Sustainable Chemistry and Pharmacy 4 (2016) 40–45

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Sustainable Chemistry and Pharmacy

journal homepage: www.elsevier.com/locate/scp

Eco-friendly one pot synthesis of caffeic acid phenethyl ester (CAPE)

via an in-situ formed deep eutectic solvent
Veronika Fischer, Didier Touraud, Werner Kunz n
Faculty of Chemistry and Pharmacy, University of Regensburg, D-93040 Regensburg, Germany

art ic l e i nf o a b s t r a c t

Article history: In this paper, a new strategy towards the synthesis of caffeic acid phenethyl ester (CAPE) is introduced.
Received 24 March 2016 The reaction is carried out in a deep eutectic solvent made of caffeic acid and choline chloride. Caffeic
Received in revised form acid is used as part of the solvent and as reactant. Phenethyl alcohol is soluble in this mixture in every
14 July 2016
molar ratio, and as a consequence no additional solvent is necessary. Reaction conditions were optimised
Accepted 28 August 2016
Available online 19 September 2016
with respect to the molar ratio of phenethyl alcohol and caffeic acid, and by varying the amount and
nature of the acid catalyst as well as the reaction time. The obtained CAPE ester could easily be separated
Keywords: from the reaction mixture by simply adding water to destroy the deep eutectic by solubilisation of
Caffeic acid phenethyl ester choline chloride in the aqueous phase.
Deep eutectic solvent
& 2016 Elsevier B.V. All rights reserved.
Green synthesis
Green solvent
Miscibility
One pot synthesis

1. Introduction organic synthesis they can be employed as reaction media as an

Caffeic acid phenethyl ester (CAPE) has become an interesting
molecule since it shows favorable pharmacological and biological
properties, such as antimicrobial effects, anti-inflammatory or
anticancer and immune modulatory activities (Demestre et al.,
2009; Natarajan et al., 1996; Orban et al., 2000; Huang et al., 1996,,
1988). Further, CAPE is an active flavonoid which plays an im-
portant role in the antioxidant activity of propolis (Russo et al.,
2002; Shahidi et al., 1992; Chen et al., 1996; Lee et al., 2000; Jung
et al., 2008; Murtaza et al., 2014). However, the isolation of CAPE
from honeybee propolis is time-consuming and suffers from re-
maining impurities (Marcucci, 1995). Moreover, there are some
disadvantages concerning the synthesis of CAPE, since hazardous
and deleterious chemical reagents are used (Chen et al., 1996; Lee
et al., 2000; Hashimoto et al., 1988; Touaibia and Guay, 2011;
Nakamura et al., 2014; Burke et al., 1995), for example dicyclohexyl
carbodiimide as condensing agent or iso-butyl chloroformate as
protecting agent or benzene or dioxane as a solvent together with
SOCl2. To overcome these drawbacks, new synthetic approaches
are investigated. For example, Ha et al. prepared CAPE via an en-
zyme-catalysed reaction, which was performed in an ionic liquid
(IL) (Ha et al., 2012,, 2013). ILs are salts which show melting points
below 100 °C and are proposed for a wide range of applications. In
n
Corresponding author.
E-mail address: Werner.Kunz@ur.de (W. Kunz).
alternative to classic organic solvents (Welton, 1999). Un-
fortunately, the used IL:[Emim][Tf2N] cannot be considered as a
green solvent, although this was precisely the goal of the men-
tioned synthesis by Ha et al.
It is well-known that a lot of ILs are (eco)toxic and harmful to
the environment (Ranke, 2007; Pham et al., 2010). Further, their
synthesis and purification is often expensive and time-consuming
(Deetlefs and Seddon, 2010; Clark and Tavener, 2007). A promising
alternative to ILs are deep eutectic solvents (DESs). In general, a
eutectic system is a mixture of chemical compounds or elements
which exhibits a single chemical composition, at which it solidifies
at a lower temperature than any other composition. The depres-
sion of the freezing point is related to the strength of interaction
between the components (Smith and Hashemi, 2003; Abbott et al.,
2003). The term deep eutectic solvent derives from the large de-
pression of the melting point, which can be up to 200 °C (Abbott
et al., 2003). Besides the easy preparation, low costs, non-volatility
and non-inflammability, they are expected to have a better bio-
degradability than ionic liquids, as many DESs are derived from
natural molecules (Abbott et al., 2004; Maugeri and Dominguez de
Maria, 2012).
DESs and low melting mixtures (LMMs) are mainly composed
of non-toxic, natural-based and environmentally benign sub-
stances (Smith et al., 2014). For instance, ChCl, which is often used
in DESs and LMMs, is biocompatible and known as former vitamin
B4. It has some important key functions in the human body, e.g. as

http://dx.doi.org/10.1016/j.scp.2016.08.002
2352-5541/& 2016 Elsevier B.V. All rights reserved.
 V. Fischer et al. / Sustainable Chemistry and Pharmacy 4 (2016) 40–45
a precursor of phospholipids and acetylcholine (Blusztajn, 1998).
ChCl is a cheap animal feed and also food additive, and as will be
shown, at the end of the reaction discussed here, it can be easily
separated from the desired product. Note that since ChCl is en-
vironmentally benign (and even edible), it fulfills an important
criterion of sustainability (IUCN/UNEP/WWF, 1991).
Further, urea, another important molecule in the development
of DESs and LMMs, is not toxic to the human body. It is produced
during the mammalian metabolism and even salvaged due to the
metabolized activity of the colonic microflora. It is further used in
the body and can be easily excreted in the urine (Jackson, 1994).
Also eco-friendly and biodegradable organic compounds like sev-
eral carboxylic acids (e.g. oxalic acid, malonic acid, succinic acid,
etc.), amino acids or sugars (glucose, sorbitol, fructose, etc.) can be
part of a DESs or LMMs (Abbott et al., 2004; Maugeri and Dom-
inguez de Maria, 2012; Imperato et al., 2005; Franciso et al., 2012;
Dai et al., 2013; Kerton and Marriott, 2013; Fischer and Kunz,
2014). DESs have been proposed for many applications, e.g. for the
extraction of glycerol from biodiesel (Abbott et al., 2007), metal
extraction (Abbott et al., 2005), electrochemistry (Nkuku and Le-
Suer, 2007), nanoscience (Liao et al., 2008), biochemistry (Choi
et al., 2011), as well as in biocatalysis (Gorke et al., 2008) and or-
ganic synthesis (Ruß and König, 2012).
With their low to vanishing toxicity, their rapid biodegrad-
ability, and their biological origin, DES perfectly fulfill several of
the 12 principles of green chemistry (Anastas and Warner, 1998):
the use of less hazardous chemicals, the use of safer chemicals and
solvents, inherently safer chemistry etc. They are also in agree-
ment with most of the 12 principles of green solvents (Gu and
Jérôme, 2013), of green engineering (Anastas and Zimmerman,
2003) and even of some principles of green extraction (Chemat
et al., 2012; Rombaut et al., 2014).
Of course, there are also Ionic Liquids, in particular those with
choline cations that fulfill many of the above mentioned criteria.
However, they have to be synthesized first, whereas DES form
spontaneously. In any case, the perfect solvent does not exist, and
hence the best solvent would be – no solvent. Indeed, there are
some efforts to make chemical reactions without any solvent
(Marvaniya et al., 2011). In the case of DES, the main disadvantage
is that it cannot be easily separated from the product by simple
evaporation (distillation). We will come back to this point later on.
Since from what we discussed in the preceding paragraph, it is
of evident advantage to perform reactions in non-toxic and bio-
degradable media, especially for the synthesis of drugs, we present
a new synthetic route to CAPE. The synthesis is carried out with no
additional solvents and the work-up is performed only with water.
The reaction scheme of the esterification of caffeic acid (CA) and
phenethyl alcohol (PA), providing CAPE, is shown in Fig. 1.
The formal reaction looks trivial; it is indeed a simple ester-
ification. But the problem is to find an acceptable solvent in which
both reactants are soluble. Benzene is an option, but it is not a
green solvent (Grodowska and Parczewski, 2010).
The novel feature of the procedure proposed here is that in a
first step, a DES is formed consisting of CA and choline chloride
(ChCl). This is necessary, since CA is nearly insoluble in PA. By
forming a deep eutectic mixture, the solubility properties of CA are
changed and the CA-ChCl (molar ratio 1:2) mixture becomes
miscible with PA in every ratio measured. As a consequence, CA is
not only a reactant, but simultaneously part of the solvent and no
further harmful solvent is required.
Fig. 1. Acid-catalyzed esterification of caffeic acid with phenethyl alcohol.
41
Of course, it is well-known and widely explored that a reactant
can also be the solvent, e.g. methanol for esterification processes.
But in that case, the second reactant is soluble in it. In our case,
caffeic acid is insoluble in the alcohol. Our approach would even
be possible if both reactants are solid, provided that one of them
can be transformed into a DES with a convenient additive.
A double role of a DES was also explored by Gore et al. (2012a,
2012b) who used a DES both as solvent and catalyst, but not as
solvent and reactant. A DES with the present composition of ChCl
and CA was first mentioned by Maugeri and Dominguez de Maria
(2012). As its melting point was determined to be 67 °C, this DES
has not received much attention. However, the required tem-
perature for the reaction proposed in the present paper is 80 °C
and thus, the high melting temperature of the DES is not a
drawback.
Of course, it is not excluded (and even probable) that an en-
vironmentally benign Ionic Liquid, for example a choline based
one with a convenient non-reactive counterion, could also dissolve
both reactants. However, choline chloride as the additive is a
cheap and readily available salt that is produced in large quan-
tities, whereas any appropriate IL would have to be synthesized
first for this purpose, which would cost further energy and require
further resources. Further, as ChCl, any imaginable choline-based
IL would also have a negligible vapor pressure and could not be
separated from the product by distillation either.
2. Materials and methods
Choline chloride (Alfa Aesar, 4 98%) and caffeic acid (Sigma
Aldrich, 98%) were combined in an inert atmosphere in a molar
ratio of 2:1. The vial was sealed and the mixture stirred at 90 °C
until a yellowish homogeneous liquid was formed. Subsequently,
the temperature was reduced to 80 °C, and phenethyl alcohol was
added under vigorous stirring until the mixture was homo-
geneous. The progress of the reaction was determined by HPLC
measurements. The samples (6.5
70 mg) were diluted with
MeOH (5 mL), filtered, and subsequently submitted to HPLC se-
paration using gradient elution. Amberlyst 15 (Sigma-Aldrich) was
added and the reaction mixture was stirred under exclusion of
light to prevent degradation. Amberlyst 15 is a macro-reticular
polystyrene based ion exchange resin with acidic sulfonic groups
which can be used for several acidic catalysed reactions (Pal et al.,
2012). Its easy removal from the reaction mixture, the un-
complicated use and regeneration afterwards are further ad-
vantages (Pal et al., 2012; Petrini et al., 1988). Amberlyst 15 was
filtered off and the remaining liquid was poured slowly into hot
water. Upon cooling to room temperature, caffeic acid phenethyl
ester precipitated and was collected by filtration. The product was
washed with water. Caffeic acid phenethyl ester was obtained as a
slightly purple to off-white powder (56.4%). Note that the reaction
conditions have been optimised with respect to the molar ratio of
PA and CA, and by varying the amount and nature of the acid
catalyst, as well as the reaction time. Without acid catalyst no
CAPE was formed. By using sulphuric acid or p-toluenesulfonic
acid the results indicated a decent conversion rate after 12 h, and
the rate was dependent on the amount of PA used. The products
have been characterized by NMR and HPLC.
Concerning the work up, only the method stated above was
used.
2.1. High-performance liquid chromatography (HPLC)
Reversed-phase high performance liquid chromatography
(RP-HPLC) was performed on a Waters HPLC system with two
Waters 515 HPLC pumps, Waters 717 plus autosampler, Waters
42 V. Fischer et al. / Sustainable Chemistry and Pharmacy 4 (2016) 40–45

Table 1 catalyst showed similar results.

Gradient table for the HPLC analysis.
Time in min Flow in mL/min vol% A vol% B
0.00 0.70 50.0 50.0
20.00 0.70 0.0 100.0
30.00 0.70 50.0 50.0
2487 UV/VIS-Detector, and Waters Empower 3 software. Separa-
tion was achieved on a Knauer Eurosphere C18-column
(100 Å, 250  4.6 mm). Compounds were eluted at a flow rate of
0.7 mL/min and a temperature of 30 °C. Elution was performed
over the gradient stated in Table 1 in a mobile phase comprising of
0.1% formic acid in water (solvent A) and methanol (solvent B). The
injection volume was 10 mL. A wavelength of 289 nm was used for
detection. Measurements were calibrated with caffeic acid phe-
nethyl ester purchased from Merck Millipore.
1
2.2. H NMR
NMR spectra were recorded on a Bruker Avance 300
(1300 MHz). All spectra were recorded at room temperature.
Chemical shifts are reported in [ppm] relative to an internal
standard (solvent residual peak). Coupling constants J are reported
in Hertz [Hz]. Resonance multiplicity of the signals is as follows:
s ¼singlet, d ¼doublet, t¼triplet, q¼ quartet, m ¼multiplet,
bs ¼broad singlet, dd¼ doublet of doublets. A typical spectrum is
given in Fig. 2.
1
H NMR (300.13 MHz, CD3OD) δ ppm 7.50 (d, J ¼15.9 Hz, 1 H),
7.33–7.18 (m, 5H), 7.01 (d, J ¼2.0 Hz, 1H), 6.92 (dd, J ¼8.2 and
2.1 Hz, 1H), 6.76 (d, J ¼8.1 Hz, 1H), 6.22 (d, J¼ 15.9 Hz, 1H), 4.35
(t, J ¼7.0 Hz, 2H), 3.98 (t, J ¼7.0 Hz, 2H).
Table 2 summarizes the conversion rates, as obtained with
HPLC, for the different reaction conditions.
3. Results and discussion
The results for using p-toluenesulfonic acid as a catalyst are
summarised in Table 3.
The highest conversion rate of CA to CAPE was obtained with a
molar ratio of 15.8:1 PA: CA. Experiments with sulphuric acid as
In a second set of experiments, two solid acids, Amberlyst 15
and Amberlite IR-120 (also from Sigma-Aldrich), were tested to
perform the reaction in a more eco-friendly way, compared to the
use of p-toluenesulfonic acid. They have the advantage of being
environmentally benign and they can be easily removed from the
reaction mixture (Pal et al., 2012). Note that in particular Amber-
lyst 15 has already been used for the catalysis of green reactions,
for which its environmentally friendly properties were discussed
in detail (Kumar et al., 2013; Srinivasa et al., 2012; Young et al.,
2011).
Both catalysts were tested with a molar ratio of 15.8:1 PA-CA.
HPLC analysis showed a molar conversion rate of 72% for Amber-
lyst 15% and 65% for Amberlite IR-120. Due to this result, we
decided to perform further experiments with Amberlyst 15. The
results are depicted in Fig. 3. They show that the conversion of
CAPE was most efficient using 7.9 wt% of Amberlyst 15.
In order to further improve the reaction conditions, the kinetic
behavior of the reaction was studied. The amount of CAPE was
recorded after 4, 8, 14 and 26 h of reaction. The results are pre-
sented in Fig. 4. A reaction time of 14 h turned out to be most
sufficient with a molar conversion of 77%.
Further to the reaction, the isolation of the product is a most
important point. In the case of classical reaction media, the sol-
vent, such as benzene, can often be evaporated. However, this
must be done quantitatively and carefully checked, since for this
reaction toxic solvents are used. In contrast, in our approach, CAPE
could easily be isolated by simple addition of water, after the se-
paration of the catalyst by filtration. ChCl is dissolved in water and
can be recycled easily by water distillation, preferably under va-
cuum. This strategy has already been applied in several syntheses,
called eco-friendly (Lobo et al., 2012; Azizi and Edrisi, 2015; Azizi
and Edrisi, 2016). However, water distillation consumes a lot of
energy and from an economical point of view, it may be non-
profitable, since ChCl is a cheap, non-toxic substance (1 g  0.06 €
(Aesar, 2015) available in large quantities, and the price of CAPE
(1 g  464 € (Sigma Aldrich, 2015)) exceeds largely the price of
the staring materials. We admit that the recycling of ChCl by water
evaporation is the week point of our approach. The situation may
be much better in the future, when separation by large scale
chromatography and crystallization has become more popular.
That this will be undoubtlessly the future, is discussed in (Jessop,
2011).

Fig. 2. 1H NMR of caffeic acid phenethyl ester in CD3OD.

 V. Fischer et al. / Sustainable Chemistry and Pharmacy 4 (2016) 40–45 43

Table 2
the composition of the reaction mixtures given in g, reaction time, concentration c(dilution) of the dilution of the reaction mixture in methanol used for HPLC measurements
given in mg/mL, the determined peak area with corresponding standard deviation (SD) and the resulting molar conversion rate of CA to CAPE in %.

Catalyst m (CA) m (ChCl) m (PA) m (acid) Reaction time c (dilution) Peak area SD Molar conversion

Sulphuric acid 0.445 0.702 0.296 0.088 1 d 7.6 6.786E þ 06 3.90E þ 05 6.2
0.464 0.680 0.713 0.115 1 d 11.8 2.043E þ 07 9.41E þ 05 14.9
0.439 0.667 1.282 0.068 1 d 5.0 1.953Eþ 07 1.02Eþ 06 44.2
0.451 0.702 1.857 0.063 1 d 4.0 1.886Eþ 07 2.32E þ 05 65.0
0.896 1.395 9 0.207 1 d 11.4 2.840E þ 07 8.15E þ 05 67.1
0.443 0.696 4.654 0.112 1 d 10 2.478E þ 07 9.53E þ 05 66.8
0.45 0.701 5.853 0.202 1 d 7.0 1.219E þ 07 4.42E þ 05 56.4

p-Toluenesulfonic acid 0.457 0.705 0.415 0.07 1d 8.6 2.034E þ 07 8.92E þ 05 17.2
0.447 0.713 0.736 0.74 1d 4.6 1.641E þ07 6.87E þ 05 31.8
0.459 0.682 1.263 0.071 1d 4.6 2.036E þ 07 7.31E þ05 48.3

p-Toluenesulfonic acid 0.463 0.702 2.252 0.045 1 d 9.4 2.704E þ 07 7.34Eþ 05 43.5
0.469 0.701 4.099 0.067 1 d 11.0 3.098E þ 07 2.60E þ 06 64.8
0.450 0.704 4.677 0.075 1 d 7.8 2.188E þ 07 1.32Eþ 06 74.5
0.443 0.7 5.894 0.088 1 d 7.8 1.625Eþ 07 7.06E þ05 67.8
Amberlite IR120 0.446 0.699 4.639 0.622 1 d 5.6 1.414E þ 07 3.26E þ 05 64.7

Amberlyst 15 0.446 0.705 4.566 0.495 1d 1.3 2.502E þ 07 7.54Eþ 05 72.1

0.455 0.752 4.606 1.322 1d 6.6 1.261E þ07 3.98E þ 05 54.4
0.455 0.752 4.600 0.501 1d 6.2 1.670E þ 07 4.88E þ 05 69.5
0.453 0.689 4.489 0.297 1d 8.6 2.166E þ07 4.48E þ 05 63.3
0.442 0.688 4.620 0.097 1d 17.8 3.315E þ 07 9.12E þ05 49.0
0.458 0.687 6.010 0.502 1d 8.0 1.758Eþ 07 1.04E þ06 69.4
0.458 0.700 2.018 0.501 1d 8.0 2.986E þ 07 1.17E þ 06 52.3
0.455 0.694 4.492 0.544 1d 9.0 2.337E þ 07 7.08Eþ 05 65.1
0.458 0.709 4.525 0.652 1d 6.4 1.569Eþ 07 3.39E þ 05 61.6
0.448 0.692 4.595 0.908 1d 14.8 2.939E þ 07 8.27Eþ05 51.4
0.439 0.700 4.482 0.499 4h 11.4 2.928E þ 07 6.95E þ 05 66.5

Amberlyst 15 0.442 0.685 4.420 0.806 4h 14.0 3.736Eþ07 5.82E þ 05 67.7

0.439 0.700 4.482 0.499 8h 11.6 3.102E þ 07 5.33Eþ 05 69.2
0.442 0.685 4.420 0.806 8h 11.0 3.319E þ 07 1.27E þ 06 76.6
0.447 0.688 4.518 0.498 14 h 7.8 2.328E þ 07 8.73Eþ05 76.3
0.465 0.710 4.465 0.814 14 h 7.0 2.167Eþ 07 5.09E þ 05 75.9
0.439 0.700 4.482 0.499 26 h 11.2 2.876E þ 07 8.20E þ 05 66.5
0.442 0.685 4.420 0.806 26 h 7.6 1.703Eþ 07 6.40E þ 05 56.9

Table 3
The tested molar ratios of PA: CA with corresponding molar conversions. The re-
actions were carried out over night at 80 °C and catalysed by p-toluenesulfonic
acid.

Molar ratio PA-CA Molar conversion of CA in %

1.4:1 17.2
2.4:1 31.8
4.1:1 48.3
7.2:1 70.4
15.8:1 74.5
19.6:1 67.8

Since PA is only a little soluble in water at 20 °C, the reaction

mixture was poured into hot water. Upon cooling, CAPE
precipitated and was collected by filtration. The product was
identified via 1H NMR spectroscopy, see Section 2.
The aqueous filtrate should contain mainly phenethyl alcohol
and choline chloride and small amounts of caffeic acid. This can be
deduced from the HPLC experiments. It is possible that side re-
actions took place, but this was not considered in details. Since
phenethyl alcohol and choline chloride are highly diluted, the
aqueous filtrate is not considered as toxic.
4. Conclusion
The proposed “green” strategy is simple and efficient and can be
extended to other chemical synthesis, with a special interest for
food and drug products, where toxic solvents should be avoided: if
the reactants, here caffeic acid and phenethyl alcohol, are of very
Fig. 3. Molar conversion of CA as a function of Amberlyst 15 in wt%. The molar ratio
of CA, ChCl and PA was kept constant.
different hydrophilicity, it may be difficult to find a harmless sol-
vent, in which both reactants are soluble. In this case, it can be
interesting to use one of the reactants to transform it into a deep
eutectic solvent, by adding a convenient, harmless and cheap ad-
ditive (here Choline Chloride). In this solvent, the second reactant,
here phenethyl alcohol, is dissolved and the reaction is carried out.
If the product, here the CAPE ester, is sufficiently hydrophobic, it is
sufficient to add water, after filtration of the catalyst, Amberlyst 15.
Then the additive (ChCl) is dissolved in the water phase, whereas
44 V. Fischer et al. / Sustainable Chemistry and Pharmacy 4 (2016) 40–45
Fig. 4. Molar conversion of CA as a function of time. The ratio of PA, CA, ChCl and
Amberlyst 15 was kept constant.
the hydrophobic product forms an immiscible phase that can be
easily separated from the aqueous phase. If, as it is the case here,
the additive is very cheap and harmless, the aqueous solutions can
be simply thrown away. It should be noted that a significant
number of Deep Eutectic Solvents can be imagined enabling a
large amount of possible syntheses without solvents (LeBlanc
et al., 2012; De Santi et al., 2012; Boudreau et al., 2012; Zhang
et al., 2012). We think that this novel strategy perfectly fulfills
several requirements, as formulated by Anastas et al. in the twelve
principles of green chemistry (Anastas and Warner, 1998).
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