Study of SNAr reactions of halobenzenes with imidazole under ultrasonic and microwave irradiation

Article abstract of DOI:10.1007/s00706-003-0141-y

Nucleophilic aromatic substitution reactions with imidazole of haloarenes having strongly electron-withdrawing groups were studied under ultrasonic and microwave irradiations. The course of the SNAr reactions was found to be strongly dependent on the electron-withdrawing properties of the substituents as well as on the leaving ability of the halogen atom. Microwave irradiation allowed to shorten the reaction time and to increase the yields compared with ultrasonic irradiation. Springer-Verlag 2004.

Full text of DOI:10.1007/s00706-003-0141-y

Monatshefte f€ur Chemie 135, 419–423 (2004)
DOI 10.1007/s00706-003-0141-y
Study of SNAr Reactions of Halobenzenes
with Imidazole under Ultrasonic
and Microwave Irradiation
ꢀ
ˇ
Maria Meciarova , Janka Podlesna, and Stefan Toma
´
ˇ
´
´
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University,
SK-842 15 Bratislava, Slovak Republic
Received November 12, 2003; accepted (revised) November 17, 2003
Published online February 5, 2004 # Springer-Verlag 2004
Summary. Nucleophilic aromatic substitution reactions with imidazole of haloarenes having strongly
electron-withdrawing groups were studied under ultrasonic and microwave irradiations. The course of
the SNAr reactions was found to be strongly dependent on the electron-withdrawing properties of the
substituents as well as on the leaving ability of the halogen atom. Microwave irradiation allowed to
shorten the reaction time and to increase the yields compared with ultrasonic irradiation.
Keywords. Nucleophilic aromatic substitutions; Halobenzenes; Imidazole; Microwave irradiation;
Ultrasonic irradiation.
Introduction
Nucleophilic aromatic substitution of haloarenes with amines generally do not
proceed smoothly under normal pressure and are limited to fluorides having a
strongly electron-withdrawing group in the para position. The SNAr reactions of
the haloarenes having mild electron-withdrawing groups such as the formyl group
need rather harsh conditions, like high pressure (up to 103 MPa) [1] or long reac-
tion time and high temperature in dipolar aprotic solvents like DMSO or DMF
[2, 3]. Several papers appeared describing the beneficial effect of ultrasonic irra-
diation [4–8] or microwave irradiation [9–13]. Buchwald [14] and Hartwig [15]
described Pd catalyzed arylation of amines, which gives good results with aliphatic
and especially alicyclic amines. The SNAr reactions of haloarenes are much more
difficult with azoles.
The aim of the present work was therefore to examine the effect of ultrasonic
and microwave irradition on the course of different SNAr reactions of halobenzenes
with imidazole.
ꢀ
Corresponding author. E-mail: mmeciarova@fns.uniba.sk

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M. Meciarova et al.
420
Results and Discussion
Cyclic secondary amines owing to its basicity, nucleophilicity, and bulkiness were
the most reactive amines in the SNAr reactions with 4-fluorobenzaldehyde, whereas
imidazole and other aromatic amines were found to be less reactive or unreactive
[5]. Thus, we decided to study the SNAr reactions of haloarenes with imidazole
under ultrasonic and microwave irradiation.
The most reactive haloarenes in the SNAr reactions with imidazol (1) were 1-
halo-4-nitrobenzenes 2a–2d. 1-(4-Nitrophenyl)imidazole (7) was isolated after
15 min sonication in 31–53% yield, whereas 3 min of microwave irradiation gave
7 in 43–80% yield (Table 1). The positive effect of non-classic reaction conditions
was demonstrated on the reactions of 1-iodo-4-nitrobenzene (2d) with 1. Although
2d was inactive in the SNAr reaction with 1 under heating and stirring for 15 min at
150ꢁC, 15 min of ultrasonic irradiation gave 31% of 7 and 3 min of microwave
irradiation yielded 43% of 7 (Table 1).
4-Haloacetophenones 3a–3c underwent the SNAr reactions with imidazole giv-
ing 4-(imidazol-1-yl)acetophenone (8) in 10–65% yield (Table 1). The best yield
of 8 (65%) gave 4-fluoroacetophenone after 3 min of microwave irradiation. 4-
Chloro- or 4-bromoacetophenone (3b, 3c) irradiated for 3 min gave 11 or 10%
of 8. Prolonging the reaction time to 7 min increased the yield of 8 to 37 or
36%. Further prolonging the time of irradiation did not increase the yields, but
undesirable polymerisation reactions took place instead. Thus, unidentified black
tarry materials were present in the reaction mixtures.
4-Fluorobenzaldehyde (4a) gave 4-(imidazol-1-yl)benzaldehyde (9) in 75%
yield after 15 min ultrasonic irradiation. A very similar yield of 9 (74%) was
Scheme 1

Study of SNAr Reactions of Halobenzenes with Imidazole
421
Table 1. Results of the SNAr reactions of haloarenes with imidazole
XC6H4Z
Z
X
Conditions
Product
Yield=%
2a
2a
2b
2b
2c
2d
2d
2d
3a
3a
3b
3c
3c
3c
4a
4a
4b
4b
4c
4c
4d
5a
5b
5c
6
NO2
F
US, 15 min, 140ꢁC
7
7
53
80
37
72
42
31
43
0
NO2
F
MW, 3 min, 240 W, tfin ¼ 165ꢁC
NO2
Cl
Cl
Br
I
US, 15 min, 140ꢁC
7
NO2
MW, 3 min, 240 W, tfin ¼ 172ꢁC
US, 15 min, 140ꢁC
US, 15 min, 140ꢁC
7
NO2
7
NO2
7
NO2
I
MW, 3 min, 240 W, tfin ¼ 173ꢁC
7
NO2
I
D, 15 min, 150ꢁC
7
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CN
F
MW, 3 min, 240 W, tfin ¼ 150ꢁC
MW, 3 min, 240 W, tfin ¼ 153ꢁC
MW, 7 min, 240 W, tfin ¼ 180ꢁC
MW, 3 min, 240 W, tfin ¼ 146ꢁC
MW, 5 min, 240 W, tfin ¼ 154ꢁC
MW, 7 min, 240 W, tfin ¼ 157ꢁC
US, 15 min, 140ꢁC
8
65
11
37
10
22
36
75
74
0
Cl
Cl
Br
Br
Br
F
8
8
8
8
8
9
F
MW, 3 min, 240 W, tfin ¼ 140ꢁC
9
Cl
Cl
Br
Br
I
US, 15 min, 140ꢁC
9
MW, 5 min, 240 W, tfin ¼ 164ꢁC
US, 15 min, 140ꢁC
9
19
0
9
MW, 5 min, 240 W, tfin ¼ 162ꢁC
9
19
0
US, 15 min, 140ꢁC
9
F
MW, 3 min, 240 W, tfin ¼ 181ꢁC
MW, 5 min, 240 W, tfin ¼ 186ꢁC
MW, 5 min, 240 W, tfin ¼ 134ꢁC
US, 30 min, 140ꢁC
MW, 5 min, 240 W, tfin ¼ 134ꢁC
10
10
10
11
11
77
38
57
0
CN
Cl
Br
F
CN
H
6
H
F
0
achieved after 3 min of microwave irradiation. Although 4-chloro-, 4-bromo-, and
4-iodobenzaldehydes (4b–4d) were inactive in the sonochemical SNAr reactions
with 1, 4-chloro- and 4-bromobenzaldehydes (4b, 4c) gave 19% of 9 after 5 min of
microwave irradiation (Table 1). 4-Chloro- and 4-bromobenzaldehydes (4b, 4c),
which were less reactive in the SNAr reactions, gave 12a, 12b, 13a, 13b, 14a, and
14b (Scheme 2) as the products of competitive reactions with the solvent. The
1
yields of 12a, 12b, 13a, 13b, 14a, and 14b were according to H NMR and GC-
MS analyses less than 5%. The results of the reactions of aromatic aldehydes with
DMSO in the presence of a base are in accord with the facts described in literature
[16].
Reactions of 4-halobenzonitriles 5a–5c with 1 under microwave irradiation
gave 4-(imidazol-1-yl)benzonitrile (10) in 38–77% yield after 3–5 min (Table 1).
Fluorobenzene (6) was inert in the SNAr reactions with 1 under both, ultrasonic and
microwave irradiations. Only starting materials were detected in the reaction mix-
tures (Table 1).
To conclude we have proved that both, ultrasonic and microwave
irradiation accelerate the SNAr reactions of imidazole with haloarenes, but
microwave irradiation is more effective because even less reactive haloarenes like

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M. Meciarova et al.
422
Scheme 2
4-chloroacetophenone (3b) or 4-chlorobenzonitrile (5b) gave reasonable yields of
the target products.
Experimental
Starting materials were commercially available or were prepared according to literature procedures and
1
purified (crystallized or distilled) before reactions. All products were analyzed by H NMR spectro-
scopy and GC-MS. The 1H NMR spectra were recorded at 300 MHz on a Varian Gemini spectrometer
in CDCl3 with TMS as internal standard. GC spectra were recorded on a GC Trace 2000 Series
instrument, mass spectra were recorded on a Voyager spectrometer. All sonochemical experiments
were carried out in a glass reactor fitted with an ultrasonic horn Ultragen (20 kHz, 300 W) under pulsed
conditions (pulse length: 4 s, 50% duty) for 15 or 30min under air atmosphere. All microwave
experiments were carried out in the Synthewave 402, Prolabo reactor (600W); the power settings,
final temperatures, and reaction times are given in Table 1.
Compounds 7 [7], 8 [8], 9 [9], 10 [13], 12a [16], 12b [16], 13a [16], 13b [16], 14a [16], and 14b
[16] were found to be identical (1H NMR data) with the data described in literature.
Microwave SNAr Reactions (MW)
Potassium carbonate (0.76 g, 5.5 mmol) was added to a solution of 0.374 g of 1 (5.5mmol) and
5.5 mmol of haloarene in 7.5 cm3 of DMSO. The reaction mixture was irradiated for 3–7 min under
conditions given in Table 1. The reaction mixture was cooled to 30ꢁC and then poured into 200cm3 of
distilled H2O. The precipitated products were usually analytically pure; they were collected by filtra-
tion under reduced pressure. When the product was an oil or not pure enough, the emulsion formed
was extracted three times with 50cm3 of diethyl ether. The ether solution was washed with H2O and
dried (Na2SO4). Ether was evaporated in vacuo and the product was purified by column chromatog-
raphy on silica using isohexane=ethyl acetate (9=1–6=1) as the eluent.
Sonochemical SNAr Reactions (US)
Potassium carbonate (1.38 g, 11mmol) was added to a solution of 0.68g of 1 (10 mmol) and 10 mmol
of haloarene in 20cm3 of DMSO. The reaction mixture was sonicated for 15 or 30min. The tempera-

Study of SNAr Reactions of Halobenzenes with Imidazole
423
ture of the reaction mixture attained 140ꢁC at the end of sonication. The reaction mixture was then
worked up as described above.
Classic SNAr Reactions (D)
Potassium carbonate (1.38 g, 11mmol) was added to a solution of 0.68g of 1 (10 mmol) and 10 mmol
of haloarene in 20 cm3 of DMSO. The reaction mixture was heated at 150ꢁC for the time period given
in Table 1. The reaction mixture was then worked up as described above.
Acknowledgements
1
´
´
The authors thank Dr. E. Solꢀcaniova and her staff for H NMR analyses and Dr. R. Kubinec and his
staff for GC-MS analyses, both from the Institute of Chemistry of Faculty of Natural Sciences,
Comenius University. Financial support by the Ministry of Education of the Slovak Republic is
gratefully acknowledged too.
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