Synthesis and reactivity of difluoroaromatic compounds containing heterocyclic central groups

Article abstract of DOI:10.1023/B:RUGC.0000016002.83302.af

The reaction of trichloroacetaldehyde with fluorobenzene, followed by a series of transformations, gave 4-fluorobenzil and 4,4′-difluorobenzil which were used in the synthesis of new difluoroaromatic compounds with a heterocyclic central group. The ¹H, ¹³C, and ¹⁹F NMR spectra of the newly synthesized difluoroaromatic compounds were studied. The charge densities on the carbon atoms attached to fluorine were calculated in terms of the PM3 and AM1 semiempirical approximations. A correlation was found between the charge on C(F) and the corresponding ¹³C and ¹⁹F chemical shifts. Using this correlation, the reactivity of difluoroaromatic compounds in nucleophilic substitution reactions was estimated.

Full text of DOI:10.1023/B:RUGC.0000016002.83302.af

Russian Journal of General Chemistry, Vol. 73, No. 9, 2003, pp. 1476 1480. Translated from Zhurnal Obshchei Khimii, Vol. 73, No. 9, 2003,
pp. 1562 1566.
Original Russian Text Copyright
2003 by Keshtov, Keshtova, Begretov, Tkhakakhov.
Synthesis and Reactivity of Difluoroaromatic Compounds
Containing Heterocyclic Central Groups
M. L. Keshtov, C. V. Keshtova, M. M. Begretov, and R. B. Tkhakakhov
Berbekov Kabardino-Balkar State Universitety, Nal’chik, Kabardino-Balkaria, Russia
Lomonosov Moscow State University, Moscow, Russia
Received November 5, 2001
Abstract The reaction of trichloroacetaldehyde with fluorobenzene, followed by a series of transforma-
tions, gave 4-fluorobenzil and 4,4 -difluorobenzil which were used in the synthesis of new difluoroaromatic
1
compounds with a heterocyclic central group. The H, 13C, and 19F NMR spectra of the newly synthesized
difluoroaromatic compounds were studied. The charge densities on the carbon atoms attached to fluorine were
calculated in terms of the PM3 and AM1 semiempirical approximations. A correlation was found between
the charge on C(F) and the corresponding 13C and 19F chemical shifts. Using this correlation, the reactivity
of difluoroaromatic compounds in nucleophilic substitution reactions was estimated.
Difluoroaromatic compounds having electron-with- trichloro-2,2-bis(p-fluorophenyl)ethane, into 4-fluoro-
drawing groups (such as CO, SO2, etc.) attract much
interest as monomers for the synthesis of aromatic
polyethers [1 4]. In the recent years, considerable
attention was given to compounds containing other,
specifically heterocyclic activating groups [5]. On the
other hand, the electronic structure of difluoroaromatic
compounds and the effect of the central fragment on
the electron density distribution in their molecules
have been studied insufficiently.
diphenylacetylene and 4,4 -difluorodiphenylacetylene
[9], respectively. The latter were then oxidized [10]
to 4-fluorobenzil and 4,4 -difluorobenzyl.
The structure of the products was confirmed by
elemental analyses and NMR and IR spectra (Tables 1
and 2). By analogy with [11], we tried to estimate the
reactivity of the newly synthesized difluoroaromatic
compounds. For this purpose, we performed PM3 and
AM1 quantum-chemical calculations of the charge
densities qC F on the C(F) carbon atoms which are
reaction centers in nucleophilic substitution. We also
measured the chemical shifts of the carbon and
fluorine atoms in the 13C and 19F NMR spectra.
In the present work we used semiempirical
quantum-chemical methods and NMR spectroscopy
to examine the effect of central heterocyclic fragments
on the electron density distribution in difluoro-
aromatic compounds. Insofar as the reaction center in
such compounds is usually the aromatic carbon atom
linked to fluorine (C4 F), our attention was mainly
focused on the variation of electron density on the
C4 F bond.
The results (Table 3) show that electron-withdraw-
ing substituents act to reduce the electron density on
the fluorine atom and carbon atom attached thereto.
As the electron-acceptor power of the substituent
increases, the reactivity toward nucleophiles increases.
The observed increase of the charge density on C4(F)
is consistent with that expected on the basis of
general concepts of the substituent effect in aromatic
compounds [12]. A satisfactory correlation is observed
between the charges on the carbon and respective
fluorine atoms (Table 3).
By analogy to the synthesis of bromoaromatic
compounds [6], one of the simplest synthetic routes to
compounds possessing quinoxaline-2,3-diyl, 2,3-di-
cyanopyrazine-5,6-diyl, and 2-arylimidazole-4,5-diyl
fragments as central moieties seems to include prepara-
tion and subsequent transformations of 4-fluorobenzil
and 4,4 -difluorobenzyl [7] (Scheme 1). 4-Fluoro-
benzil was synthesized by reaction of trichloroacet-
aldehyde with fluorobenzene and benzene, and 4,4 -di-
fluorobenzil was obtained by reaction of trichloroacet-
aldehyde with 2 equiv of fluorobenzene [8] and sub-
sequent transformations of the products, 1,1,1-tri-
chloro-2-(4-fluorophenyl)-2-phenylethane and 1,1,1-
The tendency in the variation of electron density
on the aromatic C4(F) atom, predicted by the calcula-
tions, is supported by the 13C and 19F NMR data.
The 13C F resonances in the spectra of I VII linearly
1070-3632/03/7309-1476$25.00 2003 MAIK Nauka/Interperiodica

SYNTHESIS AND REACTIVITY OF DIFLUOROAROMATIC COMPOUNDS
1477
Scheme 1.
N
N
N
N
CH2
F
F
VII
HN
N
NH
N
NH
F
F
F
F
F
F
O O
N
V
VI
Zn
F
F
CH
n = 1
n = 2
CHO
CCl3
F
+ n
CCl3
F
CH
CCl3
Zn
F
F
KMnO4
F
F
F
F
F
F
N
O
O
N
R
N
N
I
CN
CN
II
IIIa IIId
F
F
N
NH
R1
R3
R2
IVa, IVb
N
III, R = H (a), CH3 (b), Br (c), COOH (d); IV, R1 = R3 = H, R2 = Br (a); R1 = R3 = OCH3, R2 = H (b).
shift downfield as the charge density on C4 increases
(Table 3). An analogous pattern is typical of the 19F
NMR spectra of these compounds. A satisfactory
correlation exists between the 13C and 19F chemical
shifts and calculated charge densities on C4 (Table 3).
Both calculation methods predict similar trends in
the variation of electron density on the carbon atom
attached to fluorine.
Comparison of the 13C and 19F chemical shifts of
difluoroaromatic compounds with those found for
typical activated monomers, such as difluorobenzil
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 9 2003

1478
KESHTOV et al.
Table 1. Yields, melting points, and elemental analyses of difluoroaromatic compounds I VII
Found, %
Calculated, %
Comp. Yield,
mp,
C
Formula
no.
%
C
H
F
N
S
N
F
N
I
II
70
50
97
91
89
95
86
81
87
83
90
121 123
254 256
134 136
159 161
168 170
261 263
266 268
225 227
192 194
> 400b
68.31
67.81
75.38
75.39
66.23
69.35
61.09
70.11
75.49
78.44
80.49
3.35
2.48
3.81
4.21
3.15
3.23
3.09
4.63
4.21
4.42
4.41
15.69 11.21 C14H8F2O2
11.63 17.25 C18H8F2N4
68.29
67.93
75.46
75.89
66.11
69.61
61.33
70.40
75.89
78.52
80.37
3.24
2.53
3.79
4.24
3.05
3.33
3.18
4.62
4.24
4.39
4.27
15.43 11.37
11.94 17.60
11.93 8.79
11.43 8.42
10.45 11.56
10.48 7.73
9.24 6.81
9.68 7.13
11.43 8.42
6.90 10.17
6.20 9.14
IIIa
IIIb
IIIc
IIId
IVa
IVb
V
12.05
11.40
8.61 C20H12F2N2
8.19 C21H14F2N2
11.21 11.32 C20H11F2N3O2
10.69
7.42 C21H12F2N2O2
a
9.14
9.75
11.35
6.75 C21H13BrF2N2
7.21 C23H18F2N2O2
8.35 C21H14F2N2
VI
VII
6.81 10.05 C36H24F2N4
6.35 9.01 C41H26F2N4
213 215
a
b
Found Br, %: 19.09. Calculated Br, %: 19.42.
Decomposes without melting.
Table 2. NMR spectral parameters of compounds II VII
Chemical shifts , ppm (CDCl3)
13C
Comp.
no.
1H
19F
II
7.59 7.55 m (2H), 7.30 7.26 m 164.54 (Ar F), 162.06 (Ar F), 15378, 132.18, 132.09, 131.82,
(2H) 129.78, 115.87, 115.65, 113.86
108.38
IIIb 8.03 8.00 d (1H, J 84 Hz), 7.91 s 164.24 (C F), 164.19 (C F), 161.76 (C F), 161.72 (C F), 151.85, 111.79
(2H), 7.60 7.58 d (2H, J 8.8 Hz), 151.10, 141.10, 140.64, 139.52, 135.00, 134.97, 132.39, 131.65,
7.49 7.45 m (4H), 7.05 7.00 m 131.62, 131.56, 125.54, 128.48, 127.79, 115.40, 115.19, 21.75
(4H), 2.59 s (3H, CH3)
(CH3)
IIIc 9.00 s (1H), 8.51 8.49 d (1H), 164.91 (C F), 164.83 (C F), 162.41 (C F), 162.33 (C F), 154.81, 109.61,
8.26 8.24 d (1H), 7.59 7.54 m 154.21, 147.91, 143.33, 139.78, 133.97, 133.94, 133.91, 133.87, 109.89
(4H), 7.11 7.06 m (4H)
131.91, 131.82, 131.80, 131.71, 130.57, 125.35, 123.31, 115.74,
115.52
IIId 8.59 s (1H), 8.28 d (1H), 8.18
166.67 (C=O), 164.44 (C F), 164.39 (C F), 161.94 (C F), 161.69 111.03,
8.15 d (1H), 7.54 7.51 m (4H), (C F), 153.81, 153.18, 142.37, 139.75, 134.82, 132.28, 132.22, 111.213
7.25 7.21 m (4H) 132.14, 130.76, 129.69, 129.31, 115.43, 115.21
IVa 12.77 s (1H, NH), 7.96 7.94 d 163.16 (C F), 160.62 (C F), 150.50, 150.12, 137.12, 135.81,
114.39,
112.48
(2H), 7.64 7.62 d (2H), 7.49
7.45 m (4H), 7.22 7.11 m (4H)
135.09, 134.56, 132.64, 127.06, 120.77
IVb 12.42 s (1H, NH), 7.56 7.41 m 163.11 (C F), 160.67(C F), 150.91, 137.26, 135.29, 120.92, 112.67,
(4H), 7.22 s (2H), 7.21 7.09 m 120.71, 108.74, 106.24, 60.80, 35.98
(4H), 6.49 s (1H), 3.88 s (6H, CH3)
114.31
V
12.66 s (1H, NH), 8.14 7.13 m 163.40 (C F), 162.26 (C F), 160.91 (C F), 159.70 (C F), 144.70 112.49,
(13N) (4), 136.12, 134.95, 131.59, 130.90, 130.46, 128.88, 128.81, 113.00,
128.61, 128.34, 128.13, 127,74, 127.35, 127.26, 127.03, 126.96, 115.02
126.48, 115.62, 115.41, 115.03, 114.82, 35.40
VI
12.79 s (2H, NH), 8.25 7.06 m 163.51 (C F), 160.25 (C F), 145.11, 131.41, 130.62, 130.12,
113.06
(26H)
128.68, 128.42, 128.22, 128.05, 127.53, 127.42, 127.15, 127.03,
126.85, 126.23, 115.42, 115.22, 35.86
VII 8.12 8.08 m (2H), 8.04 8.02 m 164.24 (C F), 161.76 (C F), 153.36, 152.89, 152.36, 151.91,
(2H), 7.69 7.66 m (2H), 7.51 7.48 142.35, 142.33, 141.19, 141.14, 140.05, 139.99, 139.78, 134.95,
m (8H), 7.34 7.31 m (6H), 7.03 134.92, 131.69, 131.61, 129.60, 129.35, 129.25, 128.79, 128.76,
6.97 m (4H), 4.47 s (2H, CH2) 128.46, 128.36, 128.27, 128,25, 115.33, 115.11, 42.08 (CH2)
112.08
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 9 2003

SYNTHESIS AND REACTIVITY OF DIFLUOROAROMATIC COMPOUNDS
1479
and difluorobenzophenone, and nonactivated fluoro-
benzene provides information on their reactivity and
makes it possible to estimate the relative reactivity
in the series of quinoxalines IIIa IIId. The 19F che-
mical shifts for the more reactive monomer, 2,3-bis-
(4-fluorophenyl)-6-nitroquinoxaline (IIIc), are
109.61 and 109.89 ppm (two different resonanceFs
appear since the molecule is unsymmetrical). The less
reactive 2,3-bis(4-fluorophenyl)quinoxaline (IIIa) is
Table 3. 13C and 19F chemical shifts and charge densities
qC F on the C4(F) atoms in compounds I VII
Chemical shifts
qC F
Comp.
no.
, ppm
19F
13C
PM3
AM1
I
II
IIIa
IIIb
101.440
108.380
111.950
111.791
112.000
109.609
109.890
111.030
111.213
112.476
114.393
112.668
114.309
112.493
113.000
113.06
166.700
163.460
163.090
162.995
162.955
163.659
163.576
163.214
163.163
161.910
161.889
161.890
160.780
162.154
160.982
161.880
163.002
0.103
0.085
0.074
0.073
0.072
0.081
0.080
0.077
0.077
0.071
0.065
0.069
0.064
0.071
0.068
0.065
0.130764
0.112495
0.102290
0.103308
0.102050
0.109814
0.108328
0.106334
0.105043
0.099024
0.092427
0.097683
0.091039
0.100559
0.090139
0.090081
characterized by a
value of 111.95 ppm. The 19F
F
chemical shift of 2,3-dicyano-5,6-bis(4-fluorophenyl)-
pyrazine (II) is equal to 108.38 ppm. In keeping with
our previous data [11], difluoroaromatic compounds
with
larger than 110 ppm are activated to nucleo-
IIIc
IIId
IVa
IVb
V
F
philic substitution to a sufficient extent. This means
that compounds IIIc and II are sufficiently reactive
to obtain polymers therefrom. When
ranges from
F
110 to 112 ppm, more severe conditions are neces-
sary to effect polymerization. The chemical shifts
F
of compounds IIIa, IIIb, IIId, and VII, which are
activated due to the presence of quinoxaline fragment,
indicate that these compounds can be involved in
nucleophilic aromatic substitution, in keeping with
the data of [13]. Difluoroaromatic compounds with
values equal to or lower than 112.77 ppm (fluoro-
bFenzene) do not undergo polymerization. Actually,
our attempts to obtain polymeric products from imid-
azole derivatives IVa, IVb, V, and VI were unsuc-
cessful. Presumably, the imidazole ring is a stronger
electron donor than benzene.
VI
VII
112.077
0.0718 0.0995
2,3-Dicyano-5,6-bis(4-fluorophenyl)pyrazine (II).
A mixture of 0.85 g of diaminomaleonitrile, 1.64 g of
4,4 -difluorobenzil, 10 ml of acetic acid, and 50 ml of
butyl acetate was heated for 1 h under reflux with
stirring. The solvent was distilled off, and the residue
was recrystallized from ethyl alcohol to obtain 1.06 g
(50%) of compound II as bright yellow crystals with
mp 254 256 C.
The 13C chemical shifts of difluoroaromatic com-
pounds (difluorobenzophenone, difluorobenzil) which
successfully react with nucleophiles, range from
C
164.5 to 166.7 ppm, whereas nonactivated fluoroben-
zene is characterized by a
value of 162.29 ppm
C
2,3-Bis(4-fluorophenyl)quinoxaline.
A
flask
[13]. The chemical shifts of C(F) for compounds II,
IIIa IIId, and VII having pyrazine and quinoxaline
central fragments appear in the region of 163 ppm,
and they are capable of undergoing nucleophilic sub-
stitution [13]. Compounds IVa, IVb, V, and VI are
equipped with a gas-inlet tube (for argon supply) was
charged with 3.18 g of compound I, 1.08 g of
o-phenylenediamine, 45 ml of chloroform, and 5 ml
of methanol. The mixture was left to stand for 24 h
at room temperature under argon, and the solvent
was distilled off on a rotary evaporator. The residue
was recrystallized from ethyl alcohol to obtain 3.05 g
(98%) of compound IIIa as colorless crystals with
mp 134 136 C. Compounds IIIb IIId and VII were
synthesized in a similar way. Their yields, melting
points, and analytical and spectral data are given in
Tables 1 and 2.
characterized by
values lower than 162.29 ppm;
C
therefore, they are inactive in nucleophilic substitution
reactions (Table 3).
EXPERIMENTAL
The initial compounds and solvents were purified
by known methods. The 1H (400 MHz), 13C
(100.61 MHz), and 19F (188.3 MHz) NMR spectra of
2-(4-Bromophenyl)-4,5-bis(4-fluorophenyl)imid-
azole (IVa). A mixture of 1.23 g of 4,4 -difluoro-
benzil, 0.925 g of 4-bromobenzaldehyde, 2.69 g of
ammonium acetate, and 50 ml of acetic acid was
heated for 7 h under reflux with stirring. The mixture
was then cooled and poured into water. The precip-
solutions in CDCl3 (c
0.4 M) were recorded on
Bruker AMX-400 and Bruker AC-200 spectrometers,
respectively. Semiempirical quantum-chemical cal-
culations were performed using the PM3 and AM1
methods with full geometry optimization.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 9 2003

1480
KESHTOV et al.
itate was filtered off, thoroughly washed with water,
and dried for 10 h at 100 C under reduced pressure.
Yield 1.79 g (87%), colorless crystals, mp 266
268 C. Compounds IVb, V, and VI were synthesized
in a similar way. Their yields, melting points, and
analytical and spectral data are given in Tables 1
and 2.
3. Mullins, M.J. and Woo, E.P., J. Macromol. Sci. Rev.,
1987, vol. 27, p. 313.
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p. 810.
ACKNOWLEDGMENTS
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This study was financially supported by the
Ministry of Education of the Russian Federation
(Nauchnye issledovaniya vysshei shkoly po prioritet-
nym napravleniyam nauki i tekhniki Higher School
Research in the Priority Fields of Science
and Technics Scientific and Technical Program
and Khimiya i khimicheskie produkty Chemistry
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vol. 27, p. 654.
and Chemical Products
no. 203.02.06.018).
Subprogram; project
11. Rusanov, A.L., Keshtov, M.L., and Keshtova, S.V.,
Izv. Ross. Akad. Nauk, Ser. Khim., 1998, no. 4,
p. 623.
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