization of 1,1-diphenylethene (15) as a model alkene substrate, with F-TEDA-BF4.
The reaction between the substrate 15 and F-TEDA-BF4 performed in [bmim][PF6] at room
temperature for 24 h did not provide any product, while under similar reaction conditions applied in
[bmim][BF4] a modest transformation occurred, yielding 1,1-diphenyl-1-hydroxy-2-fluoroethane (16b,
25%) and 1,1-diphenyl-2-fluoroethene (17, 17%) (Table 2). Raising the temperature to 50 °C resulted
in the almost complete conversion of the substrate in the hydrophilic IL [bmim][BF4] (Table 2, entry
7), while in [bmim][PF6] the conversion yield of the reaction performed at 50 °C and in the absence of
a nucleophile was still modest (Table 2, entry 2). The experimental data indicate a difference in the
selectivity of fluorotransformation obtained in an IL with [BF4] as the anionic part from the outcome
of the reaction carried out in [bmim][PF6] (Scheme 5). In the latter, which forms a two-phase system
with water, the substrate was converted to addition-elimination product 1,1-diphenyl-2-fluoroethene
(17) with high selectivity, regardless of the presence of a nucleophile (MeOH, H2O, MeCN) (Table 2,
entries 3-5). On the other hand, the addition product, namely vicinal hydroxy- or methoxyfluoroalkane
16b, 16a, prevailed in the reaction mixture when [bmim][BF4] was used as the reaction medium
(Table 2, entries 8, 9).
Scheme 5. The selectivity of fluorotransformation of 1,1-diphenyl ethane (15) in reaction
with F-TEDA-BF4 in an IL.
Ph
[bmim][PF6]
17
F-TEDA-BF4 /
NuH (5-50 equiv.)
50 °C
Ph
F
Ph
Ph
Ph
Ph
Nu
H
15
[bmim][BF4]
Ph
Ph
Nu
H
+
17 +
F
H
F
F
18a, Nu=OMe
18b, Nu=OH
16a, Nu=OMe
16b, Nu=OH

Molecules 2009, 14
2401
Table 2. Effect of reaction conditions on fluorotransformation of 1,1-diphenyl ethene (15)
with F-TEDA-BF4 in ILsa.
Ph
Ph
MeO
16a
H
H
Ph
Ph
HO
16b
H
H
Ph
Ph
MeO
18a
H
Ph
Ph
HO
H
Ph
Ph
Ph
Ph
F
F
F
F
F
F
F
15
17
18b
Entry ILb
NuHc
T
Product distributiond
[°C]
22
50
50
50
50
22
50
50
50
15
16a
/
/
/
/
/
/
/
16b
/
/
/
/
/
25%
65%
6%
76%
17
/
18a
/
/
22%
/
/
/
/
18b
/
/
12%
9%
/
/
19%
/
21%
1
/
/
100%
64%
7%
13%
30%
58%
2%
2
3
4
5
6
7
8
9
[bmim][PF6]
[bmim][BF4]
36%
60%
78%
70%
17%
14%
1%
MeOH
H2O
MeCN
/
/
MeOH
H2O
/
76%
/
17%
/
3%
/
a Reaction conditions: 0.2 mmol substrate, 0.24 mmol F-TEDA-BF4, 1 mL IL, 24h; b Ionic liquid; c
d
1
nucleophile (5 molar equivalents); The distribution of products determined from H- and 19F-
NMR spectra of the crude reaction mixture.
Additionally, we investigated the effect of various amounts of a nucleophile (MeOH or H2O; 5, 10,
20 and 50 molar equivalents) on the fluorination of 1,1-diphenylethene (15) with F-TEDA-BF4 in both
studied ILs (Figure 2). We found that the presence of 10-20 molar equivalents of MeOH or H2O in
[bmim][PF6] considerably enhanced the efficiency of transformation of 15 into 1,1-diphenyl-2-
fluoroethene (17). Furthermore, 1,1-diphenylethene (15) with F-TEDA-BF4 and in the presence of 5-
50 equivalents of MeOH was completely converted after 24 h at 50 °C if the reaction was carried out
in [bmim][BF4], thus highlighting the improved efficiency of the transformation in the presence of a
nucleophile in this hydrophilic IL. In these cases, the major product corresponded to 1,1-diphenyl-1-
methoxy-2-fluoroethane (16a), while 1,1-diphenyl-2-fluoroethene (17), 1,1-diphenyl-1-hydroxy-2-
fluoroethane (16b) and 1,1-diphenyl-1-methoxy-2,2-difluoroethane (18a) could be detected in minor
amounts from the NMR spectra as well. In cases where H2O was used as the source of the external
nucleophile in [bmim][BF4], 1,1-diphenyl-1-hydroxy-2-fluoroethane (16b) formed as the major
product, while the addition-elimination product 17 and 1,1-diphenyl-1-hydroxy-2,2-difluoroethane
(18b) were present as minor products. Vicinal methoxy- or hydroxy-fluoroalkane (16a or 16b) were
produced most efficiently in [bmim][BF4] when the reaction was performed at 50 °C and in the
presence of 50 equivalents of the corresponding nucleophile.
Evaluating the experimental results obtained for fluororotransformations of 1,1-diphenylethene (15)
with F-TEDA-BF4 as fluorinating reagent in the presence of a nucleophile in ILs, in comparison with
published results carried out in organic solvents (a mixture MeCN/MeOH, their ratio corresponding to
9/1) [31], preference should be given to the use of organic solvents. This can be ascribed to the fact
that in a mixture of MeCN/MeOH (9/1 ratio) substrates of alkenic moiety were quantitatively
converted into the corresponding vicinal methoxyfluoroalkanes, following Markovnikov type of

Molecules 2009, 14
2402
regioselectivity at room temperature and for this transformastion required a considerably shorter
reaction time, while authors do not report on the formation of side products [31]. On the other hand,
for the formation of vicinal hydroxyfluoroakanes priority should be given to water [33] as reaction
medium over ILs.
Figure 2. Effect of the amount of nucleophile on the product distribution for fluorination
of 1,1-diphenyl ethane (15) with F-TEDA-BF4 in [bmim][BF4] and [bmim][PF6]a,b.
4
a) [bmim][BF ]
3
7
5
8
4
6
12
1
1
100%
80%
60%
40%
20%
0%
8
17
13
5
6
1
15
21
1
6
6
18b
18a
17
Ph
Ph
15
89 92
80 94
76
81
81
76
16b
16a
Ph
Ph
H
H
16a
MeO
F
5
10 20 50
MeOH
5
10 20 50
H2O
Ph
Ph
HO
H
H
F
16b
17
Amount of nucleophile (mol equiv.)
6
b) [bmim][PF ]
Ph
Ph
F
5
4
100%
80%
60%
40%
20%
0%
7
7
8
1
14
13
14
6
8
3
15
12
12
9
Ph
Ph
MeO
H
18b
18a
17
22
18a
18b
F
F
78
90
80 88 82
60 88
78
16b
16a
Ph
Ph
H
F
8
4
HO
F
5
10 20 50
MeOH
5
10 20 50
H2O
Amount of nucleophile (mol equiv.)
a
Reaction conditions: 0.2 mmol substrate (15), 0.24 mmol F-TEDA-BF4, nucleophile (MeOH or
H2O; 5, 10, 20 or 50 molar equivalents), 1 mL IL ([bmim][BF4] or [bmim][PF6]), 50 °C, 24 h; b The
distribution of products determined from 1H- and 19F-NMR spectra of the crude reaction mixture.
The investigation of fluorination with F-TEDA-BF4 in IL media was further expanded to methoxy
substituted benzene derivatives. During previous studies in our laboratory, we already reported
regulation of the regioselectivity of fluorination of aryl alkyl ketones with N-F reagents by the proper
choice of organic solvent. While in acetonitrile fluorofunctionalization took place efficiently and
regioselectively onto the aromatic ring, α-alkyl position next to the carbonyl group was selectively
fluorinated when MeOH was used as reaction solvent [34]. In an attempt to fluorinate some aryl alkyl
ketones (19, 20, 21, 22) with F-TEDA-BF4 in ILs, we found that in addition to the substantially lower
efficiency of fluorotransformations of these substrates in IL media also the aryl/alkyl selectivity failed
to be controlled (Table 3).

Molecules 2009, 14
Table 3. Transformations of aryl alkyl ketones with F-TEDA-BF4 in ILsa.
2403
Conv.b
10%
14%
6%
Product distributionc
19a: 9%, 19: 90%d
19a: 11%, 19b: 2%, 19: 86%d
Entry Substrate
Ionic liquid t (h)
Products
COCH3
COCH2-F
COCH3
1
5
2
3
[bmim][BF4]
[bmim][PF6]
18
5
F
19a: 6%, 19: 94%
19a: 9%, 19: 90%d
OCH3
OCH3
OCH3
4
18
10%
19
COCH3
19a
19b
COCH3
F
5
[bmim][BF4]
[bmim][PF6]
20
20
28%
7%
20a: 28%, 20: 72%
20a: 7%, 20: 93%
OCH3
OCH3
6
OCH3
OCH3
20a
20
7
5
18
5
29%
47%
18%
10%
49%
61%
22%
11%
21a: 17%, 21b: 5%, 21c: 7%,
21: 71%
O
[bmim][BF4]
[bmim][PF6]
[bmim][BF4]
[bmim][PF6]
X2
X3
O
8
H3CO
21a: 27%, 21b: 7%, 21c: 13%,
21: 53%
X1
H3CO
21
21a: X1=F, X2=X3=H
21b: X2=F, X1=X3=H
21c: X3=F, X1=X2=H
9
21a: 12%, 21b: 3%, 21c: 3%,
21: 82%
10
11
18
5
21a: 7%, 21b: 2%, 21c: 1%,
21: 90%
22a: 29%, 22b: 6%, 22c: 11%,
22d: 3%, 22: 51%
O
X2
X3
O
12
18
5
H3CO
22a: 30%, 22b: 7%, 22c: 16%,
22d: 8%, 22: 39%
X1
H3CO
22a: X1=F, X2=X3=H
22b: X2=F, X1=X3=H
22c: X3=F, X1=X2=H
22d: X1=X3=F, X2=H
22
13
22a: 16%, 22b: 3%, 22c: 3%,
22: 78%
14
18
22a: 8%, 22b: 2%, 22c: 1%,
22: 89%
a
b
Reaction conditions: 0.2 mmol substrate, 0.24 mmol F-TEDA-BF4, 1 mL ionic liquid, 70 °C;
Conversion of substrate determined from 1H- and 19F-NMR spectra of the crude reaction mixture; c
1
The distribution of compounds in the reaction mixture was determined from H- and 19F-NMR
spectra; d Also the presence of 1% of 4-fluoroanisole.
The substituted benzaldehydes (23: 4-methoxybenzaldehyde, 24: 3,4-(methylenedioxy)-
benzaldehyde, and 25: 4-hydroxybenzaldehyde) remained unchanged in the reactions with F-TEDA-
BF4, performed in the investigated ILs. A slight transformation was noticed only in the case of the
reaction of 4-methoxybenzaldehyde (23) with F-TEDA-BF4, carried out for 20 h at 70 °C in
[bmim][BF4], where the substrate was converted into 3-fluoro-3-methoxybenzaldehyde (23a, 9%).

Molecules 2009, 14
2404
In the cases of dimethoxy- and trimethoxy-substituted benzenes, the fluorotransformation with F-
TEDA-BF4 in IL media proved to be crucially dependent on the structure of the substrate. In the case
of 1,3-dimethoxybenzene (26) and 1,3,5-trimethoxybenzene (27), which are both highly activated
toward electrophilic substitution, the corresponding reaction mixture in [bmim][BF4], as well as in
[bmim][PF6], contained at least 4 different products after 3 h reaction performed at 70 °C (Figure 3).
On the other hand, the substrates 1,2-dimethoxybenzene (28), 1,4-dimethoxybenzene (29) and 1,2,3-
trimethoxybenzene (30) remained mostly unreacted or fluoro-functionalization occurred only to a
minor extent. 1,3-Dimethoxybenzene (26) in a reaction performed for 3 h at 70 °C in [bmim][BF4] was
over 80% converted into a mixture of fluorinated products, with the formation of 4-fluoro-1,3-
19
dimethoxybenzene (26a) as the major product, while from the F-NMR spectra the presence of the
minor products 4,6-difluoro-1,3-dimethoxybenzene (26b), 2-fluoro-1,3-dimethoxybenzene (26c) and
4,6,6-trifluoro-3-methoxy-2,4-cyclohexadienone (26c) was established. The substrate 26 subjected to
similar reaction conditions in [bmim][PF6] was 60% converted into a mixture of products 26a, 26b,
26c and 26d, with 4-fluoro-1,3-dimethoxybenzene (26a) prevalent. The efficiency of transformation
and the distribution of the fluorinated products formed resembled the outcomes of reactions which
occur under comparable reaction conditions in MeCN or in MeOH. The reaction of another reactive
substrate, namely 1,3,5-trimethoxybenzene (27) with F-TEDA-BF4 in the studied IL media after 4 h at
70 °C provided a mixture of the products: 2-fluoro-1,3,5-trimethoxybenzene (27a, >50%) and in
smaller quantities 2,4-difluoro-1,3,5-trimethoxybenzene (27b, ~5%), 4,4-difluoro-3,5-dimethoxy-2,5-
cyclohexadienone (27c, 10-20%) and 2,2-difluoro-3,5-dimethoxy-3,5-cyclohexadienone (27d, <5%).
Regarding the efficiency and the product distribution of the reaction, this was a similar result to the
case when fluorination with F-TEDA-BF4 was carried out in MeCN [35] or in MeOH.
Figure 3. The mixture of products obtained in reaction of 1,3-dimethoxybenzene (26) or
1,3,5-trimethoxybenzene (27) with F-TEDA-BF4 in the IL [bmim][BF4] or [bmim][PF6]
(70 °C, 3-4 h).
Major product
Substrate
Minor products
OMe
F
OMe
OMe
O
F
OMe
F
F
:
F
OMe
OMe
OMe
OMe
OMe
F
F
26c
26b
26a
26
26d
19F NMR (285 Hz,CDCl3)
-146.3
(m)
-142.0
(t, J=8.5 Hz)
-159.5
(t, J=6.9 Hz)
-101.5 (m, 2F),
-123.1 (m, 1F)
δ v ppm from CFCl3
OMe
OMe
F
OMe
F
O
OMe
:
MeO
OMe
MeO
OMe
MeO
27b
OMe
MeO
OMe
MeO
O
F
F
F
F
F
27
27a
27d
27c
19F NMR (285 Hz,CDCl3)
-169.0
(t, J=6.2 Hz)
-160.9
(d, J=7.5 Hz)
-113.0
(t, J=2.2 Hz)
-113.8
(t, J=2.3 Hz)
δ v ppm from CFCl3

Molecules 2009, 14
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3. Experimental
3.1. General
The reactions were performed in 5-mL round bottom flasks with 1 mL of IL ([bmim][BF4] or
[bmim][PF6]) as reaction medium. Firstly, F-TEDA-BF4 (0.24 mmol) was vigorously stirred in the IL
at 70 °C until its complete dissolution. Then, substrate (0.2 mmol) was added and the reaction mixture
continued to be stirred at the appropriate reaction temperature (22-70 °C). After the reaction had
ceased, the products were extracted with t-BuOMe (4x2 mL), the combined organic phase was washed
with water and after drying of the organic phase over anhydrous Na2SO4, the insoluble material was
filtered off, while the reaction mixture was concentrated in vacuo. The crude reaction mixture was
analyzed by TLC, 1H-NMR, 19F-NMR and MS and the products identified on the basis of comparison
of their spectroscopic data with literature values [27-30,33-51].
4. Conclusions
The transformations of organic molecules with F-TEDA-BF4 investigated in the hydrophilic IL
[bmim][BF4] and in the hydrophobic IL [bmim][PF6] and their evaluation in comparison to the
corresponding reactions carried out in organic solvents revealed that these ILs are less convenient
media for the fluoro-functionalization of alkyl substituted phenols (4a, 4b, 4c, 9, 13), 1,1-diphenyl-
ethene (15) and methoxy-substituted aryl alkyl ketones (19, 20, 21, 22) than MeCN or MeOH.
Reactions of alkyl substituted phenols, namely 4-methylphenol (4a), 4-i-propylphenol (4b), 4-t-butyl-
phenol (4c), 2,4,6-tri-t-butylphenol (9) and 3,4,5-trimethylphenol (13), with F-TEDA-BF4, depending
on the substrate structure and reaction conditions, lead to the formation of either of the following
fluorofunctionalised products: the corresponding ortho-fluorosubstituted product 5 as a result of
electrophilic substitution at the ortho position of the phenol, difluorocyclohexadienone 6 formed
following another fluorine introduction into 5, 4-alkyl-4-fluoro-cyclohexa-2,5-dienone (7) as a
consequence of the addition-elimination process after fluorine attack at the para position of 4-alkyl
phenol, while 4-fluorophenol (8) was produced through ipso substitution and dealkylation at the para
position. The transformations were higher in the hydrophilic IL [bmim][BF4] than in the hydrophobic
[bmim][PF6]; however, compared to the published results of reactions performed in MeOH or in
MeCN they were considerably less efficient and with a different distribution of products. Also for a
substrate with an aromatic alkene moiety, namely 1,1-diphenylethene (15), when reacted with F-
TEDA-BF4 a higher conversion was obtained in the hydrophilic IL than in the hydrophobic one. In
addition, a markedly different selectivity of product formation was observed in the studied ILs. In
[bmim][PF6], which with water forms a two-phase system, the substrate 15 was, regardless of the
nucleophile present (MeOH, H2O or MeCN), transformed into an addition-elimination product, namely
1,1-diphenyl-2-fluoroethene (17), with high selectivity. On the other hand, when the reaction was
performed in [bmim][BF4] the major product corresponded to vicinal hydroxy- or methoxy
fluoroalkane (16b or 16a). In an attempt to fluorofunctionalize some methoxy substituted aryl alkyl
ketones using F-TEDA-BF4 in ILs, we found that in addition to the very low efficiency of the
transformation, the reactions also proved unselective, thus giving preference to MeOH or MeCN for
these fluoro-functionalizations. The efficiency of fluorination and the distribution of products in the

Molecules 2009, 14
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cases of the reactions of 1,3-dimethoxybenzene (26) and 1,3,5-trimethoxybenzene (27) with F-TEDA-
BF4 in the studied ILs was similar to the outcome of the reactions performed in MeCN or MeOH.
Finally, we would like to point out that a small variation in reaction conditions may severely affect the
outcome. Moreover, due to the lack of data on their physico-chemical properties, as well as long-term
environmental influence of ILs one should be very cautious before proclaiming them as ‘greener’
alternative to organic solvents.
Acknowledgements
The authors are grateful to the staff of the Slovenian NMR Centre at the National Institute of
Chemistry in Ljubljana for assistance in recording NMR spectra, to Dr. B. Kralj and Dr. D. Žigon for
MS spectra and to the Slovenian Research Agency for financial support.
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