Continuous ion-exchange resin catalysed esterification of eugenol for the optimized production of eugenyl acetate using a packed bed microreactor

Article abstract of DOI:10.1039/c5ra08457a

A green scalable flow-synthesis process for the production of eugenyl acetate, an eugenol derivative with potential applications in food and medicinal chemistry, was developed. Through batch experiments, the anion-exchange resin Amberlyst A-21 was recognized as a suitable catalyst for the esterification of eugenol with acetic anhydride. Next, the process was switched from batch- to flow-mode by using a packed-bed microreactor integrated in an instrumental platform that permitted at the same time continuous control of the main process parameters (flow rate, feed mixture composition, temperature) and the on-line HPLC analysis of the reactor effluent. Thanks to this apparatus, a number of experiments with different reaction conditions have been easily performed to evaluate the effects of temperature and reagent molar ratios on eugenyl acetate production. The results have been used to carry out a central composite rotatable experimental design (CCRD) whose derived response surface model (RSM) suggested an optimal temperature and acetic anhydride to eugenol molar ratio of 95 °C and 3:1, respectively. The goodness of these theoretically deduced parameters has been experimentally confirmed obtaining, with a flow rate of 40 μL min^-1, a 95% conversion. The Amberlyst A-21 packed-bed microreactor also demonstrated good long-term stability ensuring, under the above optimized conditions, a high and stable conversion (over 93%) for prolonged reaction times.

Full text of DOI:10.1039/c5ra08457a

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Journal Name
ARTICLE
Continuous ion-exchange resin catalysed esterification of eugenol
for the optimized production of eugenyl acetate using packed bed
microreactor
Received 00th January 20xx,
Accepted 00th January 20xx
L.A. Lerin,*a M. Catani,a D. Oliveira,b A. Massi,a O. Bortolini,a A. Cavazzinia and
P.P. Giovanninia
DOI: 10.1039/x0xx00000x
www.rsc.org/
A green scalable flow-synthetic process for the production of eugenyl acetate, an eugenol derivative with
potential applications in food and medicinal chemistry, was developed. Through batch experiments, the anion-
exchange resin Amberlyst A-21 was recognized as the suitable catalyst for the esterification of eugenol with
acetic anhydride. Next, the process was switched from batch- to flow-mode by using a packed-bed microreactor
integrated in an instrumental platform that permitted at the same time the continuous control the main process
parameters (flow rate, feeding mixture composition, temperature) and the on-line HPLC analysis of the reactor
effluent. Thanks to this apparatus, a number of experiments with different reaction conditions have been easily
performed to evaluate the effects of temperature and reagents molar ratio on the eugenyl acetate production. The
results have been used to carry out a central composite rotatable experimental design (CCRD) whose derived
response surface model (RSM) suggested optimal temperature and acetic anhydride to eugenol molar ratio of
95 °C and 3:1, respectively. The goodness of these theoretically deduced parameters has been experimentally
confirmed obtaining, with a flow rate of 40 µL.min-1, a 95% conversion. The Amberlyst A-21 packed-bed
microreactor also demonstrated a good long-term stability ensuring, under the above optimized conditions, a
high and stable conversion (over 93%) for prolonged reaction time.
pharmaceuticals and food products. Eugenol has shown antimicrobial,
antioxidant, anti-inflammatory, antispasmodic, antidepressant,
antigenotoxic, and anticarcinogenic properties.8,9 However, the
efficiency of this compound in therapeutic treatments is limited by its
poor water solubility and chemical instability.10
Introduction
The continuous expansion of the demand for safe and natural
products has increased interest among researchers in using essential
oils as natural additives for food, cosmetics and pharmaceuticals. The
reason is that they can replace different kinds of chemical additives,
thanks to the properties displayed by their components. As for many
other biological active natural products, even for essential oils
intensive studies have been conducted in order to identify simple and
safe strategies for the preparation of semi-synthetic derivatives with
enhanced properties.1 The esterification of hydroxylated bioactive
compounds is probably the most common transformation adopted to
modulate activity and stability,4-7 as demonstrated by, e.g., the
historical example of aspirin, the first semi-synthetic drug based on a
natural product. Eugenol (4-allyl-2-methoxyphenol) is the major
constituent of several important essential oils such as clove, pimento
berry, bay, nutmeg and cinnamon oil. It is commonly used as a
Among the strategies to increase the therapeutic efficacy of
eugenol via chemical modification, the esterification of the hydroxyl
group appears the simplest and the most promising one. Indeed, esters
of eugenol bearing either aliphatic, aromatic or heteroaromatic acyl
groups (Table 1) have been synthesized and introduced as potential
future drugs against many diseases.8-9 For instance, the simple
eugenyl acetate derivative showed an increased stability12 and
exhibited its potential as antimicrobial against Gram-positive and -
negative bacteria,13,14 as well as antileishmanial therapeutic agents.15
In addition, it has been proposed also as eco-friendly larvicidal
compound against larvae of Aedes aegypti with lower toxicity and
increased activity than eugenol.16
Finally, like eugenol, eugenyl acetate has been authorized for
use in foods by the Joint Expert Committee on Food Additives
(JECFA)17 and the European Food Safety Authority (EFSA)18
and it is currently listed in the European Union database of
flavouring substances.
fragrance and flavouring agent in
a variety of cosmetics,
a.Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via L.
Borsari 46, CAP: 44121, Ferrara, Italy. Email: lindomaralberto.lerin@unife.it
b.Departamento de Engenharia Química e Engenharia de Alimentos, Universidade
Federal de Santa Catarina, C.P. 476, Florianópolis, SC, CEP: 88040-900, Brazil.
† Electronic Supplementary Information available: Performance evaluation, Pareto
chart, ANOVA by 22 CCRD and typical chromatogram for eugenyl acetate conversion
in fixed bed microreactor. See DOI: 10.1039/x0xx00000x
In recent years, several eugenol esters have been prepared
following either biocatalytic or chemical approaches (Table 1). Apart
from the recent use of the solid super acid modified zirconium
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UDCaT-5,11 all the chemical catalysed transformations were Table 1. Eugenol esters derivatives and synthetic conditions.
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DOI: 10.1039/C5RA08457A
performed through homogeneous acid or basic catalysis. Even if these
conditions are the most employed for the esterification of natural
products, such processes have been developed with the purpose of
maximizing product yield, without considering the environmental
impact of inorganic waste produced during the separation stage of the
process, when a typical water quench and neutralization (for acidic or
R
X
Catalyst
Reference
alkaline systems) is needed. Driven by an increasing demand for
greener chemistry and technology, efforts have been made to develop
environmentally friendly, yet cost effective processes for
esterification reactions. In recent years, a great deal of attention has
been focused towards the use of supported catalysts19,20 that not only
can be easily recovered and reused but have also favoured the
development of continuous flow processes for a number of
industrially important productions.21,22 Most of the articles or patents
describing the esterification of natural products promoted by
heterogeneous catalysts, falls in the field of biofuels production23-26
and, in several cases, ion-exchange resins have been successfully
employed as acid27,28 or basic catalysts.29
Phenyl
Cl
NaOH
8, 9
Phenyl
OH
UDCaT-5
NaOH
11
n-alkyl chain (C11-C15) Cl
8
Cyclic alkyl
Pyridyl
Cl
Cl
NaOH
10
Pyridine
10
Methyl
Acetyl None
12
Methyl
Acetyl Novozym 435
Acetyl Amberlyst A-21
13, 14
This work
Methyl
Based on all these promising features, the aim of this work was to
set up an optimized continuous-flow process for eugenyl acetate
production based on the use of an ion-exchange resin as catalyst and
acetic anhydride as acylating agent. A preliminary study conducted
under batch conditions allowed to identify the Amberlyst A-21 as the
suitable catalyst. This was used to prepare a packed-bed microreactor
where the continuous-flow eugenyl acetate production was optimized.
The assessment of optimal process variables (i.e., flow rate, reagent
molar ratio and temperature) was carried out through experimental
design and response surface methodology.30,31 Moreover, the
operational stability of the catalyst was examined in order to assess its
potential use for commercial application.
Table 2. Results of eugenyl acetate conversion for the preliminary
tests in batch mode.a
Resinb
Molar Ratioc
Conversion (%)d
1:5
1:3
1:1
1:5
1:3
1:1
100
89
78
99
68
38
Amberlyst A-21
Amberlite IR120
a Reaction conditions: solvent-free system, 2 h, 50 °C, orbital shaking 120 rpm.
b 20% (w/v). c Eugenol to acetic anhydride. d Determined by HPLC analysis.
Results and discussion
Experiments in batch conditions
Figure 1. Scheme of the experimental set up employed to
monitor reaction progress.
Based on the current literature,27,28 the ion-exchange resins
Amberlyst A-21 and Amberlite IR120 were identified as potential
catalysts for the esterification of eugenol. Experiments in batch mode
were conducted in order to verify their efficiency. The results reported
in Table 2 show that the highest conversions were obtained using
Amberlyst A-21. It was also evident that the excess of acyl donor
contributed to increase the eugenyl acetate production. Indeed, by
using a 1:5 eugenol to acetic anhydride molar ratio, both catalysts
afforded approximately quantitative conversions. Taking into account
these results, further studies were carried out using the anion exchange
resin Amberlyst A-21 as catalyst.
Optimization of continuous esterification of eugenol in a
fixed bed microreactor
The continuous production of eugenyl acetate was carried out
using the experimental apparatus represented in Figure 1. The system
consists of two binary HPLC pumps, one of which feeds the packed
bed microreactor with adjustable ratios of eugenol and acetic
anhydride, while the other is connected to an analytical
chromatographic column (C18 reversed-phase) for the on-line
monitoring of the process.
The two lines are connected by a remotely-controlled multiport
valve, which allows for the sampling of microreactor effluent at
determined times. Besides automation, the instrumental platform
allows for a flexible control of experimental conditions (such as, the
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easy modification of the mixture composition feeding the microreactor could also be observed, since the formation of by-
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DOI: 10.1039/C5RA08457A
products in all experiments was not observed.
microreactor).
Successively, data obtained from the experimental design
were analysed by response surface methodology with the scope
of finding a semi-empirical correlation for conversion as a
function of temperature and eugenol to acetic anhydride molar
ratio. This study led to the following equation:
Effect of flow rate
Our optimization study started from the investigation of the effect
of flow rate (or residence time, RT) on reaction conversion. This
parameter is particularly important in flow chemistry as it is
commonly acknowledged that if, on the one hand, low flow rates
(allowing for longer RTs) favour conversion, on the other way it
negatively impact production yield. Therefore, a compromise between
RT/conversion has to be found. The results of this study are reported
in Figure 2, where eugenyl acetate conversion is plotted as a function
of flow rate. As it can be seen by the plot, a flow rate of 40 µL.min-1
represents a satisfactory starting point for further optimization studies
as it allowed obtaining both reasonable conversion (60%) and RT (29
min). The gain of conversion achievable at the cost of reducing the
flow rate at 30 µL.min-1 is too small (only about 3%) in comparison
to the corresponding increase of RT (+35%). On the other hand, the
study of high-flow rate regime, showed that conversion decreased
rapidly with increasing the flow rate (it is only about 45% at 100
µL.min-1 and even smaller than 30% at 500 µL.min-1) to make these
conditions competitive.
퐶 = 66.61 + 20.22 × 푀푅 − 9.54 × 푀푅2 + 15.10 × 푇 − 0.71 × 푇2 +
1.19 × 푀푅 × 푇
(1)
where C represents the conversion of eugenol to eugenyl acetate
(%), T is the temperature (ºC) and MR the eugenol to acetic
anhydride molar ratio. The analysis of variance (ANOVA) was
used to assess the goodness of fit of the model. Based on F-test,
the conclusion can be drawn that the model is predictive. In fact,
the calculated F value is about fifteen times larger than the
tabular F (Fcalculated=77.5 vs. F0.95;5;5=5.05) with a regression
coefficient satisfactory enough (0.987). Therefore, the model
expressed by Equation (1) was used to generate the response
surface of Figure 3 and to predict the effects of experimental
conditions on eugenyl acetate production (column 5 of Table 3).
Results of experimental design and data of Table 3 suggest not
only that it is not convenient to use an eugenol to acetic
anhydride molar ratio lower than 1:3 but also that with this
composition the conversion can be significantly enhanced by
increasing temperature.
Figure 2. Effect of flow rate on eugenyl acetate production.
Figure 3. Response surface of eugenyl acetate conversion as a
function of temperature and eugenol to acetic anhydride molar
ratio.
Reaction conditions: eugenol to acetic anhydride molar ratio 1:5 and 50 °C.
Experimental design
Based on the previously obtained results, a 22 central
composite rotatable experimental design (CCRD) with triplicate
repetitions of the central point30,31 was carried out to evaluate the
effect of temperature and reagent molar ratio on reaction
conversion at constant flow rate (40 µL.min-1). Table 3 presents
the matrix of the experimental design. Eleven experiments were
performed, nine of them (runs 1-9) with different combinations
of temperature/reagent molar ratio, while the experiments from
the central point of the planning design (runs 9, 10 and 11) were
conducted at the same temperature (65 °C) and with the same
eugenol to acetic anhydride molar ratio (1:3). The conversion
percentage reported in Table 3 are referred to the steady-state
conditions that, as shown by Figure 3, were reached after about
1.5 h. Highest steady-state conversions (91% and 86%) were
obtained in runs 4 and 8, at temperature of 80.0 and 86.1 ºC and
eugenol to acetic anhydride molar ratio of 1:5 and 1:3,
respectively. The experimental points obtained for runs 9, 10 and
11 allowed to verify the excellent reproducibility of the
experimental data. A high selectivity in the continuous
esterification of eugenol with Amberlyst A-21 in a fixed bed
Experimental data and conditions shown in Table 3.
Based on this information, the temperature was increased
from 85 to 95 °C, by keeping the feeding composition constant
(eugenol to acetic anhydride molar ratio equal to 1:3). Figure 4
shows indeed that increasing temperature favours the
conversion. Remarkably in agreement with the proposed model,
at 95 °C, the conversion was 95%.
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Operational stability of Amberlyst A-21
of glycerol.33-35 To assess the stability of Amberlyst A-21, the
View Article Online
DOI: 10.1039/C5RA08457A
following conditions were employed: eugenol to acetic
The stability of the catalyst was detailed investigated, as this
is a key parameter for evaluating its potential for industrial scale
continuous esterification processes. High operational stability
for ion-exchange-resin-based (micro)-reactors has been already
observed in various continuous flow processes, such as the
esterification of acidified oil with methanol32 and the ketalization
anhydride molar ratio of 1:3, feed flow rate 40 µL.min-1 and
temperature 95 °C. As demonstrated in Figure 5, eugenyl acetate
conversion was practically constant (over 93%) during the entire
observation time (32 h) showing thus the excellent operational
stability of the catalyst.
Table 3. Matrix of the experimental design (coded and real values) with responses in terms of eugenyl acetate conversion.
Run
1
2
3
4
5
6
7
8
Molar Ratioa
-1 (1:1)
1 (1:5)
-1 (1:1)
Temperature (°C) Experimental Conversion (%)
Predicted Conversion (%)
RED (%)b
16.64
-1.65
6.16
-2.35
-35.57
3.38
-4.73
-0.39
0.20
-0.09
-0.07
-1 (50.0)
-1 (50.0)
1 (80.0)
1 (80.0)
0 (65.0)
27
59
53
91
14
79
42
86
67
66
66
22
60
50
93
19
76
44
86
66
66
66
1 (1:5)
-1.41 (1:0.18)
1.41 (1:5.82)
0 (1:3)
0 (65.0)
-1.41 (43.8)
1.41 (86.1)
0 (65.0)
0 (65.0)
0 (65.0)
0 (1:3)
0 (1:3)
0 (1:3)
0 (1:3)
9
10
11
a Eugenol to acetic anhydride. b Relative error deviation - RED = (퐶푒푥푝−퐶푝푟푒푑) 푥100.
퐶푒푥푝
Figure 4. Evaluation of the effect of temperature on eugenyl amine; particle size: 490-690 µm; operating pH: 0-14; capacity:
1.3 meq·min-1 by wetted bed volume; maximum operating
temperature 100 °C). Both catalysts were from Sigma-Aldrich.
HPLC grade methanolwas also from Sigma-Aldrich. Before all
experiments, resins were dried in oven at 100 °C for 24 hours.
acetate production.
Figure 5. Evaluation of operational stability of Amberlyst A-21.
Experimental conditions: eugenol to acetic anhydride molar ratio of 1:3, flow rate
of 40 µL.min-1, and temperature of 86, 90 and 95 °C.
Experimental
Materials
Experimental conditions: eugenol to acetic anhydride molar ratio of 1:3,
temperature of 95 °C and flow rate of 40 µL.min-1.
The substrates used in the esterification reactions were
commercial eugenol (Aldrich, 99% purity) and acetic anhydride
(Riedel-de Haën, 99% purity). Analytical standard of eugenyl
acetate is commercially available from Fluka. As heterogeneous
catalysts the following materials were employed: Amberlite
IR120 hydrogen form (cation exchange resin; physical form:
beads; matrix: styrene divinylbenzene copolymer; matrix active
group: sulfonic acid; particle size: 620-830 µm; operating pH: 0-
14; capacity: 1.8 meq·min-1 by wetted bed volume; maximum
operating temperature 121 °C) and Amberlyst A-21 (anion
exchange resin; physical form: beads; matrix: styrene
divinylbenzene (macroporous); matrix active group: alkyl
Experiments in batch conditions
Solvent-free batch reactions were carried out in 2 mL-tube
with orbital shaking (120 rpm) at 50 °C. In all experiments the
eugenol/acetic anhydride molar ratio was 1:5, resin
concentration was 0.2 g.g-1 (based on substrates) and reaction
time 2 hours. After each experimental run, the resin was
separated from the reaction medium and product quantification
was performed by High-performance Liquid Chromatography
(HPLC).
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Effect of flow rate
Quantification of eugenyl acetate by HPLC
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DOI: 10.1039/C5RA08457A
The effect of flow rate was evaluated by performing a series
of experiments at different flow rates (500, 100, 40 and 30
µL·min-1) keeping constant the temperature (50 °C) and feed
concentration (eugenol/acetic anhydride molar ratio 1:5). At
each flow rate, reaction conversion was measured under steady-
state conditions. Residence times were calculated as described
by Dalla Rosa et al.37 At flow rates of 500, 100, 40 and 30
µL.min-1, residence time was, respectively, 2.3, 11.6, 29.0 and
38.7 min.
Quantification was carried by means of calibration curves
built with standard solutions of eugenol and eugenyl acetate in
the range of 0-25 mM and 0-33 mM, respectively.
In order to validate the method, parallel analyses were carried
out by 1H-NMR analysis dissolving the sample mixture (10 L)
in deuterated chloroform (1 mL). The signals of the methoxy
groups of eugenol (singlet ta 3.97 ppm) and eugenyl acetate
(singlet ta 3.80 ppm) were considered and the conversion was
calculated from the ratio between the integral of the product
signal and the sum of the integrals of product and substrate
signals.
Optimization of eugenyl acetate production: effect of substrate
concentration and temperature
A 22 Central Composite Rotational Design (CCRD) was
carried out. Eugenol to anhydride acetic molar ratio was varied
from 1:0.18 to 1:5.82 and temperature from 43.5 to 86.1 °C. Flow
rate was 40 µL.min-1. In all experiments, reaction was monitored
for 5.5 hours. For statistical analysis of experimental design, the
mean conversion of four steady-state points (2.5, 3.5, 4.5 and 5.5
h) of each run was calculated. The center point of the design was
repeated three times in order to allow a better estimate of the
experimental error and to provide extra information about the
significance of effects.30 All results were analyzed using
Statistica® 8.0 (Statsoft Inc., Tulsa, OK, USA), considering a
significance level of 95% (p<0.05). Based on the information
from experimental design, the effect of temperature was
evaluated with a molar ratio of eugenol to acetic anhydride of
1:3. In these experiments, the following temperatures were
considered: 86, 90 and 95 °C.
Continuous esterification of eugenol in packed bed
microreactor
Preparation of the microreactor
Microreactor was prepared by gravity packing. A 10-cm long
chromatographic column (0.46 cm internal diameter) was used. 514
mg of resin Amberlyst A-21 were necessary to fill the column. The
packed bed void fraction (ε), calculated according to Shang et al.36,
was 0.58 mL.
Experimental apparatus and procedure
Reaction progress was monitored by using the experimental
set up shown in Figure 6. This consists of two binary HPLC
pumps (Agilent 1100 series, Agilent Technologies) connected
through a remotely controlled 2-position 6-port switching valve
(Rheodyne). One capillary pump (first dimension) feeds the
microreactor with adjustable ratios of eugenol and acetic
anhydride. The microreactor was placed in a thermostatic bath
(Grant – TC 120) with controlled temperature (±0.1 °C) and its
outlet was connected to a fraction collection system, or to waste
depending on need. The second pump (second dimension)
delivers a mobile phase made of a binary mixture of
methanol:water (70:30, v/v) to a chromatographic column (C18-
RP Symmetry from Waters, 15×0.21 cm ID, particle size: 3.5
µm), after which a diode-array detector (DAD, Agilent 1100
series) is placed. The flow rate on the second dimension was 0.1
mL.min-1 and the chromatographic column was thermostated at
30 °C. The microreactor effluent can be sampled by means of the
multiport valve, (loop between port 2 and 5) and redirected to the
chromatographic column for eugenol and eugenol acetate
quantification.
This bi-dimensional experimental platform has been
particularly convenient for monitoring the flow-mode
esterification of eugenol. Indeed the microreactor outlet was
directly analyzed on the second dimension without need of
dilution and sample handling. One µL of the microreactor
effluent was sampled (Figure 2, position-1) at given times and
injected in the C18 column (Figure 2, position-2). The detector
was calibrated so to avoid detector saturation (both product and
reagent were monitored at 302 nm). The composition of the
mobile phase (methanol:water 70:30, v/v) allows for both an
easy dissolution of the organic sample coming from the
microreactor and a timely chromatographic separation of
unreacted eugenol from eugenyl acetate.
Operational stability of Amberlyst A-21
To assess reaction operational stability, 32 hours experiments
were performed under optimized conditions (i.e., 1:3 eugenol to
acetic anhydride molar ratio, 95 °C temperature and 40 µL.min-
1 flow rate).
Conclusions
The anion exchange resin Amberlyst A-21 proved to be a very
efficient catalyst for the flow-mode production of eugenyl
acetate from eugenol and acetic anhydride. Thanks to a Central
Composite Rotational Design, a response surface model has been
built to predict the optimal parameters for the in-flow eugenyl
acetate production. Experimental results perfectly fitted with the
model and an optimized conversion of eugenol to eugenyl acetate
of 95% was reached. The catalyst did not show loss of activity
and the above conversion was ensured during 32 hours of
continuous esterification. The notable features of this method are
simplicity in operation, short reaction time, cleaner reaction
profiles, low cost, high stability and reusability of the catalyst,
easy of scaling up (for instance by simply operating in parallel
multiple microreactors) and very good to excellent product yield.
In conclusion, we have designed and optimized a completely
new, heterogeneous green process for the continuous synthesis
of eugenyl acetate.
Acknowledgements
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29 N. Shibasaki-Kitakawa, H. Honda, H. Kuribayashi, T. Toda, T.
The authors acknowledge the scholarships by CAPES-Brazil.
We would also thank Profa. Maria Isabel Rodrigues for the
support in the analysis of the experimental design.
View Article Online
Fukumura, T. Yonemoto, Bioresour. Technol., 2007, 98, 416.
DOI: 10.1039/C5RA08457A
30 M. I. Rodrigues, A. F. Iemma, Experimental design and process
optimization. Campinas: Editora Casa do Pão, 2006.
31 D. C. Montgomery, Design and analysis of experiments. New York:
Wiley, 1991.
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