A semi-molten mixture of hexadecyltributylphosphonium bromide and potassium fluoride in the synthesis of organofluorine compounds

Article abstract of DOI:10.1016/S0022-1139(99)00121-9

A facile and effective reagent system comprising of a semi-molten mixture of hexadecyltributylphosphonium bromide and potassium fluoride has been developed and its scope has been investigated in nucleophilic fluoride exchange with various organohalides. This simple and convenient reagent system provides organofluorine compounds in high yields even with haloesters in which fluoride catalysed elimination is also feasible.

Full text of DOI:10.1016/S0022-1139(99)00121-9

Journal of Fluorine Chemistry 99 (1999) 115±117
A semi-molten mixture of hexadecyltributylphosphonium bromide and
potassium ¯uoride in the synthesis of organo¯uorine compounds
Pinaki S. Bhadury, Syed K. Raza, Devendra K. Jaiswal*
Synthetic Chemistry Division, Defence Research and Development Establishment, Gwalior 474002, India
Received 20 April 1999; accepted 27 May 1999
Abstract
A facile and effective reagent system comprising of a semi-molten mixture of hexadecyltributylphosphonium bromide and potassium
¯uoride has been developed and its scope has been investigated in nucleophilic ¯uoride exchange with various organohalides. This simple
and convenient reagent system provides organo¯uorine compounds in high yields even with haloesters in which ¯uoride catalysed
elimination is also feasible. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: Semi-molten mixture; Hexadecyltributylphosphonium bromide; Organo¯uorine compounds
1. Introduction
potassium ¯uoride in the synthesis of organo¯uorine com-
pounds, including examples in which elimination reactions
are feasible and compared the results with TBAB/KF sys-
tem. The ®ndings have been discussed in this paper.
Amongst several methods and reagents developed
recently for the synthesis of organo¯uorine compounds,
quaternary onium ¯uorides are the most attractive since
they allow ¯uoride exchange to occur conveniently and
under milder conditions [1,2]. Such reagents include tetra-
butylammonium ¯uoride (TBAF), tetramethylammonium
¯uoride (TMAF), benzyltrimethylammonium ¯uoride
(BTMAF) and tetrabutylphosphonium ¯uoride (TBPF), of
which TBAF has received most attention for ¯uorination
reactions [3]. However, the preparation of `anhydrous'
TBAF is rather tedious and as an alternative, we earlier
investigated the use of a semi-molten mixture of tetrabuty-
lammonium bromide (TBAB, m.p. 103±1048C) and an alkali
metal ¯uoride (KF/CsF) as a facile ¯uorination reagent
system, and demonstrated its application for the synthesis
of organo¯uorine compounds in some model reactions [4].
During our further investigations on the scope of this reagent
it was observed in some halo esters that along with the
nucleophilic ¯uoride exchange, the elimination reaction
catalysed by F as a base was signi®cant, resulting in overall
lowering of the yield of organo¯uorine compounds. There-
fore, we have investigated the semi-molten mixture of
another signi®cantly low melting onium salt hexadecyltri-
butylphosphonium bromide (HTPB, m.p. 56±588C) and
2. Experimental details
Commercially available KF was ®nely powdered and
¯ame-dried for 30 min; HTPB was dried under vacuum
(<0.1 mm Hg) at 40±458C for 15 min immediately prior
to the reaction. The details of monitoring of the reactions by
1
GLC and characterisation of compounds by H and 19F
NMR have been described earlier [4]. The mass spectra were
recorded on a Finnigan Mat, TSQ 7000 mass spectrometer.
2.1. Preparation of 4-bromobenzyl fluoride: typical
procedure A
Dried KF (15 g, 0.26 mol), HTPB (13.1 g, 0.026 mol)
were placed in a ¯ame-dried 250 ml round bottom ¯ask
containing a stir bar and equipped with a re¯ux condenser
and a dry N2 inlet. The mixture was heated at 608C when a
semi solid mass resulted. 4-Bromobenzyl bromide (12.9 g,
0.052 mol) was added in one portion with continued stirring.
The reaction was completed after stirring for 30 min. Hex-
ane (150 ml) was added after cooling and the reaction
mixture stirred for 10 min. The hexane solution was ®ltered
and the residue extracted thrice with additional hexane
(3 Â 25 ml). After removal of hexane, the crude product
*Corresponding author. Tel.: +91-751-342806, +91-751-340245, +91-
751-340354; fax: +91-751-341148
E-mail address: root@drdrde.ren.nic.in (D.K. Jaiswal)
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 1 2 1 - 9

116
P.S. Bhadury et al. / Journal of Fluorine Chemistry 99 (1999) 115±117
obtained was puri®ed by recrystallisation from the same
solvent to give 4-bromobenzyl ¯uoride, 6.6 g (68% yield),
m.p. 14±168C.
solvent extraction followed by distillation (procedure A).
The compounds synthesised are listed in Table 1, among
these 2-¯uoroethanol, methyl 2-¯uoropropionate and ethyl
2-¯uoropropionate were isolated by procedure B and others
were worked up by procedure A. The physical and spectral
data are given in Table 2. The 1H, 19F and mass spectral data
were consistent with their assigned structure.
2.2. Preparation of methyl 2-fluoropropionate: typical
procedure B
A mixture of KF (10.0 g, 0.17 mol), HTPB (8.7 g,
0.017 mol) was heated at 608C and methyl 2-bromopropio-
nate (5.7 g, 0.034 mol) was added in one portion with
stirring. An exothermic reaction occurred and mixture
was stirred for a further 45 min. After completion of the
reaction, the product was distilled directly to give methyl 2-
¯uoropropionate, 2.9 g (80%), b.p. 1108C.
The semi-molten mixture of HTPB/KF produces organo-
¯uorine compounds from alkyl, aralkyl halides and haloe-
sters. The reaction was found to be facile and completed in
30±60 min as observed by the GC analysis of the reaction
mixture. The isolated yields of the compounds shown in
Table 1 are unoptimised. The aryl halide, however, did not
react in the case of bromobenzene. Cyclohexyl bromide on
the other hand gave only an elimination product, cyclohex-
ene and no ¯uoro compound could be detected.
3. Results and discussion
A comparative study of the HTPB/KF reagent with our
previously described TBAB/KF system was carried out; the
reactions were run for the same period of time. The alkyl
and aralkyl halides such as 2-bromoethanol, 4-bromobenzyl
bromide and diphenyl bromomethane involving predomi-
nantly nucleophilic ¯uoride exchange reaction, gave good
yield of the corresponding ¯uoro compounds. Even though
yields were slightly better with the HTPB/KF reagent, in
view of the fact that yields were unoptimised, the two
The low-melting onium salt HTPB and potassium ¯uor-
ide were taken in a 0.5 : 5 mol ratio; the mixture on heating
at 608C formed a semisolid mass. The addition of organo-
halide (1 mol) to the molten mass led to an exothermic
reaction. Fluoride exchange was facile and the products
were isolated from reaction mixture either by direct dis-
tillation from the reaction mixture (procedure B) or by
Table 1
Synthesis of organofluorine compounds
Substrate
Reaction time (min)
Fluoro compoundsa
Isolated yield (%)b
present method
TBAB method [4]
Br±CH2±CH2OH
30
45
30
45
45
45
45
45
30
60
F±CH2±CH2OH
70
67
68
80
80
89
78
60
0
61
52
57
16
4
Br±CH(C6H5)2
F±CH(C6H5)2
F±CH2C6H4±Br (p)
CH3CHFCO2CH3
Br±CH2C6H4±Br (p)
CH3CHBrCO2CH3
CH3CHBrCO2C2H5
CH3CH2CHBrCO2C2H5
CH3CH2CH2CHBrCO2C2H5
BrCH2CH2CH2CO2C2H5
cyclo-C6H11Br
CH3CHFCO2C2H5
CH3CH2CHFCO2C2H5
CH3CH2CH2CHFCO2C2H5
FCH2CH2CH2CO2C2H5
no fluorocompoundd
no fluorocompounde
2
5
Ðc
0
Br±C6H5
0
0
a All compounds were characterised by 1H and 19F NMR, and mass spectral data which were consistent with their structure and reported data [5±9].
b Yields are unoptimised.
c Reaction not studied.
d Cyclohexyl fluoride was not formed, instead cyclohexene (100%, GC yield) was formed.
e Fluorobenzene not formed, no fluoride exchange observed.
Table 2
Physical characteristics, 19F NMR and mass spectral data for compounds synthesised
Compounds
b.p./[m.p.] (8C)
ꢀF (ppm)
2JH±F (Hz)
MS (El, 70 eV) m/z (Rel. Int. %)
‡
‡
FCH2±CH2OH
104
226.52
165.77
207.62
184.89
184.56
219.89
193.67
192.13
47.8
48.8
47.8
46.4
47.8
48.8
48.8
48.9
64 (M , 53.0); 33(9.53); 31(100.0)
FCH±(C6H5)2
88±90/0.3 mm Hg
186 (M , 2.0); 185(10.3); 167(8.1); 105(100.0); 77(69.0)
‡
FCH2±C6H4±Br (p)
CH3CHFCO2CH3
[14±16]
110
121
188/190 (M , 100/98); 109 (67.3); 33(29.1)
‡
106 (M , 7.5); 75(15.1); 47(100.0)
‡
CH3CHFCO2C2H5
FCH2CH2CH2CO2C2H5
CH3CH2CHFCO2C2H5
CH3CH2CH2CHFCO2C2H5
120 (M , 6.1); 75(77.3); 47(52.5); 29(100.0)
‡
151
134 (M , 4.1); 89(100.0); 61(19.3)
‡
138
134 (M , 8.3); 128(31.3); 55(100.0)
‡
152
148 (M , 1.5); 128(31.3); 55(100.0)

P.S. Bhadury et al. / Journal of Fluorine Chemistry 99 (1999) 115±117
117
procedures can be considered to be equally effective. The
new reagent HTPB/KF, however, offers distinct advantage
in cases of haloesters where organo¯uorine compounds
were obtained in much higher yields in comparison to
TBAB/KF reagent (Table 1) in spite of the fact that in these
cases besides halogen exchange, a ¯uoride catalysed elim-
ination reaction can also occur leading to an overall reduced
yield of the organo¯uorine compound. This may presum-
ably be due to a lower reaction temperature with HTPB
(608C) compared to TBAB (1108C) thereby resulting in
lesser elimination reaction catalysed by ¯uoride as a base.
This is illustrated by the GC analysis of the reaction mixture
of a a-haloester reacted separately with the two reagents for
the same time period. Thus, methyl 2-bromopropionate
produced 99% (isolated yield 80%) of the corresponding
¯uoro compound accompanied by only 1% of methyl
acrylate resulting from the F catalysed elimination when
reaction was carried out with HTPB/KF. On the other hand,
GC analysis of the reaction mixture carried out with TBAB/
KF showed 26% methyl 2-¯uoropropionate (isolated yield
16%), 36% methyl acrylate, 38% other products including
tributylamine and unreacted starting material. Similar
advantage has also been observed in case of reaction with
ethyl 4-bromobutyrate, an example of a g-haloester.
with organohalide. The method is simple and convenient.
The method is similar to TBAB/KF in cases where nucleo-
philic ¯uoride exchange is a predominant reaction. How-
ever, the present method has an advantage in the case of
haloesters wherein the ¯uoro compounds are obtained in
considerably higher yields as ¯uoride catalysed elimination
products are reduced possibly due to the lower reaction
temperature.
Acknowledgements
We thank Dr. R.V. Swamy, Director, DRDE, Gwalior for
his keen interest in this work.
References
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4. Conclusion
[7] M. Redmann, J. Am. Chem. Soc. 70 (1948) 3605.
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In conclusion, the semi-molten mixture of HTPB and
KF is a facile reagent for the ¯uoride exchange reaction