Efficient amide formation from arylamines and esters promoted by AlCl 3/Et3N: An experimental and computational investigation

Article abstract of DOI:10.1007/s11164-012-0517-x

Efficient and selective preparation of amides from arylamines and esters has been achieved with an AlCl₃/Et₃N pair under mild conditions. A large number of arylamines were successfully acylated to the corresponding amides in high yields and short reaction times. For instance, a 94% yield of p-bromoacetanilide was obtained from p-bromoaniline and ethyl acetate in 10 min at room temperature. In addition, a computational study on the N-acylation of amines was performed using density functional theory. It was found that the energy barrier for N-acylation of aniline is 10 kcal/mol higher than that of methylamine. In the presence of AlCl3, the activation energy for the N-acylation of aniline was reduced by 27.7 kcal/mol with the endothermic process becoming exothermic. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0517-x

Res Chem Intermed (2012) 38:1961–1968
DOI 10.1007/s11164-012-0517-x
Efficient amide formation from arylamines and esters
promoted by AlCl3/Et3N: an experimental
and computational investigation
•
•
•
Xinli Tong Zhangshun Ren Xiaolong Qu¨
•
Qiwu Yang Wenqin Zhang
Received: 26 January 2012 / Accepted: 21 February 2012 / Published online: 6 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Efficient and selective preparation of amides from arylamines and esters has
been achieved with an AlCl3/Et3N pair under mild conditions. A large number of
arylamines were successfully acylated to the corresponding amides in high yields and
short reaction times. For instance, a 94% yield of p-bromoacetanilide was obtained from
p-bromoaniline and ethyl acetate in 10 min at room temperature. In addition, a com-
putational study on the N-acylation of amines was performed using density functional
theory. It was found that the energy barrier for N-acylation of aniline is 10 kcal/mol
higher than that of methylamine. In the presence of AlCl3, the activation energy for the
N-acylation of aniline was reduced by 27.7 kcal/mol with the endothermic process
becoming exothermic.
Keywords Amide Á N-acylation Á Arylamines Á AlCl3/Et3N pair Á DFT calculations
Introduction
The N-acylation of amines is one of the most important transformations carried out in
organic synthesis [1, 2], and the amide products are of biological and synthetic
significance in medicinal chemistry [3–6]. N-aryl amides especially represent a very
important family of intermediates widely employed in the preparation of fine chemicals,
Electronic supplementary material The online version of this article
(doi:10.1007/s11164-012-0517-x) contains supplementary material, which is available
to authorized users.
X. Tong Á Z. Ren Á X. Qu¨ Á Q. Yang Á W. Zhang (&)
Department of Chemistry, Tianjin University, Tianjin 300072, People’s Republic of China
e-mail: zhangwenqin@tju.edu.cn
X. Tong
School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384,
People’s Republic of China
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X. Tong et al.
cosmetics, and food additives [7–9]. However, owing to the existence of the p–p
conjugation effect, arylamines are lessactive thanprimary aliphatic amines [10,11];thus,
the efficient and selective N-acylation of arylamines is an attractive research objective.
Current N-acylation methods of arylamines generally involve the use of toxic and
corrosive reagents (acid anhydride or acyl chloride) with poor atom economy, which
generate considerable waste [12–14]. In addition, these reactions are water-sensitive
and the efficient removal of water is a critical factor in the system [14, 15].
Considering economic cost and cleaner synthesis protocols, the direct N-acylation
of arylamines with inexpensive carboxylic acids or esters is a very promising
approach [7, 15–18]. In recent years, several catalytic methodologies and efficient
catalytic systems have been developed for the preparation of N-aryl amides from the
N-acylation of amines with carboxylic esters [19–28]. For example, catalyst systems
containing an organomagnesium reagent [19], lithium amide base [20], and sodium
hexamethyldisilazide [21] have been reported for the N-acylation of aniline.
Moreover, the use of metallic aluminum as the promoter has also been carried out
[22–28]. Specifically, Novak et al. [27] reported the efficient synthesis of primary
amides in the presence of air-stable (AlMe3)2ÁDABACO (1, 4-diazobicy-
clo[2.2.2]octane), and Gustafsson et al. [28] found that AlMe3 could successfully
mediate amide bond formation in a microreactor system during the preparations of
rimonabant and efaproxiral. These investigations showed that aluminum-containing
compounds have a remarkable promotion effect in the N-acylation of arylamines
with esters, which is a hopeful direction for future industrial applications.
For the last 40 years, much attention had been given to the study of the mechanism
for the N-acylation of amine with esters [29–31]. Menger and Smith [30] proposed the
possible formation of a tetrahedral intermediate and indicated that the collapse of the
tetrahedral intermediate could be the rate determining step. Moreover, Zipse et al. [31]
have studied the model system for the polyether-catalyzed aminolysis of esters using
an ab initio method, and found that the reaction occurred via a direct displacement
pathway. Recently, Drueckhammer et al. [32] reported that the aminolysis of
oxoesters and thioesters occurred as a stepwise mechanism, and that the activation
energy could be decreased owing to water-promoting proton transfer. Schaefer et al.
[33] found that all transition states in the base-catalyzed aminolysis of methylformate
with ammonia are 10–17 kcal/mol lower than those in the uncatalyzed process.
However, up to now, no theoretical investigations of the N-acylation of arylamines
promoted by Lewis acid have been performed.
In this paper, the efficient and selective N-acylation of arylamines with carbox-
ylic esters has been successfully performed using a simple and inexpensive AlCl3/
Et3N pair under mild conditions. The carbonyl group of the carboxylic ester is
activated by AlCl3 and the reaction is further impelled owing to the formed acid
being neutralized with Et3N. Furthermore, the role of AlCl3 and the reaction
mechanism has been investigated using the density functional theory (DFT) method.
Results and Discussion
In the first series of experiments, the acetylation of arylamines with ethyl acetate in
the presence of AlCl3/Et3N at room temperature (Scheme 1) was investigated and
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An experimental and computational investigation
1963
the results are summarized in Table 1. It was found that a 96% yield of acetanilide
was obtained for acetylation of aniline in 5 min (entry 1). When o-methoxyaniline
or p-methyoxyaniline was acetylated, a 90 or 86% yield of the corresponding
methoxyacetanilide was obtained, respectively (entries 2 and 3). Similarly, in the
cases of o-methylaniline and p-methylaniline, the obtained product yields were both
90% in 10 min (entries 4 and 5), which means that the methoxy and methyl groups
have no steric ‘‘ortho effect’’ in the reaction. When the aniline was substituted with
F, Cl or Br, the yield of the corresponding acetanilide remained in the 80–94%
range (entries 6–11), and the para-substituted reactants are more active than the
ortho-substituted ones. This is especially true for the acetylation of p-bromoaniline.
A 94% yield of p-bromoacetanilide was obtained in 10 min (entry 11). However,
Scheme 1 The acetylation of
arylamines with ethyl acetate
Table 1 Acetylation of arylamines with ethyl acetate mediated by AlCl3/Et3N
Entry
R
Time
Yield (%)a
1
H
5 min
30 min
10 min
10 min
10 min
5 min
10 min
10 min
10 min
3 h
96
90
86
90
90
89
93
85
88
80
94
trace
74c
53d
91
93
94
2
o-MeO
p-MeO
o-CH3
p-CH3
o-F
3
4
5
6
7
p-F
8
o-Cl
9
p-Cl
10b
11
12c
13
14c
15
16
17
o-Br
p-Br
10 min
24 h
o-NO2
p-NO2
2,6-(CH3)2
m-NO2
3,5-(CF3)2
a-Naphthyl
20 min
24 h
10 min
10 min
30 min
Reaction conditions: arylamine (0.02 mol) was acetylated with ethyl acetate (0.10 mol), in the presence
of AlCl3 (0.018 mol) and Et3N (0.054 mol) at room temperature
a
Isolated yields after recrystallization
b
The reaction is performed under refluxing
c
The precipitated p-nitroacetanilide was combined with those dissolved in EtOAc after the acidification
d
The unreacted arylamine was detected by TLC after the reaction
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X. Tong et al.
only an 80% yield of o-bromoacetanilide was obtained from o-bromoaniline after
being refluxed for 3 h (entry 10). The steric and dipole effects of the bromine atom
at the ortho-position are probably responsible for the low activity. Nitroanilines
were also used to investigate the promotion effect of the AlCl3/Et3N pair. It was
found that p-nitroaniline could be acetylated with ethyl acetate and a 74% product
yield was obtained (entry 13); whereas, o-nitroaniline was nearly inert in the
acetylation process (entry 12), which indicates that the ortho-electron-withdrawing
nitro group offers the greatest negative steric and dipole effects. In the case of 2,
6-dimethylaniline, only a 53% yield of 2,6-dimethylacetanilide was obtained after
being refluxed for 24 h (entry 14) due to the ortho steric effect of the two methyl
groups. However, when m-nitroaniline or 3, 5-di(trifluoromethyl)aniline was used as
a substrate, excellent product yields (91–93%) were obtained in 10 min (entries 15
and 16). These results show that the ortho-position steric effect obviously hinders
the reaction, and that the meta-electron withdrawing groups are not sensitive to the
acetylation reaction. In addition, in the case of a-naphthylaniline, a 94% yield of
N-a-naphthyl acetamide was obtained (entry 17), which indicates this system is also
suitable for N-acylation of fused ring aromatic compounds.
The N-acylation of aniline with different esters in the presence of AlCl3/Et3N
was also investigated and the results are shown in Table 2. A 96 or 71% yield was,
respectively, obtained in 10 min when aniline was N-acylated with ethyl formate or
ethyl propionate (entries 1 and 2). Aromatic esters were also employed as N-acylating
agents in the reaction. When ethyl benzoate or ethyl isonicotinate was used, the yield
of N-phenylbenzamide or N-phenylisonicotinamide was 92 or 80% after 5 min,
respectively (entries 3 and 4). In the case of ethyl chloroacetate, a 92% yield of
2-chloroacetanilide was obtained in 15 min (entry 5). Remarkably, the nucleophilic
substitution product of ethyl N-phenylglycinate was not detected. A 95% yield of
N-phenylcinnamide was obtained when methyl cinnamate was used as the
N-acylating agent (entry 6), and no Michael addition product was formed. These
experiments indicate that this method has satisfactory chemoselectivity.
In Table 3, a series of aliphatic and aromatic amines and esters were employed
for the N-acylation reaction using the AlCl3/Et3N pair. Benzylamine and several
other aromatic amines were successfully N-acylated with ethyl benzoate and ethyl
Table 2 N-acylation of aniline with different esters in the presence of AlCl3/Et3N
Entry
Esters
Time (min)
Yield (%)a
1
2
3
4
5
6
HCOOEt
10
10
5
96
71
92
80
92
95
C3H7COOEt
Ethyl benzoate
Ethyl isonicotinate
ClCH2COOEt
Methyl cinnamate
5
15
60
Reaction conditions: aniline (0.02 mol) was acetylated with a special ester (0.10 mol), in the presence of
AlCl3 (0.018 mol) and Et3N (0.054 mol) at room temperature
a
The data are the isolated yields after chromatographic purification
123

An experimental and computational investigation
1965
butyrate, and the yields of the corresponding products were 70–93% (entries 1–5).
These results show that the AlCl3/Et3N pair is effective for both aliphatic/aromatic
amines and esters. When benzylamine and n-butylamine were used to react with
methyl cinnamate, the high yields of 93 and 94% further demonstrated the pair’s
excellent selectivity for the N-acylation process rather than the Michael addition.
In order to further investigate the mechanism for the N-acylation of amines and
the promotion effect of AlCl3, DFT calculations (see SI) were carried out with a
computational method similar to one previously reported in the literature [33].
Ammonia was chosen as a proton transfer reagent to replace aniline in order to
simply the calculations. The stepwise pathway for the N-acylation reaction starts
with the addition of the N atom from aniline and the H atom from ammonia to the
C=O bond in the ester (Fig. 1). The reaction intermediates occur when the carbonyl
carbon is converted to sp3 hybridized and a hydrogen bond is formed between the
Table 3 N-acylation of different amines with carboxylic esters in the presence of AlCl3/Et3N
Entry
Arylamines
Esters
Time
Yield (%)a
1
2
3
4
5
6
7
Benzylamine
Ethyl benzoate
40 min
5 min
2 h
87
93
70
93
86
94
93
4-Methoxyaniline
4-Nitroaniline
2-Bromoaniline
2-Methoxyaniline
Benzylamine
24 h
C3H7COOEt
30 min
40 min
2 h
Methyl cinnamate
n-Butylamine
Reaction conditions: amines (0.02 mol) were acetylated with different esters (0.10 mol), in the presence
of AlCl3 (0.018 mol) and Et3N (0.054 mol) at room temperature (entries 2, 3 and 7) or under reflux
(entries 1, 4–6)
a
The data were isolated yields after chromatographic purification
Fig. 1 The energy profiles for acetylation of aniline with ethyl acetate in the presence of ammonia. The
values in kcal/mol are relative free energies optimized in toluene (data at the top line), in the gas-phase at
298.15 K (data in the round brackets) and in the gas-phase at 0 K (data in the square brackets)
123

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X. Tong et al.
reaction intermediate and ammonia. The C–O bond then rotates and the position of
ammonia shifts with the assistance of the hydrogen bond in the transition states.
Next, another hydrogen transfer transition state occurs and the transition vector
corresponds to this proton transfer, yielding the recovery of the C=O double bond,
which leads to the formation of the amide. In addition, the acetylation of
methylamine was calculated (for the energy profile, see SI). It was found that the
rate-determining step for the reaction is the first addition process, and the energy
barrier for acetylation of aniline is 10 kcal/mol higher than that of methylamine.
Moreover, in the acetylation of methylamine, the whole process is exothermic and a
high temperature is advantageous to advance the reaction, whereas, in the
acetylation of aniline, the whole process is endothermic and the reaction equilibrium
tends towards the reactants under typical conditions. Thus, it is concluded that the
N-acylation reactions of aliphatic amines can be performed without a catalyst;
however, in the N-acylation of arylamines, a special activation step or promoter is
needed. This validates the experimental results presented above and those previ-
ously reported in the literature [34–37].
In order to explain the promotion effect of the AlCl3/Et3N pair, the role of AlCl3
in the acetylation of aniline and the energy profiles were also investigated and the
results are given in Fig. 2. Therein, the carbonyl in the ester coordinates with AlCl3
which improves the electrophilicity of the carbonyl group. This greatly decreases
the activation energy for the acetylation of aniline, and the endothermic process
becomes exothermic. The calculated energy barrier is only 10.8 kcal/mol which is
27.7 kcal/mol lower than that without AlCl3. Furthermore, the rotation of the C–O
bond and the hydrogen transfer is hardly affected by AlCl3 during the reaction. The
acylated product can be stabilized by AlCl3 which facilitates the whole process and
increases the product selectivity (for the structures of intermediates and product, see
SI). These theoretical calculations agree well with our experimental results. In
addition, the Et3N is helpful for the removal of the formed acid, and thus the
efficiency of the AlCl3/Et3N pair is confirmed for the N-acylation of arylamines.
Fig. 2 The energy profiles for acetylation of aniline with ethyl acetate promoted by AlCl3. The values in
kcal/mol are relative free energies optimized in toluene (data at the top line), in the gas-phase at 298.15 K
(data in the round brackets) and in the gas-phase at 0 K (data in the square brackets)
123

An experimental and computational investigation
1967
Experimental
Reagents
Aniline, ethyl acetate, and other liquid substrates were purified by rectification.
AlCl3 and Et3N were purchased from Alfa Aesar-A Johnson Matthey. All other
reagents used were analytical grade without further treatment.
General procedure for N-acylation of various Arylamines
All N-acylation experiments were performed in a 100-mL round-bottom flask
equipped with magnetic stirring and automatic temperature control. The typical
procedure for N-acetylation of aniline was as follows: a solution of aniline
(0.02 mol) and ethyl acetate (0.01 mol) were charged into the round-bottom flask;
under stirring, the temperature was kept at 25 °C for the certain time. After the
reaction, the crude product was obtained after the distillation of reaction mixture.
The obtained product was further purified through the recrystallization and the yield
was calculated based on the weight of pure product.
Conclusion
In summary, highly efficient N-acylation of arylamines with different esters was
successfully performed with an AlCl3/Et3N pair under mild conditions. In addition,
DFT calculations indicate that, in the presence of AlCl3, the activation energy for
the acetylation of aniline is greatly reduced with the endothermic process becoming
exothermic.
Acknowledgement This work was financially supported by the National Natural Science Foundation of
China (Project No 20834002 and No 21003093).
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