A novel improvement in ArLPdF catalytic fluorination of aromatic compounds

Article abstract of DOI:10.1016/j.apcata.2010.12.039

In this study, we used reverse micellar medium for overcoming the disadvantages of ArLMF catalytic fluorination of aromatic compounds. It not only enhanced the fluorination rate, but also widened the scope of reaction for bromoaromatics with electron donating and withdrawing functionalities at ortho position. Various bromoaromatic compounds were fluorinated using the biarylphosphine ligand i.e. cyclohexyl BrettPhos ligand, along with [cinnamylPdCl]₂, and CsF as the fluoride source in reverse micellar media. The anisotropic palisade layer of reverse micelles provided the active site for reaction. The most crucial factor in the critical reductive elimination step could be the spatial orientation of ArLPdF complex in the palisade layer; forming ArF as the final product in high yield with excellent selectivity.

Full text of DOI:10.1016/j.apcata.2010.12.039

Applied Catalysis A: General 394 (2011) 191–194
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Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
A novel improvement in ArLPdF catalytic fluorination of aromatic compounds
Bhupesh S. Samanta,∗, Sunil S. Bhagwatb
a Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Grahamstown 6140, South Africa
b Department of Chemical Engineering, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, we used reverse micellar medium for overcoming the disadvantages of ArLMF catalytic fluo-
rination of aromatic compounds. It not only enhanced the fluorination rate, but also widened the scope of
reaction for bromoaromatics with electron donating and withdrawing functionalities at ortho position.
Various bromoaromatic compounds were fluorinated using the biarylphosphine ligand i.e. cyclohexyl
BrettPhos ligand, along with [cinnamylPdCl]2, and CsF as the fluoride source in reverse micellar media.
The anisotropic palisade layer of reverse micelles provided the active site for reaction. The most crucial
factor in the critical reductive elimination step could be the spatial orientation of ArLPdF complex in the
palisade layer; forming ArF as the final product in high yield with excellent selectivity.
© 2011 Elsevier B.V. All rights reserved.
Received 21 October 2010
Received in revised form
29 November 2010
Accepted 30 December 2010
Available online 11 January 2011
Keywords:
Reverse micelles
Aromatic fluorination
Cyclohexyl BrettPhos
[CinnamylPdCl]2
1. Introduction
An important approach to obtain ArF compounds is electrophilic
substitution of F+ on aromatic ring by using transition metals
Micelles are self-assembled nanostructures of amphiphilic
monomers forming an outer hydrophilic shell area and an inner
hydrophobic core. There is an extensive use of micelles as a reac-
tion medium to catalyse the reaction rate and selectivity. This is
also been investigated in detail for different reactions in aqueous
and organic media [1–3].
Most aromatic compounds have low solubility in water. The
product yield is adversely affected by the presence of water.
Consequently organic solvents (non polar media) are used for
the aromatic substitution reactions. The scope of organic reac-
tions can be enhanced using cost effective and eco-friendly option
of reverse micellar aggregates as microreactors. The interface of
reverse micellar aggregates is located between the outer organic
bulk (hydrophobic) and the inner hydrophilic core. This anisotropic
surface provides useful reaction site to enhance the rate and selec-
tivity for various reactions.
In the previous study, we have described an improvement in the
regioselectivity for chlorination of phenol and ortho-chlorophenol
in the presence of micelles [4]. Here, we like to present a novel
improvement in aromatic fluorination reaction. Fluorinated aro-
matic compounds (ArF) have various applications in the field of
medicine, particularly 18F labeled organic compounds are very
important for positron emission tomography (PET) [5–8].
[9–13]. However, some of these processes require stoichiometric
amounts of metal in the reaction [10,11] and reactions which pro-
ceeds with catalytic quantity of metal require special activating
groups [9,12,13] thus, limiting general applicability of these meth-
ods. Another important drawback for electrophilic 18F reagents is
the low specific activity which limits their use to excess 18F labeled
compounds in PET applications [14,15].
There are various methods described in the literature to intro-
duce fluorine on aromatic compounds; such as, fluorination by
CF3SO3 and Selectfluor® [16], Balz-Schiemann reaction for con-
version of amine by the action of HBF4 [17], Halex reaction by
using chloroarenes and KF [18], action of CuF2 on aryl iodides [19],
and arylodonium salts [14]. However, most of them require harsh
conditions and are limited to a particular class of the substrates.
The conditions for Halex reaction have been improved by using
tetrabutylammonium fluoride [20]. Nonetheless, applicability of
this improved Halex reaction is limited to excess fluorination of
aromatics with electron withdrawing functionalities. These limi-
tations to reach towards ArF and their important applications in
the field of medicine has increased the research interest in find-
ing methodologies that are applicable to aromatic compounds with
heavy functionalities, and enabling aromatic fluorination in the
later stages of total synthesis. In this regards the conversion of aryl
halides (ArBr) with the action of alkali metal fluorides to form aryl
fluoride is the most suitable process.
Recently, there has been a report of the metal catalyses conver-
sion of aryl halides or sulfonate with nucleophilic fluorine source
to ArF in which ArLMX (L is ligand such as biarylphosphine ligands,
∗
Corresponding author. Tel.: +27 46 603 8395; fax: +27 46 636 1205.
E-mail addresses: B.Samant@ru.ac.za,
bhupesh.samant@gmail.com (B.S. Samant).
0926-860X/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.apcata.2010.12.039

192
B.S. Samant, S.S. Bhagwat / Applied Catalysis A: General 394 (2011) 191–194
M is metal such as Pd or Rh, X is halide or sufonate) complexes are
formed by the action of LM on aryl halides or sulfonates [21–25].
These ArLMX complexes react with nucleophilic reagents such as
cesium fluoride (CsF) or silver fluoride (AgF) to form ArLMF, which
undergoes critical reductive elimination to form ArF as the final
product. This pathway is very useful for synthesizing ArF com-
pounds. However, some drawbacks such as the formation of dimer
of ArLMF as an undesired product (due to the reaction between
LPd(0) and ArLPdF complex), loss of regioselectivity, and low yield
in the case of polar media limit its use. It is observed that reduc-
tive elimination of ArLMF to form ArF product is a difficult step to
achieve which affects negatively on the yield of the reaction [26].
It is also the main cause of skepticism on the mechanism of the
complete reaction process [27]. In this process the use ArBr as a
starting compound gave advantage by thermodynamically favor-
ing oxidative addition of ArBr to palladium complex. However, the
opposite reaction i.e. the reductive elimination of ArBr is difficult
[28]. In this paper, we intend to improve the pathway from ArBr to
ArF by using reverse micelles as a reaction medium. It will provide
insights in understanding the complex mechanism of this catalytic
system.
Fig. 1. BiarylPhosphine ligand (cyclohexyl BrettPhos) for aryl fluorination.
agitator of 0.3 cm diameter. The speed of agitation was maintained
at 1.67 Hz. Isothermal conditions were maintained at 100 ◦C. After
cooling to room temperature, CTAB (60 mmol) and toluene (5 cm3)
solution was added in the reaction mixture and agitated for another
10 min. The mixture was filtered through a plug of Celite. Filtrate
was concentrated under reduced pressure and purified by flash
chromatography on silica gel using hexane to give the fluorinated
product 1-bromonaphthalene as a yellow oil; b.p. 107 ◦C; yield:
105 mg (72% yield). All experiments were performed in replicates of
three. The variation in the results from the reported average values
was within 0.75%.
2. Experimental
2.1. Materials
1-Bromo-naphthalene,
4-bromo-3-methyl-phenol,
4-
bromo-2-methyl-phenol,
2-bromo-1-methyl-4-nitrobenzene,
4-bromo-3,5-dimethyl-phenol,
1-bromo-2-methyl-4-
nitrobenzene, 4-bromo-quinoline and CsF were purchased
from Aldrich Co. 5-Bromo-quinoline was obtained from Alfa
Aesar Co. Anhydrous toluene (with molecular sieves and sep-
tum), sodium dodecyl sulphate (SDS) (electrophoretic grade),
linear alkylbenzene sulphonate (LABS) (electrophoretic grade),
and cetyltrimethylammonium bromide (CTAB) (electrophoretic
grade) were obtained from Sigma–Aldrich Co. The purity of these
surfactants was ascertained tensiometrically. [CinnamylPdCl]2
was prepared as described previously [29] and stored at −20 ◦C.
Cyclohexyl BrettPhos was prepared according to the literature
procedure [30]. All other reagents from commercial sources were
used as received. Flash chromatography was performed with
Merck silica gel 60 (230–400 mesh ASTM). Each experiment was
repeated thrice independently.
3. Results and discussion
3.1. Fluorination of bromonaphthalene in reverse micellar media
The biarylphosphine ligand i.e. cyclohexyl BrettPhos ligand [29]
(Fig. 1) along with [cinnamylPdCl]2, [30] and CsF as the fluoride
source were used for fluorination of bromonaphthalene. The con-
version of bromonaphthalene to fluoronaphthalene is negligible
without sodium dodecyl sulphate (SDS), (Table 1, entry 1) because
there was no reductive elimination of ArLPdF complex to form ArF
and LPd(0). On the other hand, when reaction was performed in
60 mmol SDS toluene solution remarkable enhancement in con-
version was observed (Table 1, entries 2–4).
Gas chromatography technique was employed to determine the
exact % conversion of bromonaphthalene to fluoronaphthalene,
while isolated yield of fluoronaphthalene was confirmed by com-
paring integration of the 19F NMR resonance of 4-fluorotoluene
2.2. General analytical information
All the products formed were identified satisfactorily using 1H
NMR (300 MHz), 13C NMR (75.46 MHz), 19F NMR (282 MHz). Peak
positions are given in parts per million (ı) from tetramethylsilane
(1H and 13C) and FCCl3 19F) as internal standard, and coupling
(
Table 1
Optimization of bromonaphthalene fluorination.
constant values (J) are given in Hertz. The yield is determined by
comparing integration of the 19F NMR resonance of 4-fluorotoluene
(−118.0 ppm). Conversion of reaction was analyzed using a gas
chromatograph (Chemito 8610) with a flame ionization detector.
A 4 m long and 0.37 cm i.d. S.S. column packed with 10% SE-30 on
chromosorb WHP was employed for the analysis. Nitrogen at the
flow rate of 0.5 × 10−7 m3 s−1 was used as carrier gas.
2.3. General procedure for fluorination
Entry
SDS (mmol)
Pd (mol%)
Conversiona (%)
Yieldb (%)
Mixture of 1-bromonaphthalene (207 mg, 1 mmol, 1 eq),
ligand cyclohexyl BrettPhos (6.4 mg, 0.012 mmol, 10 mol%),
(cinnamylPdCl)2 (10.4 mg, 0.02 mmol, 2 mol%) and CsF (228 mg,
1.5 mmol, 1.5 eq) was added in SDS (60 mmol) toluene (10 cm3)
solution and mixture was agitated for 6 h under argon atmosphere
in a 50 cm3 baffled glass reactor equipped with a six-blade turbine
1
2
3
4
0
60
60
60
10
10
5
Trace
100
100
90
–
72
70
60
2
a
Conversion was determined by gas chromatograph.
Isolated yield.
b

B.S. Samant, S.S. Bhagwat / Applied Catalysis A: General 394 (2011) 191–194
193
(−118.0 ppm). Final product was further analyzed by using 1H and
100
13C NMR spectroscopy.
It is thus anticipated that the presence of reverse micelles in the
reaction media enhanced the rate of fluorination reaction. Thus,
60 mmol SDS in reaction media gave an advantage to use 2–5% mol
of Pd catalyst to convert bromo to fluronaphthalene to almost 100%
with average isolated yield of 70%.
80
60
40
20
0
3.2. The mechanism of fluorination in reverse micellar media
The exact mechanism of this reaction in micellar media is still
unknown. At first it was speculated that the presence of water
and ionic surfactants make the fluoride source soluble and more
likely to engage in ion exchange with Pd(II) in the nonpolar sol-
vent. However, the selectivity towards particular product indicates
the influence of reverse micellar interface on the reaction mecha-
nism. Hence, on the basis of the results obtained, we hereby propose
a hypothetical mechanism for this reaction in reverse micellar
media.
0
10
20
30
40
50
60
70
80
Surfactant concentration (mmol)
Fig. 2. The effect of surfactant concentration (
SDS,
LABS,
CTAB) on fluo-
rination of bromonaphthalene in the presence of 2 mol% (cinnamylPdCl)2, 10 mol%
cyclohexyl BrettPhos ligand, 1.5 eq CsF and 30 cm3 toluene at 110 ◦C for 6 h. Each
experiment was done three time independently. The variation in the results from
the reported average values was within 0.75%.
The anisotropic area, which is known as palisade layer, seems
to be a useful reaction site for the formation of ArLPdBr com-
plex. The complex further reacts with fluoride source (Cs+F−)
to form ArLPdF. The reductive elimination of ArLPdF complex is
the most important and crucial step in this fluorination reaction.
ArLPdF complex is made of hydrophilic fluorine and hydropho-
bic ligand. The attraction force on hydrophobic ligand towards
the surface of reverse micelle may reduce the Ar–Pd–F angle and
bring Ar and F substituents close to each other. The hydrophobic
and hydrophilic balance in ArLPdF complex may reduce the sta-
bility so that reductive elimination takes place rapidly to form
ArF as the final product. Previously efforts were made to sup-
press the LM-F bond formation and promote the desired ArF
reductive elimination [27]. In that regards, this positive effect of
palisade layer on the reductive elimination of ArF is very impor-
tant.
The hydrophobic LPd(0) might migrate near the surface of
reverse micelle, and its exclusion from the reaction site might pre-
vent the formation of dimeric complex (ArLMF)2. Hence, reverse
micellar media in this reaction overcomes the obligation to use
ArBr in excess. Selectivity in fluorination may be due to the spa-
tial orientation of ArLPdBr in palisade layer, which gave inclination
of bromo towards hydrophilic core (i.e. in the direction of attack-
ing Cs+F− fluorine source). The effect of preferred average spatial
orientation in the domain of the surfactant micelle has been ascer-
tained by studies in substitution reactions [31,32] as well as by 1H
NMR spectroscopy [33–35].
3.3. The effect of nature and concentration of surfactant
Fig. 2 explains the effect of surfactant concentration on the
conversion of bromo to fluoronaphthalene. There was an enhance-
ment in the % conversion of bromonaphthalene fluorination with an
increase in the surfactant concentration and it attained a constant
value beyond a certain (60 mmol SDS) surfactant concentration.
The effect of two types of ionic surfactant concentrations such
as cationic surfactant (CTAB) and anionic surfactant (LABS and SDS)
has been studied to understand the consequence of micellar head
group charges on the rate and selectivity in the fluorination reac-
tion. However, there is inconspicuous difference observed on the
rate or yield of reaction product amongst these surfactants. This
indicates that the effect of hydrophobic and hydrophilic media is
the most influencing factor on the fluorination reaction than the
nature of charges on micellar head and tail groups.
Salutary features of this study are the use of commercially
available, cost-effective bromo-derivatives as starting compounds
(which gave thermodynamically favored addition reaction with Pd
complex) and the use of cyclohexyl biarylphosphine ligand without
formation of any dimeric complex.
3.4. Fluorination of various bromoaromatic compounds
Applicability of this fluorination reaction for various ArBr is
shown in Table 2. Aromatic compounds with electron withdraw-
Table 2
Fluorination of various ArBr.
Entry
Substarte
Product (conversiona %, yieldb %)
1
2
3
4
5
6
7
4-Br-3-me-phenol
4-Br-2-me-phenol
4-Br-3,5-dimethylphenol
2-Br-1-me-4-nitrobenzene
1-Br-2-me-4-nitrobenzene
5-Br-quinoline
4-Fluoro-3-me-phenol (91%, 71%)
4-Fluoro-2-me-phenol (90%, 70%)
4-Fluoro-3,5-dimethyl-phenol (100%,78%)
2-Fluoro-1-me-4-nitrobenzene (92%,72%)
1-Fluoro-2-me-4-nitrobenzene (90%,70%)
5-Fluoro-quinoline (100%, 65%)
6-Br-quinoline
6-Fluoro-quinoline (100%, 69%)
a
Conversion was determined by gas chromatograph.
Isolated yield.
b

194
B.S. Samant, S.S. Bhagwat / Applied Catalysis A: General 394 (2011) 191–194
ing functionalities (Table 2, entries 4 and 5) and electron donating
functionalities (Table 2, entries 1–3) have been converted into their
corresponding fluorinated analogues with excellent yield. Success-
ful fluorination of naphthalene and quinolines (Table 2, entries 6
and 7) proves that aromatics with two rings and heterocyclic groups
could be fluorinated with high yield using this method to obtain
pharmaceutically important fluorinated analogues. Though reac-
tion time required for this method is long to obtain 18F labeled
compounds for PET, experiments with polymeric micelles and vari-
ous phosphine ligands for fluorination of hindered ArBr compounds
are underway to facilitate the access towards medical imaging
reagents.
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Acknowledgments
The authors are grateful to Rhodes University Joint Research
Committee (JRC) for providing financial support for this work
(Rhodes University JRC grant number 35047). The authors thank
Dr. Mugdha G. Sukhthankar (St. Jude Children’s Research Hospi-
tal, Memphis, TN, USA) for discussion on medical imaging reagent
study.
Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.apcata.2010.12.039.