Catalysis Communications 8 (2007) 1834–1837

www.elsevier.com/locate/catcom

Efficient synthesis of benzophenone derivatives in Lewis acid

ionic liquids
a,b a,b a,*
Changzhi Li , Wujun Liu , Zongbao (Kent) Zhao
a
Dalian Institute of Chemical Physics, CAS, Dalian 116023, PR China
b
Graduate School of the Chinese Academy of Sciences, Beijing 100039, PR China

Received 13 June 2006; received in revised form 9 February 2007; accepted 15 February 2007
Available online 23 February 2007

Abstract

Benzophenone and its derivatives were prepared via Friedel–Crafts acylation reactions using ionic liquids (ILs) of BmimCl–FeCl3,
BmimCl–AlCl3 and BmimCl–ZnCl2 as dual catalyst–solvent. Among them, BmimCl–FeCl3 showed much higher catalytic activity than
that observed for the other two ILs, and in conventional organic solvents. In these reaction systems, good to excellent yields (up to 97%)
of acylation products were obtained in a short reaction time. This method features high yield, a simple product isolation procedure, ILs
reusability and reduced waste discharge, thus rendering this catalytic system both efficient and environmentally friendly.
 2007 Elsevier B.V. All rights reserved.

Keywords: Ionic liquids; Friedel–Crafts reaction; Acylation; Benzophenone; Lewis acid

1. Introduction tion of the acid by coordination to the products. In addi-

Benzophenone and its derivatives are important fine
chemicals or intermediates in dyes, pharmaceutical and
other chemical industries [1–3]. In the pharmaceutical
industry they are used as farnesyltransferase inhibitors [4]
and non-nucleoside reverse transcriptase inhibitors of
HIV-1 [5], they are recognized to be effective anesthetics
[6] and the strongest photosensitizer among non-steroidal
anti-inflammatory drugs [7]. Modified benzophenones are
regarded as novel fluorescent materials [8] and powerful
probes in surface photochemistry [9–11]. In the fragrance
industry, benzophenone is a useful additive in perfumes,
colognes and scented soap. Generally, benzophenone and
its derivatives are prepared via Friedel–Crafts acylation
of aromatic compounds (Scheme 1) catalyzed with Lewis
acids, such as BF3, AlCl3, TiCl4, or ZnCl2 [12–14].
However, the acylation reaction requires more than a
stoichiometric amount of a Lewis acid due to the consump-
*
Corresponding author. Tel./fax: +86 411 84379211.
E-mail address: zhaozb@dicp.ac.cn (Z. (Kent) Zhao).
tion, all these acids have drawbacks, e.g., are toxic and
corrosive and result in severe pollution, are difficult in their
reuse and cause problems during products isolation. To
avoid these problems, solid acid catalysts such as SiC-b
[15], B2O3/ZrO2 [16] and Fe–Na–Y [17] zeolite, superacid
SiO2–Si–SCF3 and Al2O3–Si–SCF3 [18], heteropolyacid
and other supported catalysts like Fe3+-montmorillonite
[19], InCl3/Si-MCM-41 [20] as well as bis(oxazolinyl) pyri-
dine–Sc(III) triflate complex [21], have recently been used
as heterogeneous catalysts for the Friedel–Crafts reaction
of benzoyl chloride with benzene and its derivatives. In
spite of the good yields and simplified use of solid acid cat-
alysts, some of these catalysts deactivate rapidly due to the
build-up of coke under rather drastic working conditions
and their preparation procedures are generally tedious.
Hence, the development of a more efficient technology
for the synthesis of benzophenone and its derivatives is
strongly sought after.
We have shown that Lewis acid ILs including 1-butyl-3-
methylimidazolium chloride–ZnCl2 (BmimCl–ZnCl2),
1-butyl-3-methylimidazolium chloride–FeCl3 (BmimCl–
FeCl3) and 1-butyl-3-methylimidazolium chloride–FeCl2

1566-7367/$ - see front matter  2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2007.02.023
 C. Li et al. / Catalysis Communications 8 (2007) 1834–1837 1835

O products were carried out with gas chromatography on a

O GC-7890F (Techcomp Scientific Instrument Co., Ltd.,
Cat.
+ R2 R1 Shanghai, China) equipped with SE-54 column
R1
Cl R2
(30 m · 0.32 mm · 0.50 lm) and flame ionization detector.
Operating conditions were as follows: N2 carrier gas 40 ml/
Scheme 1. Friedel–Crafts acylation reaction of acyl chloride with benzene min, injection port temperature 280 C, detector tempera-
derivatives. ture 300 C, oven temperature programme: initial tempera-
ture: 150 C, initial time: 3 min, rate: 20 C /min, final
(BmimCl–FeCl2), etc., can act as both solvents and catalysts temperature: 200 C, final time: 10 min. Quantitative data
in Friedel–Crafts alkylations [22] and Diels–Alder reactions were analyzed using an N2000 chemistation supplemented
[23]. The non-volatile and moisture-stable ILs have shown with the GC instrument. Conversion and yields were calcu-
excellent catalytic activity and can be conveniently recycled lated based on starting acyl chlorides.
and thus the generation of waste and safety-related prob-
lems are minimal. Therefore, these Lewis acid ILs may be 3. Result and discussion
suitable candidates for the synthesis of benzophenone and
its derivatives through a Friedel–Crafts acylation reaction. 3.1. Comparison of benzophenone synthesis in either organic
In this paper, we report the results on Friedel–Crafts acyla- solvents or ILs
tion of benzene or mono-substituted benzene with benzoyl
chloride or phenyl acetyl chloride in ILs of BmimCl–FeCl3, Table 1 summarizes the results of a comparative study
BmimCl–ZnCl2 and 1-butyl-3-methylimidazolium chlo- of benzophenone synthesis through Friedel–Crafts reac-
ride–AlCl3 (BmimCl–AlCl3). tions in several ILs of BmimCl–FeCl3, BmimCl–AlCl3 or
BmimCl–ZnCl2 as compared to using organic solvents. In
2. Experimental organic solvents, solid acid catalyzed Friedel–Crafts acyla-
tion required a longer reaction time (up to 12 h) for high
2.1. Chemicals yields (entries 1–4). Compared with the solid acid catalyzed
systems, all reactions performed in ILs produced benzo-
All chemicals were used as received unless otherwise phenone in a shorter time, although the yields varied
specified. Anhydrous ZnCl2 (98%), AlCl3 (98%) and FeCl3 (entries 5–10). BmimCl–FeCl3 showed outstanding cata-
(97%) were purchased from National Medicine Ltd. Shang- lytic activity with a high yield (89%) of benzophenone
hai, China. Benzoyl chloride (98%), phenyl acetyl chloride achieved within 1 h and an excellent yield of 97% was
(98.5%), benzene (99.5%), toluene (99.5%), chlorobenzene achieved after 6 h (entries 5–7). BmimCl–AlCl3 exhibited
(99%) and bromobenzene (99%) were obtained from a local moderate results; a yield of 65% was obtained after 3 h
supplier. N-Methylimidazole (99%) was obtained from (entry 9). BmimCl–ZnCl2, which has been suggested as a
ACROS Organics. 1-Chlorobutane (98%) was purchased
from ABCR (Associação Brasileira de Captadores de Table 1
Recursos) and redistilled before use. The results of Friedel–Crafts reactions between benzene and benzoyl
chloride in different solvents
2.2. General procedures for the synthesis of ILs Entry Solventa Reaction time (h) Yield (%)
b
1 benzene 12 89
1-Butyl-3-methylimidazolium chloride (BmimCl) was 2 benzenec 17 80
synthesized according to known methods [24,25]. 3 benzened 13.1 74
4 benzenee 10.4 50
BmimCl–FeCl3, BmimCl–ZnCl2 and BmimCl–AlCl3 ILs
5 BmimCl–FeCl3 1 85
were prepared according to the procedures described else- 6 BmimCl–FeCl3 4 93
where [22,23]. The colors of the ILs are black, white and 7 BmimCl–FeCl3 6 97
pale yellow, respectively. 8 BmimCl–AlCl3 1 56
9 BmimCl–AlCl3 3 65
10 BmimCl–ZnCl2 7 2
2.3. Reaction procedure and analysis
a
Unless otherwise noted, the amount of ionic liquid is 1 ml, the molar
fraction of MClx in BmimCl–MClx is 0.67 and the reaction temperature is
In a typical reaction procedure, 1 ml of IL was placed in
80 C.
a 10-ml oven-dried round-bottomed flask equipped with a b
Ref. [18], the reaction condition is as follows: benzoyl chloride
stirrer, a reflux condenser and a thermometer. Then 10 mmol, benzene 20 mmol and the catalyst Al2O3–Si–SCF3 is 0.2 g at
7 mmol of benzene (0.56 g) or its derivatives and 3.5 mmol 80 C.
c
of benzoyl chloride (0.49 g) were mixed and heated to Ref. [20], the reaction condition is as follows: benzoyl chloride 1 ml,
benzene 13 ml and the catalyst GaCl3/kaolin is 0.4 g at 80 C.
80 C for the desired time. The mixture was then extracted d
Ref. [20], the reaction condition is the same as c and the catalyst is
with cyclohexane (2 ml · 3), the IL phase was washed with Ga2O3 (20%)/Si-MCM-41.
hexane (3 ml · 2), dried in vacuo and directly reused in e
Ref. [27], the reaction condition is the same as c and the catalyst is
subsequent runs. Quantitative analyses of the reaction In2O3 (20%)/Si-MCM-41.
1836 C. Li et al. / Catalysis Communications 8 (2007) 1834–1837

novel reaction media and a Lewis acid catalyst for Friedel–
Crafts alkylation reactions [22], only afforded a 2% yield at
80 C after 7 h (entry 10). To summarize, for the acylation
of benzene and its derivatives, the catalytic capability of the
ILs is in the following order: BmimCl–FeCl3 > BmimCl–
AlCl3 > BmimCl–ZnCl2. Generally speaking, the catalytic
activity is determined by the acid strength in acid catalysis.
Yang and Kou [26] have determined the Lewis acidity of
some ILs by FT-IR using pyridine as a probe and showed
that Lewis acidity increases in the order BmimCl–
AlCl3 > BmimCl–ZnCl2 > BmimCl–FeCl3 where the molar
fraction of MClx (M = Fe, Zn or Al) is 0.67. To our knowl-
edge, the suitable acidity of IL may play an important role
in the order of acylation capability whilst other side reac-
tions may occur when using BmimCl–AlCl3 or BmimCl–
ZnCl2 as dual solvent and catalyst in our reaction system.
In addition, as BmimCl–AlCl3 is more moisture sensitive
and would be partially decomposed upon contact with
these commercial reagents, this IL is likely to be less effec-
tive. Therefore, the catalytic performance of Lewis acid ILs
in Friedel–Crafts acylation was not only related to the
acidic strength, but was also significantly affected by the
metal ion [27].
It is noteworthy that the work-up for traditional metal
halides promoted aromatic acylation is problematic, where
hydrolysis, neutralization and washes are usually needed,
resulting in side reactions and severe waste production.
In this system, ILs acted as dual catalyst–solvent, the prod-
uct could be readily extracted with a non-polar solvent
such as cyclohexane, escaping tedious work-up and severe
waste discharge. This also suggests that the acylation prod-
ucts are not so strongly associated with FeCl3 in compari-
son with Friedel–Crafts acylation in organic solvents where
FeCl3 is tightly associated with the products [28].
3.2. Synthesis of different aromatic ketones
in BmimCl–FeCl3
Further, we carried out reactions between benzoyl chlo-
ride or phenyl acetyl chloride and various activated or
Table 2
Results of different Friedel–Crafts alcylations in BmimCl–FeCl3 ionic
liquida
Entry Substrate Conversion (%) Yield (%) Selectivityb (%)
deactivated aromatics to explore the reaction scope of
BmimCl–FeCl3 in Friedel–Crafts reactions; the results are
shown in Table 2. As can be seen, all these reactions pro-
ceeded well, whereas the reaction activity varied. Because
the acylation is mechanistically governed by carbenium
intermediates [29], the reactants with electron donating
groups will stabilize the intermediates, leading to higher
conversion as compared to those with electron withdraw-
ing groups. Thus, toluene and ethyl benzene with electron
donating groups showed similar but higher reaction activ-
ities than benzene when acylated with benzoyl chloride
(Table 2, entries 1–3). In comparison, chlorobenzene and
bromobenzene showed poorer results due primarily to the
attachment of electron withdrawing groups (entries 4 and
5). We also revealed significant differences between differ-
ent acylating agents, i.e., benzoyl chloride and phenyl
acetyl chloride (entries 6 and 7). When phenyl acetyl chlo-
ride was employed the yield was much lower and this might
be due to its inferior electron delocalizing ability of the
reactive intermediate.
It should be noted that it is difficult to obtain good
yields in traditional Friedel–Crafts acylation with aromatic
compounds less reactive than benzene [30], whereas in the
catalytic systems presented here, good yields were realized
(entries 4 and 5). This might be due to the strong polarity
and electrostatic field of BmimCl–FeCl3 that stabilize the
carbenium intermediates.
3.3. Recycling and reuse of BmimCl–FeCl3
BmimCl–FeCl3 used as a dual catalyst–solvent was recy-
cled in order to investigate the reusability of the IL. After
extracting the products, the IL was washed with hexane
to remove any leftover organic residues, dried in vacuo
and directly reused in subsequent runs. The results are
shown in Fig. 1. BmimCl–FeCl3 could be recovered with
little activity loss from the first to the third run. However,
the yield dropped drastically to <30% in the fourth run.
80
60
Yield/%

1 Toluene 98 96 12/3/85
2 Ethyl benzene 98 95 12/3/86 40
3 Benzene 93 90 –
4 Chlorobenzene 78 72 5/1/94
5 Bromobenzene 57 53 6/2/92
20
6c Toluene 90 90 4/4/92
7c Benzene 46 46 –
a
The reaction conditions were as follows: 1 ml of BmimCl–FeCl3 IL
0
(molar fraction of FeCl3 = 0.67), 7.0 mmol benzene or its derivatives and 1 2 3 4 5 6 7 8 9 10
3.5 mmol acyl chloride, at 80 C for 3 h. The yields of monoacylated
Run time
products based on GC analysis.
b
meta-Isomer/ortho-isomer/para-isomer. Fig. 1. Reuse of BmimCl–FeCl3 in the Friedel–Crafts benzoylation. For
c
Phenyl acetyl chloride was employed as the acylating reagent. reaction conditions, see footnote in Table 2.
 C. Li et al. / Catalysis Communications 8 (2007) 1834–1837
Similar recycling profiles for ILs have also been observed
during Friedel–Crafts alkylations and acylations promoted
by the Lewis acid ILs BmimCl–FeCl3 and BmimCl–AlCl3
[31–33]. 1H NMR analysis of the recycled sample showed
that trace amount of product was present in the IL layer
[31]. As such, the interaction between the IL and the prod-
ucts can lead to the leaching of metal halide. Other contrib-
utors to activity loss were likely the deteriorative effect of
residual water introduced during work-up and mechanical
losses [34]. We noticed that the molar fraction of FeCl3 in
the BmimCl–FeCl3 was critical for catalysis. When the ILs
were freshly prepared with FeCl3 molar fraction of 0.52
and 0.6, benzophenone yields were about 20% and 65%,
respectively, under identical reaction conditions as those
used for the recycling experiment. Therefore, we tentatively
ascribe the sudden drop in yield in the forth run to cumu-
lative FeCl3 loss during each run which led to an IL sample
with an inferior FeCl3 molar fraction. To take full use of
the BmimCl, after the fourth run, the leftover BmimCl–
FeCl3 was cautiously washed with water (2 ml · 3), dried
in vacuo, and mixed with 2 equiv. of anhydrous FeCl3.
Thus, the in situ regeneration of a functional IL was real-
ized in the following runs (Run 5–7) which afforded good
yields. As can be seen, the reaction yield was only slightly
decreased in comparison with Run 1–3. The third recycle
of BmimCl also showed excellent performance (Run
8–10). Reuse of the novel reaction medium may contribute
to the development of a green strategy for the highly effi-
cient synthesis of benzophenone and its derivatives.
4. Conclusions
The work presented herein discloses a facile and envi-
ronmentally friendly method of preparing benzophenone
and its derivatives using Lewis acid ILs as dual catalyst–
solvent. Among the ILs tested, BmimCl–FeCl3, with inter-
mediate Lewis acidity and good moisture-resistance
showed much higher catalytic activity than conventional
acid catalysts and could be easily recovered for reuse.
Catalysis by ILs avoided the usage of volatile organic
media and led to a considerable simplification in product
isolation. This system can be regarded as an environmen-
tally friendly alternative to the existing homogeneous or
heterogeneous catalytic systems for Friedel–Crafts acyla-
tion reactions.
Acknowledgement
Funding from the Chinese Academy of Sciences ‘‘Hun-
dred of Talents’’ Program was greatly appreciated.
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