New fluoride ion reagent from pentafluoropyridine

Article abstract of DOI:10.1016/j.jfluchem.2004.12.013

A new nucleophilic fluorinating agent, derived from reaction of dimethylaminopyridine (DMAP) with pentafluoropyridine, has been synthesised and assessed in various carbon-fluorine bond forming processes.

Full text of DOI:10.1016/j.jfluchem.2004.12.013

Journal of Fluorine Chemistry 126 (2005) 571–576
www.elsevier.com/locate/fluor
New fluoride ion reagent from pentafluoropyridine
c
Christopher B. Murray a, Graham Sandford a, , Stewart R. Korn ,
*
Dmitrii S. Yufit b, Judith A.K. Howard b
a Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
b Chemical Crystallography Group, Department of Chemistry, University of Durham,
South Road, Durham DH1 3LE, UK
c Avecia, P.O. Box 521, Leeds Road, Huddersfield HD2 1GA, UK
Received 4 October 2004; received in revised form 20 December 2004; accepted 24 December 2004
Available online 23 February 2005
Dedicated to our colleague and close friend, Prof. Dick Chambers, on the occasion of his 70th birthday.
Abstract
A new nucleophilic fluorinating agent, derived from reaction of dimethylaminopyridine (DMAP) with pentafluoropyridine, has been
synthesised and assessed in various carbon–fluorine bond forming processes.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Fluorination; Fluoride ion; Nucleophilic fluorinating agents; Pentafluoropyridine
1. Introduction
ammonium salts [9,10] and hydrogen fluoride/amine
systems [11–13] have been developed but, in many cases,
the low solubility, harsh reaction conditions required and the
difficulty of isolating products from the aprotic solvent
media employed, offers considerable scope for improvement
for wider synthetic application.
Development of efficient carbon–fluorine bond forming
methodology that enables the selective fluorination of
systems which are involved in the latter stages of target
molecule synthesis remains an important goal in organo-
fluorine chemistry [1,2]. The increasing importance of
fluorinated systems in healthcare, plant protection and high
technology products [1] stimulates research in this field and
a number of fluorinating agents [3–6] have been studied
extensively to meet the varying demands of both academia
and industry.
Reaction of tertiary amines with perfluorinated alkenes
gives ammonium fluoride salts (Scheme 1) which, once
formed in situ, catalyse oligomerisation of the fluoroalkene
substrate [14]. However, reaction of a tertiary amine with a
perfluorinated system, such as pentafluoropyridine, that is
susceptible towards nucleophilic attack [15,16] but is not
oligomerised in the presence of fluoride ion (Scheme 1),
would provide access to fluoride ion reagents that may be
useful for carbon–fluorine bond forming reactions.
In this paper, we describe the synthesis and application
of a new fluorinating agent from a tertiary amine and
pentafluoropyridine. Whilst related fluoride salts have been
synthesised from reactions between tertiary amines and
either hexafluorobenzene [17] or pentafluoropyridine [18],
the viability of using such systems for carbon–fluorine bond
formation has not been assessed.
Fluorinating agents that are sources of nucleophilic
fluoride ion have been the subject of great development due
to the ready availability of several fluoride salts and a wide
variety of systems bearing halogen, nitro and sulfonate ester
groups that are useful substrates for both aliphatic and
aromatic nucleophilic substitution processes. Many fluoride
ion reagents [6], such as the alkali metal fluorides [7,8],
* Corresponding author. Tel.: +44 191 3342039; fax: +44 191 3844737.
E-mail address: graham.sandford@durham.ac.uk (G. Sandford).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.12.013

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C.B. Murray et al. / Journal of Fluorine Chemistry 126 (2005) 571–576
Scheme 1.
Scheme 2.
2. Results and discussion
twisted relative to each other (the torsion angle of C2–C3–
N2–C4 is 64.2(1)8). In the crystal, ion pairs of 2-form layers
perpendicular to the (0 1 0) direction.
After initial experiments involving reactions between
pentafluoropyridine and a variety of 4-substituted pyridine
derivatives (R–C5H4N; R = H, Me, OMe, NH2), we found
that reaction between pentafluoropyridine and strongly
nucleophilic dimethylaminopyridine (DMAP) in acetoni-
trile after stirring at room temperature for several minutes
gave a yellow precipitate, which we attribute to either a
fluoride salt 1a or the s-bonded system 1b (Scheme 2). Due
to difficulties in isolating the highly hygroscopic fluoride
salt 1, we sought to synthesise a more stable salt by counter
anion exchange for identification purposes. Consequently, a
slurry of sodium tetrafluoroborate was added to the reaction
mixture and the stable tetrafluoroborate salt 2 was isolated,
purified and characterised by X-ray crystallography (Fig. 1),
supporting the suggested structure of the analogous fluoride
salt 1a, although fluoride abstraction from 1b would also
lead to salt 2. Overall, therefore, substitution of fluorine
located at the 4-positon of pentafluoropyridine by the
dimethylaminopyridine nucleophile occurs selectively, in
accordance with well-established principles [15,16]
The potential of using 1 as a nucleophilic fluorinating
reagent was determined in reactions with a short series of
model halogenated substrates in which the leaving group is
attached to a variety of sp2 and sp3 hybridised carbon sites
(Table 1). The halogenated substrates were added to a slurry
of 1 in acetonitrile and, after stirring overnight with heating
if necessary, the yields of fluorinated products were obtained
by quantitative 19F NMR with reference to a known mass of
1,4-difluorobenzene. In all cases, fluorination of the
substrate occurred and fluorinated products were obtained
in modest-good yields.
The low yield of 1-fluorooctane from 1-bromooctane was
attributed to the formation of oct-1-ene, which could be
identified by GC/MS, and formed by fluoride ion promoted
elimination of hydrogen bromide. A further yield-limiting
process was found to be reaction of the electrophilic substrate
with free DMAP, generated by fluoride ion attack on 1. For
example, in a separate experiment we confirmed that reaction
of 1-bromooctane with DMAP in acetonitrile, under the same
reaction conditions as those used for fluorination, resulted in
the formation of 4-(dimethylamino)-1-octylpyridinium bro-
Cations and anions in 2 are located in special positions at
the 2-fold axes and the two aromatic rings of the cation are

C.B. Murray et al. / Journal of Fluorine Chemistry 126 (2005) 571–576
573
Fig. 1. X-ray structure of 2.
Table 1
Fluorination of organo-halides using 1
R-X
R-F
Temperature (8C)
Reflux
Time (h)
17
Yield (%)
57a
20
1
53b
Reflux
Reflux
20
24
17
18
47b
10a
72b
a
Reaction mixture heated upon addition of pentafluoropyridine, halogenated substrate added when reflux attained.
b
DMAP and pentafluoropyridine alowed to react for 5 min at 20 8C prior to addition of halogenated substrate and heating if neccessary.
mide 3 in quantitative yield (Scheme 3). Pyridinium groups
are, of course, good leaving groups and may be susceptible
towards nucleophilic attack by fluoride ion. However,
reaction of 3 with anhydrous caesium fluoride in refluxing
acetonitrile gave no fluorinated products, as observed by
NMR and GC techniques, indicating that alkylation of the
electrophilic substrate by DMAP effectively removes the
substrate from the fluorination process.
Reaction of 1 with 1-bromooctane was carried out in a
range of solvents without any significant increase in yield
from that achieved in acetonitrile (Table 2). An exception to
this was the use of DMF, which gave a slight increase in the
yield of fluorinated product. However, acetonitrile is
probably the most effective reaction medium for these
processes because of the well-known difficulties of isolating
products from DMF in the longer term.

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C.B. Murray et al. / Journal of Fluorine Chemistry 126 (2005) 571–576
Scheme 3.
Table 2
was solved by direct method and refined by full-matrix
least squares on F2 for all data using SHELXL software.
Fluorination of 1-bromooctane in different solvents
Solvent
1-Fluorooctane (%)
Ethylene glycol
DCM
0
19
23
24
31
37
4.1. 4-(Dimethylamino)-1-(2,3,5,6-tetrafluoropyridin-4-yl)
pyridinium tetrafluoroborate 2
THF
Toluene
MeCN
A two-necked flask equipped with a condenser, magnetic
stir bar, septa and inert gas inlet was charged with DMAP
(2.41 g, 20 mmol) and MeCN (40 mL), followed by penta-
fluoropyridine (3.38 g, 20 mmol). After stirring for 20 min at
20 8C, a paleyellow solutionandthick lightyellow precipitate
had formed. The reaction mixture was filtered using Schlenk
techniques and washed twice with portions of cold MeCN. A
pale yellow solid was isolated and slurried with MeCN
(40 mL). Sodium tetrafluoroborate (2.20 g, 20 mmol) was
added, resulting in the almost immediate dissolution of the
paleyellow solidto form a yellow solutionfrom which awhite
solid slowly precipitated. After stirring overnight, the solution
was filtered and the solvent was evaporated to yield the crude
product as a yellow solid (2.68 g). Recrystallisation from
acetonitrile gave 4-(dimethylamino)-1-(2,3,5,6-tetrafluoro-
pyridin-4-yl)pyridinium tetrafluoroborate 2 (1.22 g, 17%) as
colourless crystals; mp >250 8C; (Found: C, 39.7; H, 2.8; N,
11.4. C12H10BF8N3 requires C, 40.1; H, 2.8; N, 11.7%); dH
(DMSO) 3.34 (6H, s, N(CH3)2), 7.35 (2H, d, 3JHH 7.6, Ar-H),
8.39 (2H, d, 3JHH 7.6, Ar-H); dF (DMSO) À88.7 (2F, m, F-2),
À147.0 (2F, m, F-3), À148.7 (4F, s, B- F4À); dC (DMSO) 40.6
(s, N(CH3)2), 108.6 (s, (NMe2)C-C), 131.0 (m, N+-C-CF),
DMF
3. Conclusions
In summary, therefore, a new nucleophilic fluorinating
reagent, derived from reaction of dimethylaminopyridine
with pentafluoropyridine has been prepared. A short series
of fluorination reactions established that the fluoride salt 1 is
a reasonably efficient fluorinating agent, although the
relatively low solubility of the salt 1 in acetonitrile limits
the fluorinating ability of the system. Related pyridine/
DMAP type fluoride ion reagents would have to be more
soluble in organic solvents before such fluorinating agents
can be considered to approach the utility of more established
sources of fluoride ion.
4. Experimental
All starting materials were obtained commercially
(Aldrich) and all solvents were dried using literature
procedures. NMR spectra were recorded in deuteriochloro-
form, unless otherwise stated, on a Varian VXR 400S n.m.r.
spectrometer with tetramethylsilane and trichlorofluoro-
methane as internal standards. In 19F NMR spectra, upfield
shifts are quoted as negative and coupling constants are
given in Hz. Mass spectra were recorded on either a VG
7070E spectrometer or a Fissons VG Trio 1000 spectro-
meter coupled with a Hewlett Packard 5890 series II gas
chromatograph. Elemental analyses were obtained on
either a Perkin-Elmer 240 or a Carlo Erba Elemental
Analyser. Melting points were recorded at atmospheric
pressure and are uncorrected. Single crystal data were
collected on a Bruker SMART-CCD 6000 diffractometer
((-scan, 0.38/frame) at 120.0(2) K using graphite mono-
137.8 (dd, JCF 263, JCF 38, N+-C-CF), 141.2 (s, N+-CH),
142.8 (dt, 1JCF 245, 3JCF 16, N-CF), 156.6 (s, N-C-CH); m/z
(EI+) 272 (M+, 100%). Suitable crystals were obtained for
X-ray diffraction by slow evaporation of their MeCN
solution.
Crystal data for 2:1 C12H10BF8N3, M = 359.04, mono-
clinic, space group C2/c, a = 7.9938(8), b = 22.540(2),
1
3
3
˚
˚
c = 7.8484(5) A,( = 103.46(4)8, U = 1375.3(2) A , F(000)
= 720, Z = 4, Dc = 1.734 mg mÀ3, ( = 0.181 mmÀ1. 4976
reflections (1.81 ꢀ ( ꢀ 27.58) were collected yielding 1568
unique data (Rmerg = 0.023). Final wR2( F2) = 0.1201 for all
1
CCDC contains the supplementary crystallographic data for this paper.
These data can be viewed free of charge via http://www.ccdc.cam.ac.uk/
cont/retrieving.html or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK. Fax: +44 1223 336033. E-mail: deposit@ccdc.cam.ac.uk.
˚
chromated Mo K( radiation (( = 0.71073 A). The structure

C.B. Murray et al. / Journal of Fluorine Chemistry 126 (2005) 571–576
575
Table 3
Fluorination reactions of fluoride ion source 1
Substrate
Quantity
Product (dF)
Temperature (8C)
Time (h)
Yield (%)
PhCOBr
1.29 mL, 10 mmol
1.15 mL, 10 mmol
1.80 mL, 10 mmol
1.80 mL, 10 mmol
1.99 g, 10 mmol
PhCOF (+18)
Reflux
20
17
1
57a
13b
20b
10a
64b
PhCH2Br
PhCH2F (À204)
n-C8H17Br
n-C8H17F (À217)
Reflux
Reflux
20
24
17
18
CH3CHBrC6H13
2,4-Dinitrochlorobenzene
a
CH3CHFC6H13 (À171)
2,4-Dinitrofluorobenzene (À108)
Reaction mixture heated upon addition of pentafluoropyridine, halogenated substrate added when reflux attained.
b
DMAP and pentafluoropyridine allowed to react for 5 min at 20 8C prior to addition of halogenated substrate and heating if neccessary.
data (132 refined parameters), conventional R( F) = 0.0416
for 1344 reflections with I ꢁ 2(, GOF = 1.065.
mide 2 (3.15 g, 100%) as a very pale yellow hygroscopic
solid; (Found: C, 56.8; H, 8.5; N, 9.1. C12H27BrN2 requires
C, 57.1; H, 8.6; N, 8.9); dH 0.83 (3H, t, 3JHH 7.0, CH3), 1.23
(10H, m, CH3CH2CH2CH2CH2CH2), 1.84 (2H, m, 3JHH 7.0,
4.2. Fluorination reactions – general procedure
3
N+CH2CH2), 3.25 (6H, s, N(CH3)2), 4.31 (2H, t, JHH 7.5,
3
A two-necked round-bottom flask was equipped with a
condenser, magnetic stir bar, septa and inert gas inlet. The
flask was charged with DMAP (1.22 g, 10 mmol) and
acetonitrile (20 mL). Depending on the substrate, one of two
procedures was then followed (see Yield entries in Table 3):
N+CH2), 7.03 (2H, d, JHH 7.5, N(CH3)2CH), 8.46 (2H, d,
3JHH 8.0, N+CH);m/z (ES+) 235 (M+, 100%).
4.4. Attempted reaction of 3 with caesium fluoride
A two necked flask was charged with 3 (2.70 g,
8.6 mmol) and anhydrous CsF (1.45 g, 9.5 mmol) in a
glove box. The flask was removed from the glove box and a
condenser and inert gas inlet were attached. MeCN (10 mL)
was added and the flask was stirred at 20 8C. A pale yellow
solution resulted and, after stirring overnight, 19F NMR
showed that no reaction had occurred. The reaction was then
heated to reflux for 23 h but no fluorinated products were
observed by 19F NMR analysis. The volatile fractions were
then removed by vacuum transfer to yield a colourless
liquid, which was shown by GC analysis to be MeCN only.
(i) When the DMAP had dissolved, pentafluoropyridine
(1.69 g, 10.0 mmol) was added via a syringe and the
mixture was heated to reflux. A yellow solution formed
immediately on mixing and within a five-minute period
a thick yellow precipitate had formed that dissolved at
reflux. Halologenated substrate (10 mmol) was then
added via a syringe as soon as reflux temperature had
been attained and the reaction was stirred at reflux until
the reaction was complete.
(ii) When the DMAP had dissolved, pentafluoropyridine
(1.69 g, 10.0 mmol) was added via a syringe and the
mixture was left to stir for five minutes at 20 8C. A
yellow solution formed immediately on mixing and
within the five-minute period a thick yellow precipitate
had formed. Halogenated substrate (10 mmol) was then
added via a syringe and the reaction was stirred at the
desired temperature until the reaction was complete.
4.5. Screening of solvents for fluorination reactions
A six-flask Radley’s Carousel reactor was purged with
argon and five of the flasks were charged with DMAP
(1.22 g, 10 mmol), followed by the appropriate solvent
(40 mL). The condenser head was connected to a glycol/
water recirculating cryostat at À10 8C. When the DMAP had
dissolved and the head had cooled (À8 8C indicated),
pentafluoropyridine (1.69 g, 10 mmol) was added, and the
reaction mixture was stirred rapidly for five minutes. All
reactions showed the expected yellow/orange colouration,
except for the flask containing ethylene glycol which
remained colourless. 1-Bromooctane (1.80 mL, 10 mmol)
was added and the reactions were heated to reflux for 20 h.
Analysis by quantitative NMR, using 1,4-difluorobenzene as
the reference, gave the yields of 1-fluorooctane as indicated
in Table 2.
Quantitative 19F NMR using 1,4-difluorobenzene as an
internal standard allowed determination of yields of fluor-
inated products by integration to the internal standard with
reference to literature data. Substrates, quantities used, 19F
NMR shifts of products formed, reaction conditions and
yields are collated in Table 3.
4.3. 4-(Dimethylamino)-1-octylpyridinium bromide 3
A two-necked flask equipped with a condenser, magnetic
stir-bar, septa and inert gas inlet was charged with DMAP
(1.22 g, 10 mmol) and MeCN (10 mL) followed by 1-
bromooctane (1.80 mL, 10 mmol) when the DMAP had
fully dissolved. The reaction was heated to reflux and left to
stir for 15 h. Evaporation of the solvent on a rotary
evaporator gave 4-(dimethylamino)-1-octylpyridinium bro-
Acknowledgements
We thank the Avecia Company and EPSRC for the award
of an EPSRC Industrial CASE studentship to C.M.

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[10] R.D. Chambers, W.K. Gray, G. Sandford, J.F.S. Vaughan, J. Fluorine
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