Chemical Papers 68 (2) 164–169 (2014)

DOI: 10.2478/s11696-013-0433-6

ORIGINAL PAPER

Synthesis of ethyl-6-aminohexanoate from caprolactam and ethanol

in near-critical water

Zhi Qiang Hou, Li Gang Luo, Chun Ze Liu, Yuan Yuan Wang*, Li Yi Dai*

Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry,
East China Normal University, 200062 Shanghai, China

Received 6 February 2013; Revised 10 April 2013; Accepted 30 April 2013

The reaction between caprolactam and ethanol was performed in near-critical water. The pri-
mary product (ethyl-6-aminohexanoate) was identified by GC-MS. The influences of the reaction
temperature, residence time, initial ratio (reactant/water), pH, and additives on the yields of ethyl-
6-aminohexanoate are discussed. The results showed that the yield of ethyl-6-aminohexanoate could
be as high as 98 % with SnCl2 as an additive in near-critical water. At the same time, the reaction
between caprolactam and ethanol was estimated by a lumped kinetic equation as a second-order
reaction in near-critical water, and the activation energy was evaluated according to the Arrhenius
equation under acidic and basic conditions. Based on the results, the reaction mechanism between
caprolactam and ethanol in near-critical water is proposed.

c 2013 Institute of Chemistry, Slovak Academy of Sciences

Keywords: near-critical water, caprolactam, ethanol, ethyl-6-aminohexanoate, kinetics, mecha-

nism

Introduction increase in both the methyl and ethyl ester contents

The synthesis of esters played a significant role in
industrialisation because the esters were widely used
in daily life (Riemenschneider & Bolt, 2005). The tra-
ditional synthesis was performed using H2 SO4 as a
catalyst at high temperature and this method suf-
fered from some disadvantages, such as low yield,
harsh terms, corrosion, etc. The alcoholysis (Pacher
et al., 2010) of the acid amide and alcohol was a
new method of synthesising the organic ester com-
pounds and the reaction also needed acids, bases, or
some salts (Sn2+ , Cu+ , etc) as catalysts. Feng and
co-workers (He et al., 2004) investigated the effects
of water and alcohol on the mechanisms of alcoholy-
sis of N-methyl-1,2-thiazetidine-1,1-dioxide using the
B3LYP/6-31g*. Their results showed that the wa-
ter and alcohol-assisted alcoholysis of N-methyl-1,2-
thiazetidine-1,1-dioxide greatly reduced the activation
energy over the non-assisted reaction. Vieitez and co-
workers also reported that the addition of water to a
level of 10 mass % to the reaction medium led to an
by the combination of two favourable effects: increas-
ing the reaction rate and reducing the degradation of
fatty acids (Vieitez et al., 2010).
At the same time, water as a medium for non-
enzymatic organic reactions was investigated in the
past decades. Near-critical water (NCW, 423.15–
643.15 K, 0.4–21.8 MPa) (Mi et al., 2010; Abdula-
gatov et al., 1998; Yuksel et al., 2011; Bicker et al.,
2005; Watanabe et al., 2004, 2007; Díez Pascual et
al., 2007; Liu & Tobita, 2010; Kao et al., 2012; Rana
& Chandra, 2012; Delaney et al., 1982) can serve as
an environmentally acceptable solvent, a reactant and
catalyst in organic chemical reactions due to its special
properties, such as high solubility of various materi-
als, the high ion product, low dielectric constant, and
no pollution to the environment. NCW was predomi-
nantly investigated in recent decades for geochemical
modelling and for the destruction of hazardous organic
materials and waste. Hence, it could be safely handled
as an environmentally compatible solvent, reactant, or
catalyst.

*Corresponding author, e-mail: yywang@chem.ecnu.edu.cn, dai liyi@163.com

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 Z. Q. Hou et al./Chemical Papers 68 (2) 164–169 (2014)
In this paper, caprolactam and ethanol as reactants
were investigated in NCW and the primarily ethyl-6-
aminohexanoate (CAS: 371-34-6) was obtained, which
was usually used as the reagent in the laboratory
and the intermediate to synthesise the drugs. The re-
action between caprolactam and ethanol needed an
acid or base as catalyst. However, SnCl2 could greatly
promote the reaction of acid amide and alcohol and
was non-toxic. It was found that the reaction be-
tween caprolactam and ethanol could be greatly pro-
moted by SnCl2 . The experiments were conducted
with different reactant/water (r/w) mole ratios, res-
idence time, temperature, and the amount of added
SnCl2 . Finally, a high yield of ethyl-6-aminohexanoate
was obtained under optimal conditions. Other addi-
tives, such as K2 CO3 , Na2 CO3 , ZnCl2 , FeCl3 , and
H2 SO4 , were used to investigate their effects on the
reaction in NCW. At the same time, the kinetics of
the reaction was studied in NCW and the activation
energy was obtained under the acidic or basic condi-
tions. A probable mechanism for the reaction between
caprolactam and ethanol in NCW was also proposed.
The simple experimental procedure, high yield, ab-
sence of corrosion and pollution were the key fea-
tures for this methodology. At the same time, the
primary product (ethyl-6-aminohexanoate) was very
expensive. Hence, this work represents an advance
in bringing a new synthesis involving the reaction of
caprolactam and ethanol much closer to green indus-
trial development.
Experimental
Caprolactam and ethanol were commercially avail-
able from SINOPHARM GROUP Co. Water was re-
distilled after deionisation.
The additive SnCl2 (0.354 g) and caprolactam
(1.358 g) were added to the alcohol/water mixture
(20 mL) and the solution was injected into the reac-
tor. The experimental conditions were: temperatures
ranging from 533.15 K to 593.15 K, time range of 1–
3 h, and r/w mole ratios (caprolactam/water/ethanol)
ranging from 1 : 56 : 1.2 to 1 : 56 : 43. The experi-
ments were performed in different baths while keeping
the residence time, temperatures, r/w mole ratios, pH,
and additives constant, to determine the effect of these
parameters on the reaction in NCW. The reaction en-
vironment was regarded as a single-phase system.
The reaction was conducted in a high-pressure
stainless steel bath reactor (500 L). The total amount
of stock solution was calculated so that the pressure
inside the reactor reached the saturated vapour pres-
sure of water at the given temperature (Chang et al.,
2012). The solution of caprolactam and ethanol were
poured into the reactor using a microlitre syringe. The
loaded reactor was immersed in the salt bath (consist-
ing of sodium nitrite, sodium nitrate, and potassium
nitrate at a mass ratio of 40 : 7 : 53) when the temper-
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165
Fig. 1. Effects of reaction time and reaction temperatures on
yield of ethyl-6-aminohexanoate at r/w mole ratio of
1 : 56 : 28. Reaction temperature T/K: 533.15 ( ),
•
553.15 ( ), 573.15 (
), 583.15 (), and 593.15 ().
ature reached the desired value. It was cooled by ice
water to quench the reaction once the requisite reac-
tion time had elapsed. Finally, the reactor was rinsed
with ethanol three times to obtain the product using
a microlitre syringe. The sample was quantitatively
analysed using the internal standard method on an
Agilent 6890GC spectrometer (Agilent Technologies,
USA). Identification of the products was performed
by GC-MS (column RTX-50, i.d.: 0.32 mm, film thick-
ness: 0.25 m, length: 30 m).
Results and discussion
Effect of reaction conditions on yield
To investigate the influence of time and temper-
ature on the yield, all experiments were conducted
in NCW at temperatures ranging from 533.15 K to
593.15 K, residence times ranging from 1 h to 3 h,
at r/w mole ratio (1 : 56 : 28), and desired amount
of SnCl2 . Fig. 1 shows the curve tendencies at differ-
ent reaction time, reaction temperature, and r/w mole
ratio (1: 56: 28). Fig. 1 reveals that the yields of ethyl-
6-aminohexanoate increased gradually with tempera-
tures ranging from 533.15 K to 573.15 K, while they
decreased considerably above 573.15 K under the same
reaction conditions. However, the yields of ethyl-6-
aminohexanoate decreased at 583.15 K and 593.15 K
compared with at 573.15 K because the primary prod-
uct decomposed readily. Meanwhile, when the tem-
perature was changed from 533.15 K to 553.15 K, the
yields of ethyl-6-aminohexanoate increased with the
reaction time ranging from 1 h to 3 h. Subsequently,
the yields of ethyl-6-aminohexanoate began to decline
at 2.5 h when the reaction temperature was set at
573.15 K. The results showed that the most appropri-
ate residence time was 2 h at 583.15 K and 593.15 K.
When the temperature was 573.15 K and reaction
166 Z. Q. Hou et al./Chemical Papers 68 (2) 164–169 (2014)
Table 1. Effects of different r/w mole ratios on yields of ethyl-
6-aminohexanoate at 573.15 K and 2.5 h
r/w, ncaprolactam : nwater : nethanol Yield/%
1 : 56 : 1.2 12
1 : 56 : 14 62
1 : 56 : 20 70
1 : 56 : 28 98
1 : 56 : 43 93
Fig. 2. Effects of different additives on yields of ethyl-6-
aminohexanoate at 573.15 K, 2.5 h and at r/w mole
ratio of 1 : 56 : 28. Additives: Na2 CO3 ( ), K2 CO3
•
( ), ZnCl2 (
), FeCl3 (), and H2 SO4 ().
time 2.5 h, the influence of the reaction mixture com-
position was investigated by changing the r/w mole
ratio from 1 : 56 : 1.2 to 1 : 56 : 43 at 573.15 K
with the addition of SnCl2 . Table 1 shows that the
yields of ethyl-6-aminohexanoate varied with differ-
ent r/w mole ratios under the above conditions. For
instance, the yields of ethyl-6-aminohexanoate were
12 %, 62 %, 70 %, 98 %, and 93 % with the r/w mole
ratio ranging from 1 : 56: 1.2 to 1 : 56: 43 at 2.5 h, re-
spectively. The ethanol was used as both solvent and
reactant, and the experimental data suggested that
the alcohol/water mole ratio played a significant role
in the yields of ethyl-6-aminohexanoate. The yields of
ethyl-6-aminohexanoate increased gradually with wa-
ter/alcohol mole ratios up to 2 : 1 and then decreased.
In order to investigate the effect of additives on
the ethyl-6-aminohexanoate yield, solutions of addi-
tives were prepared by dissolving them in the double-
distilled water as the volume of the reactor was too
small to introduce additives directly into the reac-
tion mixture. The experiments were performed us-
ing the solutions of K2 CO3 , Na2 CO3 , ZnCl2 , FeCl3 ,
and H2 SO4 . Fig. 2 indicates that the yields of ethyl-
6-aminohexanoate were influenced by different con-
centrations ranging from 5 mole % to 25 mole % of
different additives (K2 CO3 , Na2 CO3 , ZnCl2 , FeCl3 ,
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and H2 SO4 ) at 573.15 K, 2.5 h, and the r/w mole
ratio of 1 : 56 : 28. Fig. 2 shows the same tenden-
cies in that the yields of ethyl-6-aminohexanoate de-
creased from 5 mole % to 25 mole % in the pres-
ence of ZnCl2 , FeCl3 , and H2 SO4 . However, the yield
of ethyl-6-aminohexanoate increased while increasing
the content of K2 CO3 or Na2 CO3 in solution from 5
mole % to 25 mole %. The optimal yields of ethyl-
6-aminohexanoate were 94.3 %, 89.7 %, and 45.1 %
when using FeCl3 (5 mole %), ZnCl2 (5 mole %) and
H2 SO4 (5 mole %), respectively. This indicated that
the optimal concentrations of additives were 5 mole %
for ZnCl2 , FeCl3 , and H2 SO4 . However, the optimal
yields of ethyl-6-aminohexanoate were only 47.2 %
and 39.2 % in the presence of K2 CO3 (25 mole %)
and Na2 CO3 (25 mole %), respectively. This indicated
that the acidic catalyst performed better than the ba-
sic catalyst. Here, ZnCl2 and FeCl3 played the role
of hydrolysing agent supplying the mixture with H+
ions. Hence, the hydrolytic ability of FeCl3 was better
than that of ZnCl2 under the same conditions. On the
other hand, the catalytic ability of ZnCl2 and FeCl3
was better than that of H2 SO4 . In 2007, Kruse and
Dinjus discussed the cations’ influence on the chemical
potential, the salvation energy, and the local relative
dielectric constant in high temperature water (Kruse
& Dinjus, 2007). They found that Fe3+ and Zn2+ also
played a role in promoting the reaction.
Kinetics and mechanism of reaction
Second order reaction kinetics was used to describe
this reaction. The reaction rate constant change with
temperature was expressed in the form of the Arrhe-
nius equation. Similarly, Szajna and co-workers indi-
cated that the amide alcoholysis reaction was second-
order with the reaction rate constant temperature
change obeying the Arrhenius expression (Szajna et
al., 2005).
First, a constant mole ratio of caprolactam and
ethanol was used in the presence of acidic or basic
additives. The concentration of the reactants was cal-
culated at different reaction temperatures and times.
It should be noted that the content of acidic or ba-
sic additives was maintained the same so as to show
which of them acted as the better catalyst. The yields
of ethyl-6-aminohexanoate were obtained at different
reaction temperature, residence time, and acidic or ba-
sic conditions.
Fig. 3 shows the curve tendencies of 1/C versus re-
action time at different temperatures in the presence
of acidic and basic additives. In Fig. 3, the linear plots
indicate that the reaction of caprolactam and ethanol
was of the second order. This result accords with that
achieved by Szajna et al. (2005). Fig. 4 shows the curve
tendencies of lnk (rate constant) versus T−1 in the
presence of acidic and basic additives. Fig. 4 shows
that the apparent activation energy values achieved
 Z. Q. Hou et al./Chemical Papers 68 (2) 164–169 (2014) 167

Fig. 3. 1/C versus reaction time t at different temperatures in the presence of acidic (a) and basic (b) additives. Reaction temper-
•
ature T/K: 533.15 ( ), 553.15 ( ), 573.15 (
), 583.15 (), and 593.15 ().

Fig. 4. lnk (rate constant) versus 1/T in the presence of acidic (a) and basic (b) additives.

were 85 kJ mol−1 and 116 kJ mol−1 , respectively, and
the values of the logarithm of the pre-exponential fac-
tor in the Arrhenius equation (lnA) were 13.75 and
19.96 under acidic and basic conditions, respectively.
On the basis of the products detected and the ex-
perimental results, a probable mechanism of the reac-
tion of caprolactam and ethanol in NCW was pro-
posed and is presented in Fig. 5. NCW is a rich
source of H+ because of its self-dissociation and this
self-dissociation could be enhanced by the introduc-
tion of SnCl2 , ZnCl2 , and FeCl3 , all of which gen-
erated a high concentration of H+ . In fact, the ex-
perimental results showed that the yields of ethyl-6-
aminohexanoate were greatly promoted in the pres-
ence of additives in NCW.
Initially, I was attacked by a proton originating
from NCW and the additives, resulting in the for-
mation of II. Then, the positive charge was trans-
ferred from the oxygen atom to the carbon atom
of C—O. Next, carbonium ion III was attacked by
ethanol. Subsequently, III eventually formed ethyl-6-
aminohexanoate (VI ).
It is possible that the base could also catalyse the
reaction between caprolactam and ethanol in NCW.
The mechanism could be described as follows. First, I
was attacked by OH− originating from NCW and the
additives (K2 CO3 and Na2 CO3 ), resulting in the for-
mation of an organic anion IV. Next, IV was attacked
by ethanol and formed V. Subsequently, V eventually
formed ethyl-6-aminohexanoate (VI ).
Conclusions
The reaction between caprolactam and ethanol in
NCW was investigated. The reaction parameters, in-
cluding temperature, residence time, and r/w mole
ratio, were studied to optimise the yield of ethyl-6-
aminohexanoate. The major conclusion of this study

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168 Z. Q. Hou et al./Chemical Papers 68 (2) 164–169 (2014)
Fig. 5. Mechanism of reaction between caprolactam and ethanol in the presence of acid or base in NCW.
could be as follows:
– The traditional synthesis is performed using
H2 SO4 as catalyst at high temperature, and this
method entails some disadvantages, such as low yield,
harsh terms, corrosion, etc. However, the yield of
ethyl-6-aminohexanoate could achieve a value as high
as 98 % at 573.15 K, 2.5 h, and the r/w mole ratio
of 1 : 56 : 28 in the presence of SnCl2 in near-critical
water.
– The additives, such as SnCl2 , FeCl3 , and ZnCl2
promoted the reaction in near-critical water.
– The kinetics of the reaction between caprolactam
and ethanol was investigated in the presence of an acid
and base. Activation energy values of 85 kJ mol−1
and 116 kJ mol−1 were obtained under acidic and ba-
sic conditions, respectively. It was concluded that the
acidic catalyst performed better than the base. A pos-
sible reaction mechanism was also proposed.
Acknowledgements. The authors gratefully acknowledge the
financial support provided by the National Natural Science
Foundation of China (nos. 21073064, 21003049) and the Fun-
damental Research Funds for the Central Universities.
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