Zinc Mediated Friedel-Crafts Acylation in Solvent-Free Conditions under Microwave Irradiation

Article abstract of DOI:10.1055/s-2003-42485

Zn powder is found to catalyze the Friedel-Crafts acylation of aromatic compounds with acyl halides efficiently under microwave irradiation in solvent-free conditions. Activated substrates undergo acylation predominantly at the para-position. The Zn powder can be re-used up to six times after simple washing with diethyl ether and dilute HCl.

Full text of DOI:10.1055/s-2003-42485

PAPER
2877
Zinc Mediated Friedel–Crafts Acylation in Solvent-Free Conditions under
Microwave Irradiation
Z
inc Mediate
d
a
Friedel–C
t
afts A
c
y
ylation a Paul,a Puja Nanda,a Rajive Gupta,*a André Loupyb
a
Department of Chemistry, University of Jammu, Jammu-180 006, India
Fax 91(191)505086; E-mail: rajgupta@sancharnet.in
b
Laboratoire des Réactions Sélectives sur Supports, CNRS UMR 8615, Université Paris-Sud, 91405, Orsay, France
Fax 33(1)69154679; E-mail: aloupy@icmo.u-psud.fr
Received 17 September 2003; revised 2 October 2003
Microwave (MW) irradiation has been proved to be high-
ly efficient for the rapid synthesis of a variety of com-
pounds,16 some include Friedel–Crafts acylations.17
Chemical reactions are accelerated essentially because of
Abstract: Zn powder is found to catalyze the Friedel–Crafts acyla-
tion of aromatic compounds with acyl halides efficiently under mi-
crowave irradiation in solvent-free conditions. Activated substrates
undergo acylation predominantly at the para-position. The Zn pow-
der can be re-used up to six times after simple washing with diethyl selective absorption of microwave energy by polar mole-
ether and dilute HCl.
cules being inert to the microwave dielectric loss. Among
them, heterogeneous reactions facilitated by supported re-
agents on various mineral oxides have received special at-
tention in recent years.18–21 Relatively little attention is,
however, paid to solvent-free reactions with neat reactants
in the absence of a solid support.22
Key words: Friedel–Crafts acylation, zinc powder, aromatic com-
pounds, solvent-free conditions, microwave activation
Friedel–Crafts acylation of aromatic compounds is one of
the most important synthesis of aryl ketones. In a typical
Friedel–Crafts acylation reaction, an aromatic compound
undergoes electrophilic substitution with an acylating
agent in the presence of more than one equivalent of acid
catalyst (e.g. anhydrous AlCl3) due to its complexation by
the ketone product. The catalyst used cannot be easily re-
covered and recycled. Therefore, a large amount of toxic
waste is generated. In order to solve this problem, some
catalytic Friedel–Crafts acylations have recently been de-
veloped. Ln(OTf)3–LiClO4,1 TiCl(OTf)3–TfOH,2 Re-
During the course of our studies aimed at developing sol-
vent-free procedures,20 we found that Zn powder without
any treatment, can promote the Friedel–Crafts acylation
of aromatic compounds with acyl halides to afford the
corresponding acylated products in high yields. Zn pow-
der was shown to be one of the most efficient MW absorb-
er with a very high specificity to MW heating. It was able
to reach a temperature of 581 °C after 3 minutes of irradi-
ation in a domestic oven (P = 1000 W).23
Another interesting behaviour of Zn powder lies in the
fact that it can be re-used after simple washing with dieth-
yl ether and dilute HCl, rendering thus process more eco-
nomic. This constitutes a green and efficient alternative to
the MW assisted method described by Dubac et al.17a–c us-
ing metallic chlorides as catalysts, and essentially iron(III)
chloride.
3
Br(CO)5, LiClO4–acylanhydride complex,4 FeCl3 over
K105 and clay catalysts6 have been reported as catalysts
for Friedel–Crafts acylations. In addition, the use of inor-
ganic solid supported reagents7 or solid acids8 as catalysts,
resulting in higher selectivity, easier work-up and envi-
ronmentally safe reactions, has been reported. For in-
stance, HZSM-5 zeolite has been reported to promote the
liquid phase acylation of anisole with carboxylic acids.9
However, it presents limitations with regard to generality
and efficiency. Recently, it was also shown that alumina
promotes the acylation of reactive aromatics such as ani-
sole and thiophene with carboxylic acid in the presence of
trifluoroacetic anhydride.10
Zinc was shown to have a remarkable high activity for the
acylation of aromatic compounds with acetyl chloride and
benzoyl chloride to give the corresponding acylated com-
pounds in high yields, without any of the environmental
disadvantages of using toxic homogeneous reagents such
as anhydrous AlCl3. Several substituted acetophenones
and benzophenones have been prepared by this method
(Table 1).
Zn powder, a non-toxic and inexpensive metal has been
used for a number of organic reactions like ene-cycliza-
tion,11 Diels–Alder reaction,12 synthesis of benzhydrols,13
transesterification of -ketoesters.14 Recently, Zn powder
has been also involved in acylation and sulfonation of pyr-
role.15
Experimental conditions have been carefully monitored to
regulate the use of Zn powder, irradiation time and power
level of microwave oven to get the maximum yield. High-
er proportions of Zn powder result in a quick rise of tem-
perature thereby burning of the reaction mixture. The 1:1
ratio of Zn powder to substrate is the most acceptable ratio
in terms of efficiency and safety; a power level of 300
Watts is the most suitable one.
SYNTHESIS 2003, No. 18, pp 2877–2881
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Advanced online publication: 17.11.2003
DOI: 10.1055/s-2003-42485; Art ID: Z13903SS
© Georg Thieme Verlag Stuttgart · New York

2878
S. Paul et al.
PAPER
Table 1 Microwave-Induced Synthesis of Acylated Ketones Using Zn Powder (Power = 300 W)
R = CH3 (entries 1–19); R = Ph (entries 20–36)
Entry
Substrate
Product
Reaction
Temp. (°C)
Time
(s)
Yield
(%)
Mp/Bp (°C)
Found/Reported
Liq/201–202a
Liq/226a
1
2
Benzene
Acetophenone
60–62
52–53
65–68
80–82
45–47
53–55
42–44
52–54
55–57
47–48
64–66
44–46
52–54
70–72
58–60
57–59
82–84
55–57
43–45
72–74
71–73
98–100
52–54
140–142
75–79
70–72
120–121
70–72
100–102
80–82
55–57
30
40
30
7
95
70
99
99
83
69
65
72
73
70
77
71
68
74
92
70
79
70
74
75
99
85
70
55
71
70
71
69
68
68
74
Toluene
4-Methylacetophenone
4-Chloroacetophenone
4-Methoxyacetophenone
9-Acetylanthracenec
3
Chlorobenzene
Anisol
Liq/232a
4
Liq/152–154a
74–75/75–76b
54–56/56b
5
Anthracene
Naphthalene
Pyridine
60
25
15
25
40
60
75
55
20
15
60
140
180
240
40
35
20
30
20
30
15
10
10
28
30
20
18
6
2-Acetonaphthanonec
7
4-Acetylpyridinec
Liq/212–214b
119–121/120–121b
Liq/213a
8
Biphenyl
4-Acetylbiphenyl
9
Phenol
2-Hydroxyacetophenone
2,5-Dihydroxyacetophenonec
2,4-Dihydroxyacetophenoned
3,4-Dihydroxyacetophenonec
5-Amino-3-nitroacetophenonec
4-Amino-3-nitroacetophenonec
3,4-Dimethylacetophenonec
3,4-Dichloroacetophenonec
3-Nitroacetophenonec
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Quinol
198–200/202b
144–46/147b
115–17/117b
149–52/152–153b
152–55/153–157b
Liq/243a
Resorcinol
Catechol
3-Nitroaniline
2-Nitroaniline
o-Xylene
1,2-Dichlorobenzene
Nitrobenzene
4-Cresol
70–72/72–74a
77–79/78–80a
43–44/45–48a
105–1071
2-Hydroxy-5-methylacetophenonec
4-Aminoacetophenone
Benzophenone
Aniline
Benzene
46–47/46–48a
57–58/56.5–57a
75–76/75–77a
123–124/121–124a
140–141/140–143a
91–93/92–94a
64–66/65–66a
60–62/60–63a
80–82/82b
Toluene
4-Methylbenzophenone
4-Chlorobenzophenone
4-Aminobenzophenone
4-Amino-3-nitrobenzophenone
4-Amino-2-nitrobenzophenone
2-Amino-4-methylbenzophenone
4-Methoxybenzophenone
2-Benzoylnaphthalene
4-Benzoylbiphenyl
Chlorobenzene
Aniline
2-Nitroaniline
3-Nitroaniline
3-Toluidine
Anisol
Naphthalene
Biphenyl
99–100/99–101a
147–148/148b
133-35/132-35a
Anthracene
Phenol
9-Anthraphenonec
4-Hydroxybenzophenone
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Zinc Mediated Friedel–Crafts Acylation
2879
Table 1 Microwave-Induced Synthesis of Acylated Ketones Using Zn Powder (Power = 300 W) (continued)
R = CH3 (entries 1–19); R = Ph (entries 20–36)
Entry
Substrate
Product
Reaction
Temp. (°C)
Time
(s)
Yield
(%)
Mp/Bp (°C)
Found/Reported
32
33
34
35
36
Resorcinol
Quinol
2,4-Dihydroxybenzophenone
2,5-Dihydroxybenzophenonec
3,4-Dihydroxybenzophenonec
3,4-Dimethylbenzophenonec
3,4-Dichlorobenzophenonec
50–52
49–51
46–48
57–59
55–57
55
35
70
68
68
70
71
143–146/144–146b
124–126/125b
132–134/134b
43–46/45–47a
Catechol
60
o-Xylene
180
300
1,2-Dichlorobenzene
100–102/104.5b
a Aldrich Catalog Handbook of Fine Chemicals, 2000–2001.
b Stevens, R. Dictionary of Organic Compounds, 4th Ed. Eyre & Spottiswoode Ltd. E. & F. N. Spon Ltd. 1971.
c Purified by passing through column of silica gel and elution with 100% P.E. (60–80 °C).
d Ratio of substrate to acyl halide is 1:3.
Recently, we have reported the acetylation20 and
benzoylation21 of –NH2, –SH and –OH groups using
acetyl chloride and benzoyl chloride over basic alumina as
support. It is very interesting to note that, in the case of
aniline and phenol, if Zn powder is added 15 seconds be-
fore acetyl chloride or benzoyl chloride acylation takes
place predominantly with only 10% of acetylated aniline
(acetanilide) and no phenyl acetate has been observed.
But, if acetyl or benzoyl chloride is added previously to
Zn powder, more than 30% of acetylated or benzoylated
products have been formed in addition to acylated prod-
Figure 1 Re-use studies on the Zn mediated synthesis of acetophe-
none using 1 mmol of benzene and 1.2 mmol of acetyl chloride. The
reaction was carried out in a microwave oven at 300 W. In parenthesis
ucts. Thus Zn powder is suppressing the acetylation/ben-
zoylation and catalyzing the acylation reaction. Further,
substrates with activating groups (entries 4, 9, 19, 23 etc.) irradiation reaction time is given.
undergo acylation predominantly at the para-position. As
the ortho-isomers are formed only in very small amounts,
we report here only the major isomer, which has been iso-
lated by column chromatography or crystallization.
sets of conditions of time and temperature as for the mi-
crowave-assisted method (Table 2).
Anhydrous zinc chloride24 is well known for catalyzing
the Friedel–Crafts acylation reaction. In order to check the
possibility of in situ generation of zinc chloride from zinc
powder and acylating agents, (acetyl chloride/benzoyl
chloride) we carried out the acylation reaction in case of
entries 4, 8, 27 and 29 using anhydrous zinc chloride in-
stead of Zn powder. It has been found that under the same
conditions of irradiation time and power output (cf.
Table 1), only 12–18% of acylated products were formed,
the complement being the starting materials. Thus the role
of zinc chloride formed, would be minor and the major
role is played by zinc powder, which can be reused up to
6 times by washing it with diethyl ether and HCl after each
use. However, there is loss of activity after four uses.
Significant lower yields were obtained under convention-
al heating than using MW-assisted method under identical
conditions of time and temperature. Even by extending re-
action times, yields remain lower under thermal condi-
tions when compared to MW activation. This observation
demonstrates clearly that the effect of MW irradiation is
not purely thermal. This behaviour is consistent with
mechanistic considerations of the reaction.25 As they are
connected to polarity medium, specific MW effects are
expected if the transition state (TS) is more polar than the
ground state (GS) of the reaction. Due to dipole-dipole
electrostatic interactions being more developed in the TS,
the stabilisation of the TS is superior to the GS, leading
thus to a decrease in the activation energy. In this case one
should consider the rate-determining step in the SEAr
mechanism (cf Scheme 1). In the TS, the polarity of the
system is enhanced as looser ion pairs are involved (with
Finally, in order to check the possibility of specific non-
thermal effects of microwave irradiation, reactions were
carried out using thermostated oil-baths ( ) under similar
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S. Paul et al.
PAPER
elimination of solvents or solid support. Moreover, the ac-
tivated aromatic substrates give the para-isomer as the
major product.
Table 2 Comparison of Results under Both MW and Thermal Con-
ditions (Power = 300 W)
Entry
1
Method
MW
T (°C)a
60–62
62
Time
30 s
Yield (%)b
95
20
79
70
8
Mps were determined on a Buchi melting point apparatus and are
1
uncorrected. H NMR spectra were obtained on a JNM-PMX 60
30 s
NMR spectrometer (60MHz) in CDCl3 using TMS as internal stan-
dard. The IR spectra were recorded using KBr disc on Hitachi 270-
30 spectrophotometer. The reactions were monitored by TLC. For
the microwave irradiation experiments described below a conven-
tional (unmodified) household microwave oven equipped with a
turntable was used (BPL BMO 800, 800 W and operating at 2450
MHz).
62
8 min
40 s
2
17
20
21
MW
MW
MW
MW
52–53
53
40 s
53
8 min
3 min
3 min
20 min
35 s
55
79
10
62
75
5
Preparation of Acetophenone, Entry 1; Typical Procedure
To a mixture of benzene (0.078 g, 1 mmol) and Zn powder (0.065
g, 1 mmol) in a 50 mL borosil beaker, AcCl (0.078 g, 1 mmol) was
added. The reaction mixture was mixed properly with the help of a
glass rod (10 s) and then irradiated in a microwave oven for 30 s at
300 W (monitored by TLC). The reaction mixture was cooled and
extracted with Et2O (3 × 10 mL). After drying the ether extracts
over anhydrous Na2SO4, the acetophenone was obtained by removal
of the solvent under reduced pressure. Finally, the product was pu-
rified by column chromatography (silica gel) using P.E. as eluent
(0.114 g, 95%).
82–84
84
84
72–74
74
35 s
74
12 min
20 s
60
99
28
80
71–73
76
The reaction was also performed with benzene (0.390 g, 5 mmol),
Zn powder (0.325 g, 5 mmol) and AcCl (0.390 g, 5 mmol) in a 50
mL borosil beaker following the same procedure. After an irradia-
tion time of 30 s, acetophenone (0.56 g, 94%) was obtained by pass-
ing through column of silica gel and elution with P.E.
20 s
76
6 min
a Reaction temperature was measured by immersing A glass ther-
mometer into the reaction mixture immediately after exposure to
MW irradation.
1
The structure of the products was confirmed by H NMR, IR and
comparison with authentic samples obtained commercially or pre-
pared by reported methods.
b Yields of isolated products.
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Zinc Mediated Friedel–Crafts Acylation
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Synthesis 2003, No. 18, 2877–2881 © Thieme Stuttgart · New York