Ionic liquids as media for nucleophilic flurination

Article abstract of DOI:10.1016/S0022-1139(03)00132-5

The use of Room Temperature Ionic Liquids (RTILs) for a variety of halogen exchange (Halex) fluorination processes using alkali metal fluorides is assessed. Whilst fluorination of a range of halogenated substrates is possible in good yield, the utility of RTILs as reusable, inert media for such reactions is limited by the gradual decomposition of the RTIL in the presence of highly basic fluoride ion.

Full text of DOI:10.1016/S0022-1139(03)00132-5

Journal of Fluorine Chemistry 123 (2003) 81–84
Ionic liquids as media for nucleophilic fluorination
Christopher B. Murraya, Graham Sandforda,*, Stewart R. Kornb
aDepartment of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
bAvecia, P.O. Box 521, Leeds Road, Huddersfield HD2 1GA, UK
Received 3 March 2003; received in revised form 7 April 2003; accepted 21 April 2003
Dedicated to Professor Eric Banks on the occasion of his 70th birthday
Abstract
The use of Room Temperature Ionic Liquids (RTILs) for a variety of halogen exchange (Halex) fluorination processes using alkali metal
fluorides is assessed. Whilst fluorination of a range of halogenated substrates is possible in good yield, the utility of RTILs as reusable, inert
media for such reactions is limited by the gradual decomposition of the RTIL in the presence of highly basic fluoride ion.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Ionic liquids; Fluoride ion; Nucleophilic fluorination; Green chemistry
1. Introduction
required for significant fluorination to occur. Consequently,
Halex methodology can be unsuitable for the fluorination of
less thermally robust systems. Furthermore, extraction and
purification of fluorinated products from aprotic media is
often very difficult and such environmentally hazardous
solvents are not generally recycled, leading to large waste
streams for disposal.
Methodology for the regio- and stereo-selective introduc-
tionoffluorineatomsintoorganicsystems,thatisbothsuitable
for scale up and economically realistic, remains a significant
and important challenge to organofluorine chemists [1–3].
In general, the synthesis of carbon fluorine bonds may be
accomplished by functional group interconversion of carbon
hydrogen or carbon–halogen bonds, using either an electro-
philic fluorinating agent such as SelectfluorTM [4] or ele-
mental fluorine [5], or a source of fluoride ion, using an
alkali metal fluoride, hydrogen fluoride or amine hydro-
fluoride [6,7], respectively. In particular, halogen exchange
(Halex) processes involving nucleophilic substitution of
halogens by fluorine, upon reaction of a suitably activated
halogenated substrate with an alkali metal fluoride,
have been used extensively for the synthesis of various fluo-
rinated aliphatic [3], aromatic [8] and heterocyclic systems
[8,9].
There is growing interest in the development of ‘‘green’’
chemical processes that are more environmentally benign
[10,11] and, in particular, do not lead to any hazardous by-
products or solvent waste. The development and application
of new inert reaction media, that may be recycled, is a
primary goal and, in this context, Room Temperature Ionic
Liquids (RTILs) have been widely investigated as potential
replacement solvents for a variety of chemical processes
[12,13]. RTILs, such as butylmethylimidazolium hexafluor-
ophosphate, [BMIM][PF6] (1), may, potentially, be advan-
tageous reaction media because they are essentially non-
toxic, recyclable and have a limited vapour pressure, allow-
ing efficient recovery of organic products by simple dis-
tillation under vacuum or conventional liquid–liquid
extraction techniques. Indeed, many classes of chemical
reactions [13,14], such as nucleophilic substitution, Heck
reactions, etc. have been carried out in RTILs, exemplifying
these facts.
Whilst the Halex approach has been used effectively for
a number of fluorination reactions, the low solubility of KF
and CsF even in polar aprotic solvents, such as sulpholane, N-
methylpyrrolidinone and N,N-dimethylformamide, generally
means that harsh reaction conditions (high temperatures) are
In the light of recent reports [15–18], in this paper we
report our investigations into the use of RTIL media for
Halex processes involving reaction of caesium fluoride with
a variety of halogenated organic substrates.
* Corresponding author. Tel.: þ44-191-334-2039;
fax: þ44-191-384-4737.
E-mail address: graham.sandford@durham.ac.uk (G. Sandford).
0022-1139/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00132-5

82
C.B. Murray et al. / Journal of Fluorine Chemistry 123 (2003) 81–84
2. Results and discussion
dried under vacuum and could be reused over a limited
number of reaction cycles. Unfortunately, repeated use of
the RTIL gradually led to significant discoloration and
decreased performance. Fluorinations of 1-bromooctane
using KF, KHF2 and CaF2 were attempted but only starting
material was recovered after heating in RTIL overnight.
The results of the experiments outlined in Table 1 suggest
that fluorination of very activated systems such as benzoyl
chloride and benzyl bromide occur efficiently in the RTIL
media at room temperature and a reasonable yield of pro-
ducts may be obtained. Less reactive substrates such as
bromoalkanes give lower yields of the corresponding fluor-
oalkanes because elimination, where the fluoride ion acts as
a base, is a competing process and a common feature of
Halex processes. Increasing the temperature of many of the
fluorination reactions does not lead to significant increase in
the yield of fluorinated product but, instead, leads to a
discoloration of the RTIL to give a brown, tarry oil.
We have investigated the use of the readily accessible [19]
hydrophobic RTIL, [BMIM][PF6] (1), as a medium for a
range of Halex processes, involving substitution of bromine
or chlorine located at various sp2 and sp3 carbon sites, and
these experiments are collated in Table 1.
In all reactions, both the CsF and 1 were rigorously dried
before use by heating under vacuum, except where indicated
in Table 1. CsF is not appreciably soluble in ionic liquid 1
and so all fluorination reactions were carried out with CsF
suspended in the reaction medium. After heating and stirring
the reaction mixtures overnight under an inert atmosphere at
the temperature required, product mixtures were isolated by
simple vacuum transfer directly from the RTIL fluid. Yields
of fluorinated products and by-products were assessed by
NMR spectroscopy with reference to a weighed quantity of
an NMR standard which was added to the weighed product
mixture. Identification of all products was carried out by 19
F
The discoloration of the RTIL upon heating and repeated
use suggested that 1 was not compatible with the highly
basic reaction conditions. Therefore, we heated samples of
1 with KF and CsF in Carius tubes at 150 8C to assess the
long-term stability of the medium towards fluoride ion.
After 18 h, the RTIL had visibly decomposed and volatile
and 1H NMR and GC–MS, with reference to authentic
samples [20]. In most cases, recovery of organic material
by vacuum transfer was satisfactory.
After completion of the reaction and transfer of the
organic products, the RTIL was washed with water, filtered,
Table 1
Halogen exchange processes using RTIL reaction media
R–X
CsF
T (8C)
Conversion (%)
R–F (%)a
Others (%)
PhCH2Br
CsF
20
20
70
80
80
20
20
70
70
20
63
17
26
98
76
11
17
5
PhCH2F (47)
n-C8H17F (12)
n-C8H17F (19)
n-C8H17F (55)
n-C8H17F (65)
0
–
n-C8H17Br
CsF
C6H13CH¼CH2 (3)
C6H13CH¼CH2 (5)
C6H13CH¼CH2 (7)
C6H13CH¼CH2 (11)
C5H11CH¼CHCH3 (10)
C5H11CH¼CHCH3 (1)
C5H11CH¼CHCH3 (4)
C5H11CH¼CHCH3 (13)
–
n-C8H17Br
CsF
n-C8H17Br
n-C8H17Br
2 CsF
2 CsFb
CsF
C6H13CHBrCH3
C6H13CHBrCH3
C6H13CHBrCH3
C6H13CHBrCH3
PhCOCl
2 CsF
CsF
CsF
C6H13CHFCH3 (1)
0
38
74
C6H13CHFCH3 (3)
PhCOF (40)
CsF
3 CsF
80c
–
(10)
(3)
(11)
a Yields based on conversion of starting material.
b CsF used as received from suppliers without further drying.
c Carius tube.

C.B. Murray et al. / Journal of Fluorine Chemistry 123 (2003) 81–84
83
Scheme 1.
The vessel was charged with alkali metal fluoride and RTIL
1 (15 ml) and then degassed for 10 min under vacuum to
allow distribution of the alkali metal fluoride in the liquid
media. The halogenated substrate was added under an inert
atmosphere and the mixture stirred vigorously at the required
temperature overnight. Volatile fractions were removed by
vacuum transfer to yield a weighed crude product which was
1
analysed by 19F and H NMR (after a weighed amount of
internal standard had been added) and GC–MS. Products
1
were identified with reference to literature values (19F, H
NMR) and authentic samples (GC–MS).
Scheme 2.
decomposition products could be isolated, albeit in very
small quantities, from the Carius tube by vacuum transfer.
GC–MS analysis of this very volatile material showed the
presence of several species including alkyl imidazoles,
fluoroalkanes and alkenes (Scheme 1).
Possible mechanisms for the formation of these volatile
decomposition products are outlined in Scheme 2, in which
fluoride ion acts as a base to promote elimination or sub-
stitution processes.
ThesefindingsdemonstratethatHalexfluorinationinRTILs
is possible for various systems in which relatively low tem-
peratures are adequate for successful reaction. However, there
are some significant difficulties due to the decomposition of 1
uponheatingwithfluorideion,eitherinthereactionorvacuum
transferstages.Recyclingoftheionicliquid,aprimarydriving
force for using these systems is, therefore, limited to some
extent when using alkali metal fluorides as the source of
fluoride ion for nucleophilic fluorination reactions.
3.1.2. Reaction of 1 with caesium fluoride
A Carius tube was charged first with CsF (3.60 g,
23.4 mmol) under argon and then 1 (3.1 ml, 15 mmol).
The tube was then evacuated and frozen in liquid nitrogen
before being sealed. After the tube had been heated at 150 8C
for 96 h, it was opened and the volatile materials isolated by
vacuum transfer. A small quantity of colourless liquid was
collected in the trap, the residue in the Carius tube being a
deep brown-yellow colour. The volatile fraction was ana-
lysed by GC–MS and the following products were detected:
ꢀ but-1-ene: m/z (EIþ) 56 (þMþ, 87%);
ꢀ 1-fluorobutane: m/z (EI ) 75 (Mþ ꢁ 1, 1.5 %), 56
(Mþ ꢁ HF, 100%), 47 (CH2CH2Fþ, 15%), 33 (CH2Fþ,
55%);
ꢀ N-methylimidazole: m/z (EIþ) 81 (Mþ ꢁ 1, 2%), 56 (N–
CH–N–CH3þ, 13%), 55 (CH–CH–N–CH3þ, 8%), 42 (CH–
N–CH3þ, 9%), 40 (N–CH–CHþ, 92%), 41 (N–CH–Nþ,
100%), 28 (N–CH3þ, 22%);
as compared to authentic samples.
3. Experimental
By a similar procedure, KF (0.58 g, 10 mmol) and 1
(0.83 ml, 4 mmol) were heated to 150 8C in a Carius tube
overnight and visual examination indicated that the [BMIM]-
[PF6] had decomposed due to its increased viscosity and deep
yellow-brown colour. No further analysis was conducted.
All starting materials were obtained commercially
(Aldrich) or synthesised according to published procedures
[19] and all solvents were dried using literature procedures.
NMR spectra were recorded in deuteriochloroform, unless
otherwise stated, on a Varian VXR 400S NMR spectrometer
with tetramethylsilane and trichlorofluoromethane as internal
standards. Mass spectra were recorded on either a VG 7070E
spectrometer or a Fissons VG Trio 1000 spectrometer coupled
with a Hewlett Packard 5890 series II gas chromatograph.
Acknowledgements
We thank Avecia for the award of an EPSRC Industrial
CASE Studentship to CBM.
3.1. Halogen exchange reactions in RTIL 1
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