A new efficient method for the preparation of intermediate aromatic ketones by Friedel–Crafts acylation

Article abstract of DOI:10.1007/s11164-018-3437-6

Abstract: As the most important method to prepare pharmaceutical and chemical intermediate aromatic ketones, Friedel–Crafts (F–C) acylation is used to seek a novel catalytic system which is imminently consistent with the concept of green chemistry. In this study, six deep eutectic solvents (DES) were synthesized for the Friedel–Crafts acylation reaction as a catalytic solvent. Among the six DES, choline chloride-zinc chloride ([ChCl][ZnCl₂]₂) proved to be the most competent candidate of electron-rich arenes with acylation reagent. It got the highest yield when 1.0 equivalent of [ChCl][ZnCl₂]₂ used with acyl halides at 70?°C. Recycled DES was reused directly without any extra process. After five cycles, the catalytic activity did not decrease significantly (80–85%). Finally, according to experimental validation, the possible mechanism of this reaction was considered. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-018-3437-6

Res Chem Intermed
https://doi.org/10.1007/s11164-018-3437-6
A new efficient method for the preparation
of intermediate aromatic ketones by Friedel–Crafts
acylation
Xiaojun Jin1 Ailing Wang1,3 Hongyu Cao2,3 Shujia Zhang1
•
•
•
•
Lihao Wang1 Xueliang Zheng1 Xuefang Zheng2,3
•
•
Received: 21 December 2017 / Accepted: 18 April 2018
Ó Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract As the most important method to prepare pharmaceutical and chemical
intermediate aromatic ketones, Friedel–Crafts (F–C) acylation is used to seek a novel
catalytic system which is imminently consistent with the concept of green chemistry. In
this study, six deep eutectic solvents (DES) were synthesized for the Friedel–Crafts
acylation reaction as a catalytic solvent. Among the six DES, choline chloride-zinc
chloride ([ChCl][ZnCl2]2) proved to be the most competent candidate of electron-rich
arenes with acylation reagent. It got the highest yield when 1.0 equivalent of
[ChCl][ZnCl2]2 used with acyl halides at 70 °C. Recycled DES was reused directly
without any extra process. After five cycles, the catalytic activity did not decrease
significantly (80–85%). Finally, according to experimental validation, the possible
mechanism of this reaction was considered.
Graphical Abstract
&
&
Ailing Wang
wangailing@dlu.edu.cn
Xuefang Zheng
dlxfzheng@126.com
1
2
3
Department of Chemical Engineering, Dalian University, Dalian 116622, China
College of Bioengineering, Dalian University, Dalian 116622, China
Liaoning Key Laboratory of Bio-Organic Chemistry, Dalian University, Dalian 116622, China
123

X. Jin et al.
Keywords Aromatic ketones Á Friedel–Crafts Á Acylation Á Deep eutectic
solvent
Introduction
The aromatic ketone compounds are important chemical products and intermediates
in pharmaceutical, dyes, pesticides and other fields [1], and the most important
method for preparing aromatic ketones is the F–C acylation reaction currently. In
1877, Friedel and Crafts discovered and demonstrated that aluminum halides
catalysts were effective for the acylation of aromatic compounds [2], therefore
named F–C acylation. F–C acylation reaction has become a very important reaction
and attracted a lot of attention [3, 4] for being a simple reaction system, with high
responsiveness and selectivity. In general, the reaction concerns the introduction of
a carbonyl on the benzene rings to obtain the corresponding aromatic ketone. Lewis
acid and Bronsted acids are the first reported and most common catalyst [5, 6],
however, these traditional catalysts also present a series of problems, such as heavy
dosage, rebelliousness, and the poor reusability, etc. The resulting environmental
problems contradict the concept of green chemistry. Based on this for a long time,
various environmentally friendly catalytic methods have been studied to replace
conventional catalysts, including super acid/salt [7–10] (solid acid, heteropoly acid,
etc.), ionic liquids [11–13], Zeolite [14, 15], support catalysts [16, 17] and others
[18, 19].
As a cheap, non-toxic, biodegradabile and environmentally friendly solvent, DES
was coined from 2003 [20] by Abbott et al. Until now [21], it has attracted a wide
range of concerns [22–24]. Due to the similarities of physicochemical properties, it
is categorized to the Ionic Liquid (ILs) [25, 26]. Compared to traditional organic
catalysts, it has the excellent nature of stability in water, simple preparation, post-
processing, biodegradable, biocompatible and non-toxic. It is completely consistent
with the standard of green solvents [27] and has been utilized in many commercial
applications and research areas, such as organic synthesis [28], electrochemistry
[29, 30] and material chemistry [31].
We have recently reported the DES-catalyzed F–C alkylation reaction to
electron-rich aromatic arenes and aldehydes [32] and achieved relatively good
results. Based on this work, we hereby present a DES-catalyzed F–C acylation
reaction to prepare the aromatic ketone by electron-rich aromatic arenes and the
acylation reagent. Some important factors, such as system temperature, reaction
time, catalyst ratio and reaction substrate (electron-rich aromatic arenes and
acylation reagent) were investigated. Moreover, the reusability of DES was
discussed. Finally, according to the existing theoretical and experimental facts, the
potential catalysis mechanisms were investigated.
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A new efficient method for the preparation of…
Experimental
Preparation of DES
Six DESs were synthesized according to previous work [33], following the detailed
procedure as shown below. The choline chloride (ChCl) [or Benzyltrimethylam-
monium Chloride (TMBAC), Triethylamine borane (TEAB)] with ZnCl2 [or
Trifluoromethanesulfonic acid (CF3SO3H), p-toluenesulfonic acid (p-TsOH)] was
put into a round bottom flask at the certain molar ratio, and then the mixture was
stirred at 120 °C. After the reaction was complete, a clear solution was obtained.
DES can be utilized directly without any purification.
General procedure for aromatic ketone compounds synthesis
A mixture of electron-rich arenes a (2.0 mmol), acylation reagent b ((2.0 mmol)
and catalytic solvent DES [ChCl][ZnCl2]2 (2.0 mmol) were added and stirred in a
25 mL round-bottomed flask at 70 °C for the desired time. The reaction procedure
was monitored by TLC and recorded the experimental phenomena. After
completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were
added to the mixture and then cooled to room temperature, collecting the product
and solvent from the organic phase and water, respectively. The organic phase was
washed with saturated sodium hydrogen carbonate solution and saturated brine
successively, then evaporated under high vacuum to give the target compound. Pure
DES was obtained by drying sufficiently in a vacuum, and it could be reused for
another cycle.
Results and discussion
Selection of DES
In the present experiment, 1,2,4-trimethoxybenzene (a1) and benzoyl chloride (b1)
were selected as model reaction substrates, while the traditional Lewis acid ZnCl2
and different types of DES were used as catalytic systems ,respectively, to
investigate the synthesis of the expected aromatic ketone compound 2,4,5-
trimethoxybenzophenone (c1). The progress of the reaction was monitored by the
thin layer chromatography (TLC). The results are shown in Table 1.
There is a poor yield of 27% (Table 1, Entry 1) when 1.0 eq ZnCl2 was used as
the catalyst under 1,2-dichloroethane solvent at 65 °C for 1 h. Secondly, 1.0 eq of
DES, such as [TMBAC]1.5[ZnCl2]2, [TEAB][p-TsOH]2, [ChCl][ZnCl2]2,
[TMBAC][p-TsOH] and [TMBAC][CF3SO3H], were used as the the catalytic
system, respectively, and without any extra solvents. Only [TMBAC]1.5[ZnCl2]2
(34%) and [ChCl][ZnCl2]2 (74%) as the catalyst system, which contains Lewis acids
ZnCl2 (Table 1, Entries 2,7), had the expected compounds that could be achieved.
The reaction did not proceed in use of remaining proton acid-type DES [ChCl][p-
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X. Jin et al.
Table 1 Friedel–Crafts alkylation reaction of 1,2,4-trimethoxybenzene (a1) and benzoyl chloride (b1) in
the presence of DES
O
OMe
OMe
OMe
OMe
O
Catalyst
70°C
+
Cl
MeO
c1
MeO
a1
b1
Entry
Catalyst
Time (h)
Yielda (%)
1
2
3
4
5
6
7
ZnCl2
2
1
27b
34
0
[TMBAC]1.5[ZnCl2]2
[TMBAC][p-TsOH]
[TEAB][p-TsOH]2
[TMBAC][CF3SO3H]
[ChCl][p-TsOH]
12
12
12
12
1
0
0
0
[ChCl][ZnCl2]2
74
Reaction conditions: a1 (2.0 mmol), b1 (2.0 mmol), DES (2.0 mmol), 65 °C, solvent-free
aIsolated yields after column chromatography
b1,2-dichloroethane as solvent
TsOH],[TMBAC][p-TsOH],[TEAB][p-TsOH]2 and [TMBAC][CF3SO3H] (Table 1,
Entries 3–6). Thereby, the experiment results indicated that the synthesized protonic
acid-type DES had no catalytic activity on this F–C acylation reaction, while Lewis
acid ZnCl2 and its eutectic salts, which formed by quaternary ammonium salts such
as Benzyltrimethylammonium Chloride (TMBAC) and Choline chloride (ChCl),
could effectively promote the reaction. The following experiment will screen out the
best reaction conditions and the substrate of F–C acylation reaction when
[ChCl][ZnCl2]2 is the catalytic solvent.
Optimization of the reaction conditions
The 1,2,4-trimethoxybenzene (a1) and benzoyl chloride (b1) as the model substrates
(Table 2) were used to investigate the reaction conditions through measuring the
reaction yield at different temperatures and times. Experimental results demonstrate
that the reaction cannot proceed in the absence of [ChCl][ZnCl2]2, even after 24 h
(Table 2, Entry 1). As the quantity of [ChCl][ZnCl2]2 increases, the yields promoted
gradually (Table 2, Entries 2–5) until up to 1 eq, and the reaction was expected to
be completed with a yield of 83% (Table 2, Entry 6). With additional DES, it will
not further improve the yield (Table 2, Entries 4–6). The reaction occurred more
quickly after raising the temperature (Table 2, Entries 4, 7–9). However, the
reaction time will not be further shortened as the temperature rises again, the yield
will also decrease (Table 2, Entries 9 and 10) due to the formation of the by-
products after exceeding a certain temperature (70 °C).
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A new efficient method for the preparation of…
Table 2 Friedel–Crafts
alkylation reaction
Entry
Catalyst (eq)
Temp (°C)
Time (min)
Yielda (%)
[ChCl][ZnCl2]2 catalyzed
Friedel–Crafts Acylation
reaction of a1 with b1 in
different conditions
1
0
65
65
65
65
65
65
60
70
85
90
24 (h)
90
0
22
58
83
83
81
68
85
74
68
2
0.2
0.5
1.0
1.5
2.0
1.0
1.0
1.0
1.0
3
90
4
60
5
60
6
60
7
40
Reaction conditions: a1
(2.0 mmol), b1 (2.0 mmol),
DES (2.0 mmol), solvent free
aIsolated yields after column
chromatography
8
30
9
20
10
20
Selection of the substrates
The effect of substrates was measured on the basis of the production yield in this
catalytic system. We screened the acylation reagent and the electron-rich aromatic
arenes under the optimum experimental conditions.
Using different acylating reagents (b) reacting with 1,2,4-trimethoxybenzene
(a1), [ChCl][ZnCl2]2 continues as the catalytic solvent (Table 3). Based on the
results, benzoyl chloride (b1) reacted with a1 to a relatively higher yield (85%)
(Table 3, Entry 1) in relation to p-toluenesulfonyl chloride (56%) (Table 3, Entry
7). Moreover, the reactivity of the anhydride is poorer than that of acyl halides
(Table 3, Entries 3 and 8), and even some anhydride could not obtain the target
product (Table 3, Entry 9) due to the poorer electron-withdrawing ability than acyl
chloride. In addition, the presence of p-toluenesulfonyl chloride caused larger steric
hindrance and poorer electron-withdrawing ability. Moreover, the larger reaction
yield of benzoyl chloride (Table 3, Entry 1) instead of linear acyl chloride (Table 3,
Entries 2–5), had the yields reduced (83, 80, 80, 75%) as the chain length increased.
Simultaneously, additional chlorine will further reduce the electrophilic ability
(33%, Entry 6). From Table 3, we found that the carbocation produced by the acyl
chloride reacted admirably with electron-rich aromatic arenes, which is consistent
with the general theory.
Hereafter, the applicable species of the electron-rich aromatic arenes in this
reaction system were investigated under the optimal reaction conditions. The
reaction results of multifarious electron-rich aromatic arenes (a) with benzoyl
chloride (b1) are presented in Table 4. We found that the product yields were
affected by both the electron-donating ability and steric hindrance of the electron-
rich aromatic arenes. The experimental results suggest that the yield of compounds
c1 was lower than c2 (Table 4, Entries 1 and 2), but theoretically, the electron-
donating ability of trimethoxybenzene (a1) is stronger than that of dimethoxyben-
zene (a2), which can be explained by the inhibition of the 5-methoxy group in a1.
The same explanation applies to c12 and c13 (Table 4, Entries 4 and 5). Moreover,
the yield of compounds c10, c11, c12 decreases in turn (86, 82, 78%), which can be
also available due to the promoting of the ortho-para directing group and the
123

X. Jin et al.
Table 3 [ChCl][ZnCl2]2 catalyzed Friedel–Crafts acylation reaction of various acylating agents
Entry
a
b
Product
Time (min)
Yielda(%)
O
O
OMe
OMe
Cl
1
a1
30 min
85
MeO
b1
c1
c2
O
O
OMe
Cl
2
3
a1
a1
30 min
30 min
83
80
MeO
OMe
b2
O
O
OMe
OMe
Cl
MeO
b3
c3
c4
O
O
OMe
OMe
Cl
4
5
6
a1
a1
a1
35 min
40 min
100 min
80
75
33
MeO
b4
b5
O
O
OMe
OMe
Cl
MeO
c5
O
O
Cl
OMe
OMe
Cl
Cl
MeO
b6
b7
c6
OMe
OMe
O
S
O
MeO
H3C
H
C
SO Cl
2
3
7
a1
90 min
56
c7
O
O
O
8
9
a1
a1
1 h
2 h
72
0
c8
b8
O
O
OMe
OMe
O
O
HOOC
MeO
b9
c9
Reaction conditions: a1 (2.0 mmol), b1 (2.0 mmol), DES (2.0 mmol), 70 °C, solvent free
aIsolated yields after column chromatography
suppression of the meta directing group (Table 4, Entries 2–4). However, we also
found the reaction cannot proceed for some aromatic compounds (Table 4, Entries 7
and 8) in the presence of electronic withdrawals group and weak electron donating
groups. Compared to completely non-reactive toluene, thiophene reacted oppor-
tunely but only 45% (Table 4, Entry 6), which can be interpreted that both the
induced effect and the conjugate effect exist simultaneously but offset each other,
showing weak electrons donate.
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A new efficient method for the preparation of…
Table 4 [ChCl][ZnCl2]2 catalyzed Friedel–Crafts alkylation reaction of various electron-rich arenes
Entry
1
a
b
Product
Time
Yielda(%)
OMe O
O
2
3
1
6
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
a1
30 min
85
4
MeO
5
OMe
b1
c1
OMe O
O
2
3
1
6
2
3
4
5
6
7
8
a2
a3
a4
a5
a6
a7
a8
30 min
35 min
40 min
45 min
90 min
12 h
86
82
78
80
45
0
4
MeO
5
b1
c10
O
O
2
MeO
MeO
3
4
1
6
5
b1
c11
OMe O
O
2
3
4
1
6
5
OMe
b1
c12
O
O
OMe
b1
c13
O
O
S
b1
c14
O
O
NO
2
OMe
b1
c15
O
O
12 h
0
Me
b1
c16
Reaction conditions: a (2.0 mmol), b1 (2.0 mmol), DES (2.0 mmol), 70 °C, solvent free
aIsolated yields after column chromatography
Therefore, in this [ChCl][ZnCl2]2 catalyzed F–C acylation reaction system, the
strong electron-donating aromatics system reacted excellently with the acyl halides
for its strong electron-withdrawing ability.
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X. Jin et al.
DES recycling
[ChCl][ZnCl2]2 (2.0 mmol) was used to catalyze the model reaction of substitution
a1 (2.0 mmol) with b1 (2.0 mmol) at 70 °C. After the completion of the reaction,
10 mL of water and 10 mL ethyl acetate were added to the reaction mixture for
separating the products. The dissolved [ChCl][ZnCl2]2 in the aqueous phase can be
produced by evaporating under high vacuum at 70 °C for 12 h. Recycled DES can
be reused for another cycle directly without any extra progress. The yields of
80–85% were achieved during the five recycling cycles (Fig. 1). The results
demonstrated that the DES-based catalyst was stable.
Potential mechanism catalyzed by DES
In 2012, Azizi’s group [34] succeeded in achieving the conversion of steroid
derivatives through electrophilic substitution reaction in different DES, and realized
the catalyzed F–C reaction of aldehydes and confirmed the best catalytic effect of
ChCl/SnCl2. In this paper, depending on the same mechanism of electrophilic
substitution reaction, the possible mechanism of F–C acylation of acyl compounds
catalyzed by [ChCl][ZnCl2]2 has been deduced (Fig. 2). With [ChCl][ZnCl2]2 as
solvent and catalyst in the entire system, forming an electrostatic mask ring-like
-
body, then Zn2Cl5 as a nucleophile attacks carbonyl oxygen to break the carbon–
oxygen double bond, and then triggers electron transfer to achieve the carbon-
chlorine bond breakage forming free Cl- and carbon cationic intermediates.
Carbocation attacks the rich electron aromatic arenes to form carbon–carbon bonds
for the generation of the target compound, while the liberated hydrogen and chloride
ions combine to generate a molecular hydrogen chloride.
Fig. 1 Recycling of [ChCl][ZnCl2]
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A new efficient method for the preparation of…
Fig. 2 Mechanism of Friedel–Crafts acylation reaction catalyzed by DES
Conclusion
In the synthesis of the aromatic ketone compound by F–C acylation with the
electron-rich aromatic arenes and acylating agent, the synthesized Deep Eutectic
Solvent [ChCl][ZnCl2]2 exhibits excellent catalytic effect under optimum reaction
conditions. After completion of the reaction, the recovered catalyst can be employed
for the next reaction without any extra treatment and maintain stable activity. The
method has the advantages of simple operation, high yield and environmental
friendliness, which are consistent with the concept of green chemistry. In summary,
this article provides an environmentally friendly method for the synthesis of
aromatic ketone compounds.
Acknowledgements The project was supported by the National Natural Science Foundation of China
(21506018, 21571025 and 21601025), Research Fund for the Doctoral Program of Liaoning Province,
China (201601308) and Research Fund for the Doctoral Program of Dalian University (20152QL011).
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