Electrochemical fluorination of benzamide and acetanilide in anhydrous HF and in acetonitrile

Article abstract of DOI:10.1023/B:RUJO.0000036072.78258.c2

Electrochemical fluorination of benzamide in anhydrous hydrogen fluoride does not involve the amide group but occurs exclusively at the aromatic ring, yielding isomeric fluoro- and difluorobenzamides and 3,3,6,6-tetrafluoro-1,4- cyclohexadienecarboxamide.

Full text of DOI:10.1023/B:RUJO.0000036072.78258.c2

Russian Journal of Organic Chemistry, Vol. 40, No. 4, 2004, pp. 513–517. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 4, 2004,
pp. 544–548.
Original Russian Text Copyright © 2004 by Shainyan, Danilevich, Grigor’eva, Chuvashev.
Electrochemical Fluorination of Benzamide and Acetanilide
in Anhydrous HF and in Acetonitrile
B. A. Shainyan, Yu. S. Danilevich, A. A. Grigor’eva, and Yu. A. Chuvashev
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: bagrat@irioch.irk.ru
Received September 16, 2003
Abstract—Electrochemical fluorination of benzamide in anhydrous hydrogen fluoride does not involve the
amide group but occurs exclusively at the aromatic ring, yielding isomeric fluoro- and difluorobenzamides and
3,3,6,6-tetrafluoro-1,4-cyclohexadienecarboxamide. Electrochemical fluorination of benzamide in acetonitrile
as solvent gives the same products, as well as benzonitrile and its fluorinated derivatives and products of
hydrolysis and fluorination of acetonitrile. Electrochemical fluorination of acetanilide in anhydrous HF leads to
complete tarring of the reaction mixture, while its fluorination in acetonitrile results in selective formation of
m-fluoroacetanilide.
Fluorination of aromatic compounds with various
fluorinating agents under various conditions has long
attracted researchers’ attention from the viewpoint of
synthesis of fluoroaromatic products. Direct fluorina-
tion of various aromatic compounds with elemental
fluorine [1] and their oxidative fluorination with higher
metal fluorides (AgF2, CoF3, etc.) [2] were reported.
We previously studies electrochemical fluorination of
some functionalized fatty–aromatic compounds of the
general formula PhXCH3 (X = SO2 [3], CO [4]) and
showed that the process occurs exclusively at the
aromatic ring, the methyl group remaining intact. In
continuation of our studies in this field [3–5], in the
present work we examined electrochemical fluorina-
tion of benzamide (I) and acetanilide (II) in anhydrous
hydrogen fluoride and in acetonitrile with the goal of
extending the series of substrates to compounds having
other functional groups.
formed in small amounts as shown in Scheme 1 with
N,N,N',N'-tetramethylglycine amide as an example [9].
We have found no published data on electrochemical
fluorination of aromatic amides or their derivatives.
Scheme 1.
ECF
Me2NCH2C(O)NMe2
(CF3)2NCF2C(O)F
F
F
O
F
+
(CF3)2NC(O)F
+
(CF3)3N
+
N
CF3
(F3C)2N
F
F
The product mixtures obtained by electrochemical
fluorination of benzamide (I) and acetanilide (II) were
analized by gas chromatography–mass spectrometry
(GC–MS). As with methyl phenyl sulfone [3] and
acetophenone [4], the fluorination of benzamide in
anhydrous hydrogen fluoride occurred exclusively at
the aromatic ring while the carboxamide group
remained unchanged. The major fluorination products
were o- and m- fluorobenzamides III and IV, 2,3-,
3,4-, and 2,5-difluorobenzamides V–VII, and 3,3,6,6-
tetrafluoro-1,4-cyclohexadienecarboxamide (VIII);
also, traces of pentafluoro-1,4-cyclohexadienecarbox-
amide (IX) were detected (Scheme 2). The products
were separated by column chromatography on silica
gel or preparative gas–liquid chromatography, and
Electrochemical fluorination (ECF) of the simplest
amides, such as formamide, acetamide [6, 7], and also
urea and N,N-dimethylurea [8], leads to profound
decomposition of the substrates with formation of
gaseous products: N2, N2O, CO2, NF3, CF4, COF2,
CHF3, C2F6 (the two latter were obtained only from
acetamide and N,N-dimethylurea). Electrochemical
fluorination of aliphatic carboxamides gives products
of complete fluorination of the alkyl groups and
transformation of the amide group into fluorocarbonyl
moiety. Also, α-cleavage and cyclization products are
1070-4280/04/4004-0513 © 2004 MAIK “Nauka/Interperiodica”

SHAINYAN et al.
514
Scheme 2.
CONH2
CONH2
CONH2
CONH2
CONH2
CONH2
F
F
F
ECF
+
+
+
+
F
F
F
F
F
I
III
IV
V
VI
VII
CONH2
CONH2
F
F
F
F
+
+
F
F
F
F
F
VIII
IX
1
their structure was unambiguously proved by H, 13C,
and 19F NMR spectroscopy, as well as by comparison
with published data for known compounds (see
Experimental). According to the 19F NMR spectra,
the molar ratio III:IV:V:VI:VII:VIII was 8:16:10:
6:27:33.
(2JHF = 53.6 Hz) was present in the 19F NMR spectrum.
Difluoroacetic acid was the major product: the doublet
at δF –127.27 ppm was the most intense in the
19F NMR spectrum of the product mixture.
Thus the major product of electrochemical fluorina-
tion of benzamide in acetonitrile is benzonitrile, and
the process is accompanied by transformation of the
solvent into acetamide and further reactions of the
latter. Formalistically, the process can be regarded as
functional group exchange between the amide and
nitrile. This result is very surprising, for no such reac-
tions are known in synthetic organic chemistry. Taking
into account that the electrochemical fluorination was
carried out in anhydrous medium (which was subjected
to preliminary electrolytic treatment to remove traces
of water), the following scheme of transformations
seems to be probable. Oxidation of the substrate at
an anode gives benzamide radical cation which reacts
further along two pathways. The first of these is elec-
trochemical fluorination leading to fluoro-substituted
benzamides and tetrafluorocyclohexadienecarbox-
amide VIII, and the second is reversible dehydration
with formation of benzonitrile radical cation. Electro-
chemical fluorination of the latter yields isomeric
fluorobenzonitriles, while its reduction at a cathode
affords benzonitrile. In acid medium, the solvent
(acetonitrile) is hydrolyzed with water liberated upon
dehydration of benzamide. As a result, acetamide and
acetic acid are formed, and they are then converted
into the respective electrochemical fluorination prod-
ucts (Scheme 3).
A considerably different pattern was observed in
the electrochemical fluorination of benzamide in
acetonitrile solution. GC–MS analysis of the reaction
mixture (after distillation) showed the presence of the
following compounds (in the order of increase in the
retention time; the relative peak intensities are given in
parentheses): FC6H4CN (3), PhCN (56), FC6H4CN (7),
VIII (11), F2C6H3CONH2 (6), FC6H4CONH2 (9),
PhCONH2 (8).
The structure of the resulting fluorobenzonitrile
isomers can be presumed on the basis of their relative
retention time with respect to benzonitrile. Taking into
account that a more polar compound should be charac-
terized by a lower retention time in a nonpolar column,
the isomer leaving the column first (minor) is likely
to be o-fluorobenzonitrile (which is more polar than
benzonitrile); the second isomer whose retention time
is slightly greater than that of benzonitrile, is m-fluoro-
benzonitrile. The calculated [HF/6-31G(d,p)] dipole
moments of benzonitrile and its o-, m-, and p-fluoro
derivatives are, respectively 4.85, 5.69, 4.15, and
3.23 D, in keeping with the above assignment.
Apart from the benzamide transformation products,
those resulting from hydrolysis and fluorination of
acetonitrile were formed: CH3CO2H, CF3CONH2,
CH2FCONH2, CH3CONH2, and CHF2CO2H. Difluoro-
acetic acid was identified by NMR spectroscopy.
In the 13C NMR spectrum we observed signals at
The key stage in the proposed scheme is dehy-
dration of benzamide. Here, it remains unclear why
dehydration of benzamide (which usually requires
heating in the presence of dehydrating agents, such as
P2O5, PCl5, etc.) readily occurs under conditions of
1
δC 106.83 (t, JCF = 247.8 Hz) and 165.48 ppm
2
(t, JCF = 28.2 Hz), and a doublet at δF –127.27 ppm
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ELECTROCHEMICAL FLUORINATION OF BENZAMIDE AND ACETANILIDE
515
Scheme 3.
e–
PhCONH2
PhCONH2
ECF
PhCN
PhCN
–e–
–H2O
ECF
CONH2
CONH2
CN
F
+
Fn
F
F
F
F
H+, H2O
H+, H2O
ECF
MeCN
MeCONH2
ECF
MeCOOH
CHF2COOH
CHF2CONH2
+
CF3CONH2
electrochemical fluorination in acetonitrile and why no
benzonitrile is formed in the absence of a solvent. To
answer the above questions, we performed HF/6-31G
(d,p) quantum-chemical calculations of the molecules
and radical cations involved in the process. The results
showed that the dehydration of benzamide/hydration
of acetonitrile (Scheme 4) is a weakly endothermic
reaction (∆H = 4.2 kJ/mol). On the other hand, an ana-
logous process with participation of the corresponding
radical cations (which are generated by electro-
chemical oxidation; Scheme 5) is exothermic (∆H =
–28.9 kJ/mol). These result allow us to understand the
observed transformations on a qualitative level. The
absence of benzonitrile among the products of electro-
chemical fluorination without a solvent capable of
undergoing hydration is explained as follows. As might
be expected, the process of benzamide dehydration
per se is strongly endothermic (∆H = 90.8 kJ/mol for
benzamide and ∆H = 415.5 kJ/mol for the corre-
sponding radical cation [PhCONH2]+ ·).
of isomeric trifluoromethyl-substituted benzonitriles
with formation of 10–20% of perfluoro(dimethylcyclo-
hexanes).
The possibility of using acetonitrile as solvent in
electrochemical fluorination of aromatic compounds
is determined by the fact that its anode oxidation
potential is higher than those of the substrates [11].
However, it should be taken into account that at high
potentials in the absence of more readily oxidizable
substrates acetonitrile is also capable of undergoing
fluorination to give gaseous products: CF3CN,
C2F5NF2, C2F6, and NF3 [12].
We also examined electrochemical fluorination of
acetanilide with a view to compare the effects of amide
groups attached to benzene ring through the carbon
[PhC(O)NH2] and nitrogen atoms [MeC(O)NHPh].
The reaction in anhydrous hydrogen fluoride was
accompanied by almost complete tarring, so that we
failed to isolate and identify any individual product.
By contrast, the fluorination of acetanilide in aceto-
nitrile was highly selective, and m-fluoroacetanilide
(X) was formed almost exclusively. The substrate
We observed no transformation of the cyano group
in benzonitrile into trifluoromethyl, though Yonekura
et al. [10] reported on electrochemical fluorination
Scheme 6.
NHAc
NHAc
NHAc
Scheme 4.
ECF
PhCONH2
+
MeCN
PhCN
+
MeCONH2
+
F
F
Scheme 5.
F
PhCONH2
+ MeCN
PhCN
+ MeCONH2
II
X
XI
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SHAINYAN et al.
516
conversion in 18 h (current 1.1 A) was 40%. GC–MS
analysis of the reaction mixture revealed traces of
a difluoro derivative [presumably, N-(3,4-difluoro-
phenyl)acetamide (XI)], products of hydrolysis of
acetonitrile (acetamide, acetic acid), and fluorination
products of the latter (Scheme 6). No oxidative
fluorination product, N-(3,3,6,6-tetrafluoro-1,4-cyclo-
hexadienyl)acetamide, was detected.
using gradient elution with hexane–diethyl ether (3:2),
diethyl ether, diethyl ether–methanol (16:1), and
methanol. We thus isolated pure product VIII and
fractions enriched in mono- or difluorinated products.
1
These fractions were analyzed by H, 13C, and 19F
NMR spectroscopy and by gas chromatography–mass
spectrometry.
b. A cooled electrolytic cell was charged with 100 g
of anhydrous hydrogen fluoride, 10 g of benzamide,
and 30 ml of anhydrous acetonitrile. The electrolysis
was performed at an anode current density of
1.75 A/dm2; voltage 6.0–6.8 V; temperature ~5°C.
After 35 h (39 A h), the conversion was 68%. The cell
was discharged into an evaporator, excess hydrogen
fluoride was removed, the residue was diluted with
diethyl ether, NaF was added to bind residual HF until
neutral pH, the solution was dried over MgSO4, the
solvent was distilled off, and the residue was subjected
to fractional distillation under reduced pressure. Frac-
tions boiling below 60°C and in the temperature range
EXPERIMENTAL
The 1H, 13C, and 19F NMR spectra were recorded on
a Bruker DPX-400 spectrometer at 400, 100, and
376 MHz, respectively; CDCl3 was used as solvent,
1
13
and HMDS, as internal reference (for H and C); the
chemical shifts are given relative to TMS (1H, 13C) and
CCl3F (19F). GC–MS analysis was performed on a
Hewlett–Packard HP 5971A mass-selective detector
(70 eV) coupled with an HP 5890 gas chromatograph;
Ultra-2 column (5% of phenylmethylsilicone), injector
temperature 250°C, oven temperature programming
from 70 to 280°C at 20 deg/min. GLC analysis was
performed on an LKhM-8MD chromatograph using
2000×3-mm columns packed with 15% of polyphenyl-
methylsiloxane on Chromaton N-AW; thermal con-
ductivity detector; carrier gas helium. A PAKhV-07
instrument was used for preparative gas–liquid chrom-
atography; column 5000×8 mm, stationary phase
5% of XE-60 on Chromaton N-AW DMCS.
1
60–100°C (1 mm) were collected and analyzed by H,
13C, and 19F NMR spectroscopy and by GC–MS.
1
3-Fluorobenzamide (IV). H NMR spectrum:
δ 6.1–7.5 ppm, m. 13C NMR spectrum, δC, ppm:
2
2
114.36 d (C2, JCF = 22.8 Hz), 118.50 d (C4, JCF
=
20.7 Hz), 122.87 s (C6), 129.90 d (C5, JCF = 7.3 Hz),
135.29 s (C1), 162.25 d (C3, 1JCF = 247.4 Hz), 170.80 s
(CONH2); published data [13] (DMSO-d6), δC, ppm:
114.52, 119.04, 123.87, 130.88, 134.27, 161.83, and
164.51 for C2, C4, C6, C5, C1, C3, and CONH2, re-
spectively. 19F NMR spectrum: δF –112.13 ppm. Mass
spectrum, m/z, (Irel, %): 139 (62) [M]+, 123 (100)
[M – NH2]+, 95 (52) [M – CONH2]+, 75 (25) [95 – HF]+,
44 (28) [CONH2]+.
3
Electrochemical fluorination was carried out in
a 130-cm3 stainless steel electrolyzer equipped with
nickel electrodes (overall surface area 63 cm2), valves
for supplying hydrogen fluoride and product discharge,
and a reflux condenser filled with a 1:1 acetone–di-
ethyl ether mixture which was cooled to –30°C using
liquid nitrogen.
1
2,5-Difluorobenzamide (VII). H NMR spectrum:
δ 6.1–7.5 ppm, m. 13C NMR spectrum, δC, ppm:
Electrochemical fluorination of benzamide.
a. A cooled electrolytic cell was charged with 120 g of
anhydrous hydrogen fluoride and 5.1 g of benzamide.
The electrolysis was carried out over a period of 19 h
(21 A h; anode current density 1.75 A/dm2, voltage
6.5–7.0 V, temperature ~5°C. When the reaction was
complete, the cell was discharged into an evaporator,
excess hydrogen fluoride was removed, the residue
was diluted with diethyl ether, NaF was added to bind
residual HF until neutral pH, the solution was dried
over MgSO4, and the solvent was distilled off. The
resulting mixture containing unreacted benzamide and
fluorination products (4.8 g) was separated into
fractions by preparative GLC, and each fraction was
then subjected to column chromatography on silica gel
117.46 d.d (C3, JCF = 28.4, JCF = 5.2 Hz), 120.27 d.d
2
3
(C4, JCF = 22.8, JCF = 7.3 Hz), 121.82 (C1), 124.43 d
2
3
(C6, JCF = 20.3 Hz), 156.62 d (C2, JCF = 244.8 Hz),
2
1
158.49 d (C5, JCF = 244.0 Hz), 164.52 (CONH2).
1
19F NMR spectrum, δF, ppm: –117.38 (2-F), –118.71
(5-F). Mass spectrum, m/z, (Irel, %): 157 (76) [M]+, 141
(100) [M – NH2]+, 113 (50) [M – CONH2]+, 63 (23)
[C5H3]+, 44 (34) [CONH2] +.
3,3,6,6-Tetrafluoro-1,4-cyclohexadienecarbox-
1
amide (VIII). mp 84–85°C. H NMR spectrum, δ,
3
3
ppm: 6.28 d.t (5-H, JHH = 10.3, JHF = 5.3 Hz),
4
3
6.34 d.d (2-H, JHH = 2.6, JH4F = 4.2 Hz), 6.35 d.d.t
3
3
(4-H, JHH = 10.3, JHF = 4.2, JHH = 2.6 Hz), 7.17 m
(2H, NH2). 13C NMR spectrum, δC, ppm: 109.79 t.d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 4 2004

ELECTROCHEMICAL FLUORINATION OF BENZAMIDE AND ACETANILIDE
517
(C6, JCF = 227.4, JCH = 9.8 Hz), 110.62 t.d (C3, JCF
=
3. Shainyan, B.A., Danilevich, Yu.S., Bel’skii, V.K.,
Stash, A.I., Grigor’eva, A.A., and Chuvashev, Yu.A.,
Russ. J. Org. Chem., 2002, vol. 38, p. 1462.
4. Shainyan, B.A., Danilevich, Yu.S., Grigor’eva, A.A.,
and Chuvashev, Yu.A., Russ. J. Org. Chem., 2003,
vol. 39, p. 1581.
5. Grigor’eva, A.A., Shainyan, B.A., Kaurova, G.I., Gra-
cheva, E.I., Lesnevskaya, N.B., and Barabanov, V.G.,
Zh. Prikl. Khim., 2002, vol. 75, p. 1112.
6. Tasaka, A., Sakaguchi, H., and Aki, R., J. Fluorine
Chem., 1982, vol. 21, p. 51.
7. Tasaka, A., Sakaguchi, H., Aki, R., Ihara, H., Saka, K.,
and Yamamoto, T., J. Fluorine Chem., 1985, vol. 27,
p. 23.
8. Chang, B., Watanabe, N., and Nakanishi, K., Electro-
chim. Acta, 1972, vol. 17, p. 1317.
228.5, JCH = 9.6 Hz), 128.84 d.t.t (C5, JCH = 173.6,
3
2JCF = 31.3, JCF = 9.1 Hz), 129.15 d.t.t (C4, JCH
=
2
3
173.8, JCF = 30.5, JCF = 9.4 Hz), 134.81 d.t.t (C2,
J
CH = 173.6, 2JCF = 31.6, 3JCF = 6.7 Hz), 133.59 t.t (C1,
2JCF = 27.5, 3JCF = 9.0 Hz), 161.91 (CONH2). 19F NMR
spectrum, δF, ppm: –95.59 m (3-F), –95.26 m (5-F).
Mass spectrum, m/z (Irel, %): 195 (67) [M]+, 179 (18)
[M – NH2]+, 159 (45) [179 – HF]+, 151 (18) [M –
CONH2]+, 132 (70) [C6H3F3]+, 113 (10) [C6H3F2]+, 101
(34) [C5H3F2]+, 81 (13) [C5H2F]+, 75 (18) [C3HF2]+, 63
(21) [C5H3]+, 44 (100) [CONH2]+. Found, %: C 43.20;
H 2.82; F 39.58; N 7.08. C7H5F4NO. Calculated, %:
C 43.09; H 2.58; F 38.95; N 7.18.
Pentafluoro-1,4-cyclohexadienecarboxamide
(IX). Mass spectrum, m/z (Irel, %): 213 (43), [M]+, 197
(11) [M – NH2]+, 177 (9), [M – HF]+, 169 (28) [M –
CONH2]+, 150 (33) [169 – F]+, 119 (55) [C5H2F3]+, 81
(20) [C5H2F]+, 75 (13) [C3HF2]+, 44 (100) [CONH2]+.
9. Young, A.G. and Dresdner, R.D., J. Am. Chem. Soc.,
1958, vol. 80, p. 1889.
10. Yonekura, M., Nagase, S., Baba, H., Kodaira, K., and
Takashi, A., Bull. Chem. Soc. Jpn., 1976, vol. 49,
p. 1113.
11. Rozhkov, I.N., Bukhtiarov, A.V., and Knunyants, I.L.,
Izv. Akad. Nauk SSSR. Ser. Khim., 1972, p. 1130.
12. Haruta, M. and Watanabe, N., J. Fluorine Chem., 1976,
Electrochemical fluorination of acetanilide (II) in
acetonitrile was performed as described above using
100 ml of hydrogen fluoride, 10 g of acetanilide, and
30 ml of acetonitrile; time 18 h (20 A h), voltage 6.0–
6.5 V, current density 1.75 A/dm2). The substrate
conversion was ~40%. After appropriate treatment, the
reaction mixture was distilled at 80–110°C (1 mm) and
analyzed by NMR and GC–MS.
vol. 7, p. 159.
13. De Rosa, M., Brown, K., McCoy, M., Ong, K., and
Sanford, K., J. Chem. Soc., Perkin Trans. 2, 1993,
p. 1787.
14. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scu-
seria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzew-
ski, V.G., Montgomery, J.A., Jr., Stratmann, R.E.,
Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D.,
Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J.,
Barone, V., Cossi, M., Cammi, R., Mennucci, B.,
Pomelli, C., Adamo, C., Clifford, S., Ochterski, J.,
Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K.,
Malick, D.K., Rabuck, A.D., Raghavachari, K., Fores-
man, J.B., Cioslowski, J., Ortiz, J.V., Stefanov, B.B.,
Liu, G., Liashenko, A., Piskorz, P., Komaromi, I.,
Gomperts, R., Martin, R.L., Fox, D.J., Keith, T.,
Al–Laham, M.A., Peng, C.Y., Nanayakkara, A., Gon-
zalez, C., Challacombe, M., Gill, P.M.W., Johnson, B.,
Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C.,
Head–Gordon, M., Replogle, E.S., and Pople, J.A.,
Gaussian 98. Revision A.6, Pittsburgh: Gaussian, 1998.
3-Fluoroacetanilide (X). Mass spectrum, m/z
(Irel, %): 153 (15) [M]+, 111 (100) [M – CH2CO]+, 43
(28) [COCH3]+.
Quantum-chemical calculations were performed
with the aid of Gaussian 98 software [14] which was
kindly provided by V.A. Lopyrev. The authors are
grateful to N.A. Kalinina for performing product
separation by preparative gas–liquid chromatography.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 4 2004