Study of ultrasound promoted aromatic nucleophilic substitution of halobenzenes with amines

Article abstract of DOI:10.1007/s00706-002-0505-8

The sonochemical nucleophilic aromatic substitution of substituted haloarenes with different amines were studied. The reaction course was found to be strongly depended on basicity, bulkiness, and boiling point of amines as well as on the electron-withdrawing property of the substituents.

Full text of DOI:10.1007/s00706-002-0505-8

Monatshefte f €u r Chemie 134, 37–43 (2003)
DOI 10.1007/s00706-002-0505-8
Study of Ultrasound Promoted Aromatic
Nucleophilic Substitution of Halobenzenes
with Amines
1
ˇ
M a´ ria Me cˇ iarov a´ , Stefan Toma , Jana Podlesn a´ ,
1;ꢀ
1
1
2
Michal Kiripolsk y´ , and Ivana C ´ı sa rˇ ov a´
1
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University,
SK-842 15 Bratislava, Slovak Republic
2
Department of Inorganic Chemistry, Charles University, CZ-128 40 Praque 2, Czech Republic
Received May 6, 2002; accepted (revised) May 29, 2002
Published online September 19, 2002 # Springer-Verlag 2003
Summary. The sonochemical nucleophilic aromatic substitution of substituted haloarenes with differ-
ent amines were studied. The reaction course was found to be strongly depended on basicity, bulkiness,
and boiling point of amines as well as on the electron-withdrawing property of the substituents.
Keywords. Nucleophilic aromatic substitution; Ultrasonic irradiation.
Introduction
Nucleophilic aromatic substitution of haloarenes with amines are generally difficult
to achieve and are limited to fluorides having a strongly electron-withdrawing
group, such as a nitro group at the para position. Thus, Ibata et al. [1] have
described aromatic nucleophilic substitutions of nitrohalobenzenes with different
amines. The yields range from moderate to excellent, but the reactions had to be
ꢁ
carried out under high pressure (0.6–1.2 GPa) at 50–80 C, for 20–50 h, and five
molar equivalents of amine were necessary. 4-Haloarylketones have underwent
facile nucleophilic displacement in polar aprotic solvents (DMSO, DMF) with
aliphatic and alicyclic amines using potassium carbonate as the base [2, 3]. Yields
ꢁ
of the products have been 20–95% and the reactions were carried out at 95 C for
6
h [2]. Bavetsian and Henderson [4] have investigated the synthesis of N-substi-
tuted derivatives of t-butyl 4-aminobenzoate via a palladium catalyzed reaction.
ꢁ
t
These reactions have been carried out in toluene at 100 C, with NaO Bu as the
base and PdCl =P(o-tolyl) as the catalyst. A non-conventional procedure for
2
3
nucleophilic aromatic substitution with cyclic amines has been described recently
ꢀ Corresponding author. E-mail: toma@fns.uniba.sk

3
8
M. Me ꢀc iarov a´ et al.
[
5]. Different chloroaromatic compounds have underwent nuclephilic substitutions
with secondary aliphatic cyclic amines without solvent under microwave irradia-
tion. Reaction times have been 1–2 min with yields higher than 90%. Prim and
Kirsch [6] have reported a convenient preparation of 5-N,N-disubstituted-
aminothiophene-2-carboxaldehydes by S Ar reactions in water from the corre-
N
sponding bromo derivatives. Yields of 80–90% have been achieved with reaction
times of 12–24 h and 3 equivalents of amine.
The main aim of this work was to study the ultrasound effect on nucleophilic
substitutions of different haloarenes with amines. The second aim was to examine
the structure effects of haloarenes as well as amines on their reactivity and there-
fore to study all these reactions under the same conditions.
Results and Discussion
Acoustic energy is a mechanical vibration with frequencies many orders of mag-
nitude below those of molecular vibrations. It is clear therefore, that ultrasonic
irradiation cannot be directly absorbed by molecules. The indirect mechanism of
activation of sonochemical transformation is known as acoustic cavitation [7].
During the compression phase, the cavities can collapse violently in a very short
ꢂ 6
time (10 sec). Under these adiabatic conditions, their contents reach high tem-
peratures (5000 K) and pressures (hundreds of MPa) [8]. Similar effects of high
pressures and ultrasonic irradiation on chemical reactions are well known from
literature [9–12]. Our results with 4-nitrohalobenzenes (Table 1) are in accordance
with the theory of the effects of ultrasonic cavitation as well as with the experi-
mental results described before. As follows from Table 1, application of ultrasonic
irradiation allows to perform the reactions under normal pressure, for a shorter
time, and the results are similar to those obtained under extreme conditions. We
assume that ultrasonic acceleration in these reactions is caused by very powerful
micro-streaming, which accompanies implosions of micro-bubbles and provides
effective mass transfer. Potassium carbonate particles are disrupted and its active
surface is therefore considerably enlarged which means that the catalytic activity of
potassium carbonate is also enhanced [13]. Application of ultrasonic irradiation has
also another positive effect. It enables to improve the atom economy of S Ar
N
reactions. All reactions described in this work were performed with an equimolar
amount of amine. Unlike the methods described in Refs. [1, 2, 14], no molar excess
of amine was necessary.
These S Ar reactions proceed through the Meisenheimer type intermediate and
N
the difference in reactivity of amines is attributed both to their basicity and bulki-
ness [1]. Cyclic secondary amine (piperidine, 2a) was found to be the most reactive
among the amines used in this work (Scheme 1, Table 1). On the contrary, the low
reactivity of secondary acyclic amines was due to their bulkiness as well as to their
low boiling point. Diethylamine (2d) gave at 15 min of sonochemical reaction 9%
of 3d. Prolonging the reaction time to 30 min did not increase the yield (Table 1,
ꢁ
Entries 14, 15). This is probably due to its low boiling point (55 C) because amine
ꢁ
could evaporate from the reaction mixture at a temperature at about 140–150 .
ꢁ
Boiling points of diisobutylamine (2e) (137–139 C) as well as dibenzylamine (2f)
ꢁ
(
300 C) are higher, but their bulkiness lowered the reactivity. Bulkiness as well as

Ultrasound Promoted S Ar Reactions
N
39
Table 1. Results of S Ar reactions of 4-halonitrobenzenes 1 with amines 2
N
1
HNR R
2
1
X
Time
min
Method
Product
Yield
%
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a
1a
1b
1b
1c
1d
1d
1a
1b
1c
1d
1d
1a
1a
1a
1b
1c
1d
1a
1a
piperidine (2a)
F
15
15
15
15
15
15
15
15
15
15
15
30
30
15
30
15
15
15
30
30
A
B
A
B
A
A
B
A
A
A
A
B
A
A
A
A
A
A
A
A
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3c
3d
3d
3d
3d
3d
3e
3f
82
80
56
2a
F
2a
Cl
Cl
Br
I
a
2a
50 (100 )
2a
74
50
2a
a
2a
I
16 (100 )
imidazole (2b)
2b
F
53
32
42
31
0
Cl
Br
I
1
1
1
1
1
1
1
1
1
1
2
2b
2b
2b
I
b
dipentylamine (2c)
F
62 (56 )
diethylamine (2d)
F
9
2d
F
10
a
0 (39 )
2d
2d
Cl
Br
I
0
0
0
0
2d
diisobutylamine (2e)
dibenzylamine (2f)
F
F
a
Reactions were carried out under high pressure (0.6–1.2 GPa), with 5 equivalents of amine, reaction
b
ꢁ
time 20–50 h, reaction temperature 50 C [1]; reaction was carried out without solvent, with two
equivalents of amine, gently boiling for 1–3 days [14]
Scheme 1. Method A: sonochemical reaction; method B: thermal heating with stirring
basicity of dipentylamine (2c) are similar to those of diethylamine (2d), but its
ꢁ
boiling point is 202–203 C. Thus 2c does not evaporize from the reaction mixture.
The yield of 3c was 62% (Table 1, Entry 13). We attained in 30 min better results
than Mansour et al. by his solvent free procedure [14] (56%) after 2–3 days. Later
on, we have studied the effect of an electron-withdrawing group on the course of
SNAr reactions under our conditions.

4
0
M. Me ꢀc iarov a´ et al.
Table 2. Results of S Ar reactions of haloarenes 4 with 2a
N
Entry
4
Z
X
Time
min)
Method
Product
Yield
%
(
1
2
3
4
5
6
7
8
9
4a
4b
4b
4b
4b
4c
4c
4c
4c
4c
4d
4d
4d
H
F
30
15
30
15
15
15
15
15
15
15
15
15
15
A
A
A
A
A
A
B
A
A
A
A
A
A
5a
5b
5b
5b
5b
5c
5c
5c
5c
5c
5d
5d
5d
0
a
25 (80 )
COCH3
COCH3
COCH3
COCH3
CHO
CHO
CHO
CHO
CHO
CN
F
F
59
0
Cl
Br
F
0
85
a
48 (70 )
F
Cl
Br
I
0
0
0
1
1
1
1
0
1
2
3
a
F
55 (77 )
CN
Cl
Br
0
0
CN
a
ꢁ
Reaction was carried out in DMSO, at 95 C, for 6 h [2]
From the results given in Tables 1 and 2 it follows that the fluoro compounds
underwent S Ar reactions with amines much easier than their chloro and bromo
N
analogues. These experimental results are in accordance with the theory of the
leaving group effect, as the approximate order is F>Cl, Br, I [15]. The S Ar
N
mechanism is an addition-elimination mechanism involving the formation of
a carbanion with delocalized electrons. The carbanion is stabilized by electron-
withdrawing groups in the positions ortho and para to the halogen atom. The stabiliz-
ing effect of an electron-withdrawing group on S Ar reactions decreases in the order
N
NO >COR>COH>CN [15]. This explains the observed lower reactivity of 4-
2
haloacetophenones 4b–4d, 4-halobenzaldehydes 4e–4h, and 4-halobenzonitriles
4i–4k in comparison to the reactivity of 4-halonitrobenzenes 1a–1d (Scheme 2,
Tables 1 and 2).
Scheme 2. Method A: sonochemical reaction; method B: thermal heating with stirring

Ultrasound Promoted S Ar Reactions
N
41
We have to stress that our experiments were not optimized. The yields of the
products can be increased by reaction time prolongation, as was documented in the
reaction with 4-fluoroacetophenone (4b) (Table 2, Entries 2, 3).
The low basicity of aniline (6) is probably responsible for its poor reactivity in
S Ar reactions. Ibata et al. [1] achieved very low yield of 4-nitrodiphenylamine
N
ꢁ
(
7%) under high pressure (0.9 GPa) at 50 C for 50 h with 5 equivalents of aniline.
Sonochemical reaction of 6 with 1a gave 9% of bis-(4-nitrophenyl)-phenylamine
7) and 9% of bis-(4-nitrophenyl)-ether (8). Starting material was only detected in
the reaction mixture at the silent reaction (Scheme 3). To increase the reactivity of
(
aromatic amines in S Ar rections on 1a, we performed reactions with anilines
N
having strong electron-donating groups in the para position. Sonochemical S Ar
N
reaction on 1a with 4-methoxyaniline (9) gave 46% of 4-methoxyphenylbis-(4-
nitrophenyl)-amine (10) and 10% of bis-(4-nitrophenyl)-ether (8) isolated by col-
umn chromatography. Classical reaction gave at the same time (30 min) 11% of 10
and just traces of 8 were detected in the reaction mixture by NMR spectroscopy
(
diethylaminophenyl)-bis-(4-nitrophenyl)amine (12) after the sonochemical S Ar
Scheme 4). Similarly, we isolated by column chromatography 54% of (4-N,N-
N
reaction on 1a with 4-(N,N-diethylamino)-aniline (11) and 10% of 8. Silent reac-
tion gave at the same time (30 min) just 12% of 12 and just traces of 8 were
detected in the reaction mixture by NMR spectroscopy (Scheme 5).
Scheme 3. Method A: sonochemical reaction, 30 min, 9% of 7, 9% of 8; method B: thermal heating
with stirring, 30 min, 0% of 7, 0% of 8
Scheme 4. Method A: sonochemical reaction, 30 min, 46% of 10, 10% of 8; method B: thermal
heating with stirring, 30 min, 11% of 10, traces of 8

4
2
M. Me ꢀc iarov a´ et al.
Scheme 5. Method A: sonochemical reaction, 30 min, 54% of 12, 10% of 8; method B: thermal
heating with stirring, 30 min, 12% of 12, traces of 8
Experimental
Reagents and solvents were standard grade commercial products and were used without further
1
purification. The H NMR spectra were recorded at 300 MHz on a Varian Gemini spectrometer in
CDCl with tetramethylsilane as an internal standard. GC spectra were recorded on a GC TRACE 2000
3
Series instrument, MS spectra were recorded on a VOYAGER spectrometer. Melting points were
determined on a Kofler-hot stage and are uncorrected. All sonochemical experiments were carried
out in a glass reactor fitted to an ultrasonic horn Ultragen (Nitra, Slovakia) (20 kHz, 300 W) for 15min
under an air atmosphere.
Sonochemical reaction
Potassium carbonate (2.9g, 20 mmol) was added to the solution of the appropriate amine (20 mmol)
3
and 20mmol 4-haloarene in 20 cm DMSO. The reaction mixture was sonicated for 15 (30)min. The
ꢁ
temperature of the reaction mixture attained 150 C at the end of sonication. Then the reaction mixture
ꢁ
3
was cooled down to 60 C and poured into 400 cm distilled H O. In most cases analytically pure
2
products were collected by filtration with suction. In the case when the product was an oil or not pure
3
TLC), the emulsion was extracted three times into 75cm diethyl ether. Then the ether solution was
(
washed with H O and dried (anhydrous Na SO ) and the ether was removed on a rotary vacuum
2
2
4
evaporator. The crude products (3a and 3b) were purified by crystallization from isohexane or by
chromatography (3c, 3d, 5b, 5c, 5d, 7, 8, 10, and 12) on silica using isohexane=ethyl acetate (9=1) as
the eluent. The results are given in the Tables 1 and 2.
Classical reaction
Potassium carbonate (2.9g, 20 mmol) was added to the solution of the appropriate amine (20 mmol)
3
and 20 mmol 4-haloarene in 20cm DMSO. The reaction mixture was vigorously stirred for 15min.
Then the reaction mixture was worked-up as described above.
Products 3a [3, 16], 3b [17, 18], 3c [14], 3d [19], 5b [2, 20], 5c [3, 21], 5d [2, 20], 8 [23, 24], and
1
0 [25] were found to be identical (melting points and NMR data) with the data described in literature.
Bis(4-nitrophenyl)phenylamine (7)
ꢁ
ꢁ
1
Yellow solid; m.p. 194–196 C (Ref. [22] 194.5–195.8 C); H NMR (CDCl , ꢀ, 300 MHz): 7.14–7.20
3
(
m, 6Harom), 7.32 (t, J ¼ 9.0, 1H ), 7.44 (t, J ¼ 9.0, 2H ), 8.15 (d, J ¼ 9.0, 4Harom) ppm; GC-MS:
arom
arom
+
m=z ¼ 335 (100, M ), 305 (38), 259 (30), 243 (82), 166 (22), 139 (20), 77 (27).

Ultrasound Promoted S Ar Reactions
N
43
(4-N,N-Diethylaminophenyl)-bis-(4-nitrophenyl)-amine (12)
ꢁ
1
Red solid; m.p. 158–161 C; H NMR (CDCl , ꢀ, 300 MHz): 1.21 (t, J ¼ 7.2, 2CH ), 3.39 (q, J ¼ 7.2,
3
3
2
2
1
2
CH ), 6.67 (d, J ¼ 9.0, 2H ), 6.97 (d, J ¼ 9.0, 2H ), 7.15 (d, J ¼ 9.0, 2H ), 8.11 (d, J ¼ 9.0,
2
arom
arom
arom
1
3
H
arom
) ppm; C NMR (CDCl , ꢀ, 75 MHz): 12.55, 44.46, 112.65; 121.36, 125.41, 128.88, 131.88,
3
+
42.07, 147.02, 152.19; GC-MS: m=z ¼ 406 (100, M ), 391 (100), 362 (28), 345 (22), 270 (23),
41 (43).
Acknowledgements
The authors thank Dr. E. Sol ꢀc a´ niov a´ and her staff from the Institute of Chemistry of Comenius
1
13
University for H NMR and C NMR analyses, and Dr. R. Kubinec and his staff from the Institute
of Chemistry of Comenius University for GC-MS analyses. Our thanks are due to Dr. D. V ꢁe gh from the
Faculty of Chemistry and Technology of STU, Bratislava for 4-fluoronitrobenzene. This work was
supported by the VEGA – Grant Agency, Grant No. 1=7348=20 and the auspicies COST – Chemistry
Project No. D-10=0008=98.
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