Selective electrochemical aromatic fluorination of acetophenone and benzophenone

Article abstract of DOI:10.1023/B:RUJO.0000013131.19936.5e

Electrochemical fluorination of acetofenone and benzophenone was studied in anhydrous HF and in solutions. The electrochemical fluorination of acetophenone in HF occurred exclusively in the ring and furnished ortho- and meta-isomers of fluoroacetophenone,

Full text of DOI:10.1023/B:RUJO.0000013131.19936.5e

Russian Journal of Organic Chemistry, Vol. 39, No. 11, 2003, pp. 1581 1586. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 11, 2003,
pp. 1646 1650.
Original Russian Text Copyright
,
2003 by Shainyan, Danilevich, Grigor eva, Chuvashev.
Selective Electrochemical Aromatic Fluorination
of Acetophenone and Benzophenone
,
B. A. Shainyan, Yu. S. Danilevich, A. A. Grigor eva, and Yu. A. Chuvashev
Faworsky Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Scienses, Irkutsk, 664033 Russia
Received December 11, 2002
Abstract Electrochemical fluorination of acetofenone and benzophenone was studied in anhydrous HF and
in solutions. The electrochemical fluorination of acetophenone in HF occurred exclusively in the ring and
furnished ortho- and meta-isomers of fluoroacetophenone, 2,5-difluoroacetophenone, and 1-(3,3,6,6-tetra-
fluoro-1,4-cyclohexadienyl)-1-ethanone. The fluorination of benzophenone in anhydrous HF furnished
predominantly m-fluorobenzophenone, whereas in the presence of chloroform only chlorination products
were obtained. The electrochemical fluorination of acetophenone in acetonitrile gave rise only to mono- and
difluorinated products. The reasons for readily occurring oxidative fluorination of aromatic compounds into
polyfluoro-1,4-cyclohexadienes were discussed, and the decomposition paths of fluorinated products under
electron impact were considered.
Fluorination of aromatic compounds with various
fluorinating agents under different conditions for a
long time have attracted the attention of researchers
as a way to fluoroaromatic products. The direct
fluorination with elemental fluorine of various
aromatic compounds was investigated [1], and also
the oxidative fluorination thereof with higher metal
fluorides (AgF2, CoF3 etc.) [2]. At the same time we
did not find any publications on electrochemical
fluorination of aromatic ketones. With aliphatic-
aromatic ketones the interesting problem is whether
the fluorination would occur into the side chain or
into the aromatic ring, and with benzophenone and its
analogs either unsymmetrical polyfluorination into
one ring or symmetrical process in both rings are
presumable. In this connection and in extension of
our previous studies in this field [3, 4] we carried out
electrochemical fluorination of acetophenone (I) and
benzophenone (II) in anhydrous HF and in solutions
in chloroform and acetonitrile.
and 1-(3,3,6,6-tetrafluoro-1,4-cyclohexadienyl)-1-
ethanone (VI).
The structure of all products was unambiguously
proved by their 1H, 13C, 19F NMR spectra, in
particular, by characteristic splitting of signals in
proton and carbon spectra due to coupling with one,
two, or four fluorine atoms. As additional evidence
for assignment of isomers III and IV served the
5
Liquid products from electrochemical fluorination
of acetophenone were separated by preparative GLC.
presence of long-range coupling with constants JHF
4
4.9 Hz (publ.: 4.8 Hz [5]) and JCF 7.3 Hz in the
1
Their analysis by H, 13C, 19F NMR and GC-MS
1H and 13C NMR spectra of ortho-isomer III and the
lack of this coupling in the meta-isomer IV. Accord-
methods revealed that the electrochemical fluorina-
tion, similar to oxidative fluorination with the higher
metal fluorides [2] took place exclusively in the ring
and left intact the acetyl group. The main fluorination
products were ortho-and meta-isomers of fluoro-
acetophenone (III) and (IV), 2,5-difluoroaceto-
phenone (V) (not detected in the products of fluorina-
tion with HF in the presence of CoF3 or PbO2 [2]),
1
ing to H and 19F NMR data the ratio of isomers III
and IV in the reaction mixture was 2: 1. The GC-MS
method detected in the reaction mixture alongside
2,5-difluoroacetophenone (V) another isomer of di-
fluoroacetophenone, but the insignificant amount of
the latter prevented estimation of its structure by
spectral methods. In tetrafluoride VI the proton signal
1070-4280/03/3911-1581$25.00 2003 MAIK Nauka/Interperiodica

1582
SHAINYAN et al.
of methyl group appears as a triplet due to coupling
fluoromethyl group would be regarded as an analog
of a carbonyl group, then the ease of the oxidative
fluorination of 2,5-difluoroacetophenone V into
1-(3,3,6,6-tetrafluoro-1,4-cyclohexadienyl)-1-etha-
none (VI) would be similar to the readily occurring
oxidation of hydroquinone into quinone.
with fluorine atoms in position 3 with a long-range
5
coupling constant JHF 1.5 Hz (publ.: 1 Hz [2]).
Analysis of the published [2, 6, 7] and our own
experimental data shows that formation of 1-substitut-
ed 3,3,6,6-tetrafluoro-1,4-cyclohexadienyl deriv-
atives of VI type is a general way of fluorination for
various aromatic substances. Insofar as this process
consists in oxidative addition with aromaticity distor-
tion which is not common to aromatic compounds,
apparently a certain driving force should exist that
makes up for the energy loss due to destruction of the
aromatic system. This driving force is likely a form-
ation of four very strong C F bonds, and if the di-
It should be noted that this result is specific just for
difluoromethyl group in contrast to the other dihalo-
methyl groups. We carried out comparative calcula-
tion of heat evolution in the oxidation of hydroqui-
none and the oxidative halogenation of 1,4-dihalo-
benzenes (equations 1 3). The calculation of reagents
and reaction products was performed by the procedure
B3LYP/6-311G(d,p) with full geometry optimization.
E = 35.3 kcal/mol
(1)
(2)
E = 95.2 kcal/mol
E = 1.4 kcal/mol
(3)
The oxidative fluorination turned out to be far
more exothermic than the hydroquinone oxidation
unlike the oxidative chlorination which should occur
virtually without heat evolution. Notice however that
reaction (2) only formally describes the electro-
chemical fluorination of acetophenone. The actual
process of electrochemical fluorination in liquid HF
is more close to reaction (4)
fluorination in acetonitrile solution is the composition
of the products: under conditions of hard fluorina-
tion the ratio of ortho-isomer (III) to meta-isomer
(IV) is 2: 1, and the main reaction product is tetra-
fluoride VI, whereas the soft fluorination afforded
compounds III and IV in 1: 2 ratio, and tetrafluoride
VI was not detected even in traces.
The absence of polyfluorinated compound VI in
the products of the soft fluorination is consistent
with the general rule that electrochemical fluorination
in solvents affords prevailingly monofluorinated
substances [8]. As to the direction of monofluorina-
tion and its dependence on the solvent, note that no
para-isomers were obtained in electrochemical
fluorination both of acetophenone and of phenyl
methyl sulfone that we had studied earlier [4]. We
believe that this fact testifies to the operation of
ECEC-mechanism (Electrochemical-Chemical-Electro-
chemical-Chemical) where on the first stage occurs
the one-electron oxidation of the substrate to the cor-
responding cation-radical [9]. The calculation of
cation-radicals of both substrates by AM1 procedure
showed that the electron density on carbon atom of
(4)
This reaction turned out to be endothermic, E =
1
28.4 kcal mol , but this effect is evidently com-
pensated by entropy increase due to molecular hydro-
gen evolution. The similar chlorination reaction is
1
nearly twice as endothermic, E = 49.8 kcal mol .
The electrochemical fluorination of acetophenone
in acetonitrile gave rise to ortho- and meta-isomers of
fluoroacetophenone (III) and (IV), the latter prevail-
ing, 2,5-difluoroacetopheneone (V), and likely 3,5-di-
fluoroacetophenone. The main difference of the
hard fluorination in anhydrous HF from the soft
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 11 2003

SELECTIVE ELECTROCHEMICAL AROMATIC FLUORINATION
1583
Scheme 1.
Scheme 2.
aromatic ring increased as its distance from the
electron-withdrawing substituent grew (see figure).
This means that the ortho- and meta-positions
should possess comparable activity with respect to a
nucleophile that should considerably exceed the
activity of the para-position. The change in the
ortho meta ratio depending on the solvent may be
due to the charge control of the reactivity under con-
ditions of the hard fluorination leading to prevail-
ing formation of ortho-isomer III, whereas in the
process of the soft fluorination the spin density
plays an important role, and since it is higher in the
meta-position, under these conditions meta-isomer IV
is predominant.
followed by further fragmentation of the fluoro-sub-
stituted benzoyl-cations with ejection of CO and HF
molecules (Scheme 1).
On the contrary, nonaromatic tetrafluoride VI suf-
fered fragmentation mostly at the bond Car CO with
localization of the charge mainly on the acetyl group.
The fragmentation of the molecular ion with the
charge localization on the cyclohexadiene fragment is
less probable and in a way resembles the fragmenta-
tion of the molecular ion of methyl 3,3,6,6-tetra-
fluoro-1,4-cyclohexadienyl sulfone [4].
The electrochemical fluorination of benzophenone
proceeded slowly, with considerable tarring; within
10 h the conversion did not exceed 30%. The com-
position and structure of fluorinated products were
established by 13C and 19F NMR spectroscopy and
GC-MS method. The main product was meta-fluoro-
benzophenone (VII) as confirmed by its mass spec-
trum (m/z of molecular ion 200), by the presence of
two CH signals in the 13C NMR spectrum with a
2
characteristic geminal coupling constant JCF 22 Hz
Charges (overall charges on carbon atoms and hydrogens
linked thereto) and spin density (in italics in parentheses) in
cation-radicals of phenyl methyl sulfone and acetophenone
calculated by AM1 procedure.
(C2 and C4), and a doublet of triplets in the 19F NMR
spectrum which might appear only in a meta-isomer.
As a minor monofluorination product was obtained
ortho-fluorobenzophenone (VIII). The di- and tri-
fluorinated products were present in insignificant
amounts, but just the composition of fragment ions
in their mass spectra revealed the fluorination direc-
Under electron impact compounds III V undergo
rupture predominantly at the Me CO bond with
positive charge localization on the aromatic fragment
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 11 2003

1584
SHAINYAN et al.
tion. Mass spectra of two isomeric difluorides IX and
X with m/z of molecular ions 218 are quite different.
In the prevailing isomer the following fragment ions
were observed: s m/z 141 [M-Ph]+ 113 [M-PhCO]+ ,
105 [PhCO]+ , 77 [Ph]+ evidencing, that subsequent
fluorination occurred into already fluorinated ring
affording PhCOC6H3F2. In the mass spectrum of the
minor difluorinated product the above cited peaks
were lacking, but were present peaks with m/z 123
[M-C6H4F]+ and 95 [C6H4F]+ suggesting the sym-
metrical structure of difluoride (X) (C6H4F)2CO. The
lack of peaks with m/z 105 and 77 in the spectrum of
trifluoride XI also indicates a structure with both
rings fluorinated, C6H3F2COC6H4F.
To suppress the precipitation of tar on the elec-
trodes that decreased current the reaction mixture
containing fluorinated products VII XI was diluted
with chloroform, and the process was carried on.
However the electrochemical fluorination of this
mixture did not result in higher yield of products
VII XI, but afforded only monochlorinated products
XII XIV. Their composition and the distribution of
fluorine atoms between the rings was established by
GC-MS method.
If to the electrochemical fluorination was subjected
a solution of pure benzophenone in chloroform, the
fluorination products were totally absent, and only
products of benzophenone chlorination were obtained:
XII (two isomers) and XV XVII in a ratio (%)
fragmentation predominantly occurred by rupture of
the bond between the fluorinated ring and the carbon-
yl group C6H5 nFn-COPh with charge localization on
the nonfluorinated fragment.
(XII-°) (XII-m) (XV) (XVI) (XVII),
21: 48: 10:
EXPERIMENTAL
12: 9. The reaction was slow: conversion within 12 h
was only 13%. The formation of only chlorinated
products and no mixed products with F and Cl, XIII
and XIV, means that cation-radical of benzophenone
arising in the first stage does not react with HF and
only abstracts chlorine from the chloroform molecule
for the C Cl bond is weaker than the H F bond.
1H, 13C and 19F NMR spectra are registered on
spectrometer Bruker DPX 400 (at operating frequ-
encies 400, 100, and 376 MHz respectively) from
solutions in CDCl3, internal reference HMDS,
chemical shifts are reported with respect to TMS
(1H, 13C) and CCl3F (19F). GC-MS analysis was
carried out on Hewlett Packard HP 5971A instrument
(70 eV) coupled with a column Ultra-2 (5% phenyl-
methylsilicone), vaporizer temperature 250 C, oven
temperature programming from 70 to 280 C at a rate
Unlike the above process the electrochemical
fluorination in acetonitrile proceeded fairly selectively
affording as the main product meta-fluorobenzophe-
none (VII) (19F NMR data).
1
20 deg min . GLC analysis was performed on
In the mass spectra of all fluorinated products
containing an unsubstituted phenyl group the most
abundant peak was that of ion [PhCO]+ . Thus the
chromatograph LKhM-8, column 2000 3 mm,
stationary phase 15% polymethylphenylsilicone oil
on Chromaton N-AW, detector katharometer, carrier
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 11 2003

SELECTIVE ELECTROCHEMICAL AROMATIC FLUORINATION
1585
gas helium. Preparative separation was carried out
on chromatograph PAKhV 07, columns 5000 8 mm,
stationary phase 5% SE 30 on Chromaton N-AV
DMCS.
1-(2, 5-Difluorophenyl)-1-ethanone (V).
1H NMR spectrum, , ppm: 2.57 m (3H, CH3),
7.14 m (2H, H2,4), 7.48 m (1H, H5). 13C NMR
4
spectrum, , ppm: 31.18 d (CH3, JCF 7.6 Hz),
2
3
115.99 d.d (C2, JCF 25.0, JCF 3.0 Hz), 117.76 d.d
Electrochemical fluorination was carried out in an
electrolyzer of stainless steel of 130 cm3 capacity with
nickel anodes of overall surface 63 cm3. The electro-
lyzer was equipped with an inlet for charging HF, an
outlet for discharge of fluorination products, and a
reflux condenser filled with acetone ether mixture
(1: 1) cooled with liquid nitrogen to 20 C. Into the
cooled electrolyzer cell was charged 120 g of an-
hydrous HF and 15 g of acetophenone. The electro-
lysis was carried out for 18 h (17.7 A h) at anode
2
3
2
(C5, JCF 27.2, JCF 7.8 Hz), 120.95 d.d (C4, JCF
24.6, JCF 9.5 Hz), 126.66 d.d (C1, JCF 15.7, JCF
3
2
3
6.3 Hz), 157.79 d.d (C3, JCF 251.1, JCF 1.9 Hz),
1
4
1
4
158.18 d.d (C6, JCF 244.6, JCF 1.9 Hz), 194.46 d
(C=O, JCF 3.4 Hz). 19F NMR spectrum, , ppm:
3
112.90 m (F6), 115.31 m (F3) (publ.: 115.42
and 118.04 [11]).
1-(3,3,6,6-Tetrafluoro-1,4-cyclohexadienyl)-1-
1
ethanone (VI). H NMR spectrum, , ppm: 2.60 t
2
current density 1.6 dm , cell voltage 6.2 7.4 V, cell
5
(3H, CH3, JHF 1.5 Hz), 6.32 m (2H, H4,5), 7.00 m
temperature 5 C. On completing the electrolysis the
reaction mixture was discharged, HF was evaporated,
NaF was added to the residue to scavenge the residual
HF, then the mixture was extracted with ether, the
extract was dried over CaCl2. The ether was distilled
off, the residue was distilled under reduced pressure,
bp 70 80 C (10 mm Hg), and the products were
separated by the preparative GLC.
(1H, H2). 13C NMR spectrum, , ppm: 28.87 t (CH3,
2
3
4JCF 2.6 Hz), 128.32 t.t (C5, JCF 29.6, JCF 9.3 Hz),
129.71 t.t (C4, JCF 30.6, JCF 9.3 Hz), 133.08 t.t
2
3
(C1, JCF 36.7, JCF 11.5 Hz), 133.82 t.t (C2, JCF
2
3
2
31.4, JCF 7.0 Hz), 192.37 s (C=O). 19F NMR spec-
3
trum, , ppm: 92.62 s (F3), 93.89 s (F6) (publ.:
95.27 and 96.77 [2]).
Electrochemical fluorination of benzophenone in
HF, chloroform, and acetonitrile were carried out as
described above for acetophenone. After removal of
HF the reaction mixtures were analyzed by NMR
spectroscopy and GC-MS method.
Electrochemical fluorination of acetophenone in
acetonitrile was performed in the similar fashion
100 ml of HF, 20 ml of CH3CN, 10 g of aceto-
2
phenone, 12 h, 12.3A h, 1.6 dm , 6.2 7.4 v, 8 C).
1-(2-Fluorophenyl)-1-ethanone (III). 1H NMR
(3-Fluorophenyl)(phenyl)methanone (VII). 13C
5
spectrum, , ppm: 2.62 d (3H, CH3, JHF 4.9 Hz),
2
3
4
NMR spectrum, , ppm: 116.43 d (C2, JCF 22.4Hz),
7.11d.d.d (1H, H3, 3JHF 11.2, JHH 8.3, JHH 1.1 Hz),
2
4
119.16 d (C4, JCF 21.6 Hz), 125.61 d (C6, JCF
7.20d.d.d (1H, H5, 3JHH6 7.7, 3JHH4 7.3 Hz),
3.0 Hz), 162.24 d (C3, JCF 247.8 Hz), 194.87 d
1
7.49 d.d.d.d (1H, H4, JHF 5.0, JHH 1.9 Hz), 7.85
4
4
4
(C=O, JCF 1.7 Hz). We failed to identify the signals
t.d (1H, H6, JHF 7.7 Hz). 13C NMR spectrum, ,
4
of C1 and C5 atoms. 19F NMR spectrum, , ppm:
ppm: 31.35 d (CH3, JCF 7.3 Hz), 116.60 d (C3,
4
111.71 d.t (3JHF 8.5, JHF 5.7 Hz).
4
4
2JCF 24.1 Hz), 124.32 d (C5, JCF 3.4 Hz), 128.38 d
(C1, JCF 26.3 Hz), 130.54 d (C6, JCF 2.2 Hz),
2
3
(2-Fluorophenyl)(phenyl)methanone (VIII).
19F NMR spectrum,
, ppm: 110.99 m.
134.61 d (C4, JCF 9.1 Hz), 162.20 d (C2, JCF
3
1
3
254.7 Hz), 195.87 d (C=O, JCF 3.0 Hz). 19F NMR
The authors are grateful to N. A. Kalinina for
separation of products by means of preparative GLC,
and to Professor S.Rozen (School of Chemistry, Tel
Aviv University) for fruitful discussion of the study
results.
spectrum, , ppm: 109.38 m (publ.: 110.0 [1, 8]).
1-(3-Fluorophenyl)-1-ethanone (IV). 1H NMR
spectrum, , ppm: 2.56 s (3H, CH3), 7.23 t.d.d (1H,
3
3
4
H4, JHF 8.2, JHH 8.2, JHH 1.0 Hz), 7.41 t.d
(1H, H5, JHH6 8.0, JHF 5.5 Hz), 7.60 d.d.d
3
4
(1H, H2, JHF 9.5, JHH4 2.6, JHH6 1.6Hz),
3
4
4
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1
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4
111.91 m (publ.: 112.35 [10]).
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