Highly efficient esterification of ferulic acid under microwave irradiation

Article abstract of DOI:10.3390/molecules14062118

A highly efficient synthesis of alkyl ferulates under microwave irradiation is described. The time of these reactions ranged from 3 to 5 minutes, which was much shorter than the traditional synthetic methods, and the alkyl ferulates were obtained in higher yields.

Full text of DOI:10.3390/molecules14062118

Molecules 2009, 14, 2118-2126; doi:10.3390/molecules14062118
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Highly Efficient Esterification of Ferulic Acid Under Microwave
Irradiation
Nian-Guang Li 1,3, Zhi-Hao Shi 2, Yu-Ping Tang 1,*, Bao-Quan Li 1 and Jin-Ao Duan 1,*
1
Jiangsu Key Laboratory for TCM Formulae Research, Nanjing University of Chinese Medicine,
Nanjing, Jiangsu 210046, China; E-mails: linianguang@163.com (N-G.L.);
libaoquan121@163.com (B-Q.L.)
2
Division of Organic Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 211198, China;
E-mail: sszh163@163.com (Z-H.S.)
3
Department of Medicinal Chemistry, Nanjing University of Chinese Medicine, Nanjing, Jiangsu
210046, China
* Authors to whom correspondence should be addressed; E-mails: yupingtang@njutcm.edu.cn
(Y-P.T.), dja@njutcm.edu.cn (J-A.D.); Tel.: +86-25-85811916; Fax: +86-25-85811916
Received: 14 May 2009; in revised form: 30 May 2009 / Accepted: 8 June 2009 /
Published: 10 June 2009
Abstract: A highly efficient synthesis of alkyl ferulates under microwave irradiation is
described. The time of these reactions ranged from 3 to 5 minutes, which was much shorter
than the traditional synthetic methods, and the alkyl ferulates were obtained in higher
yields.
Keywords: esterification; ferulic acid; microwave irradiation; highly efficient
1. Introduction
It is well established that under normal conditions, there is a steady state balance between pro-
oxidants and antioxidants, which is necessary to ensure the optimal efficiency of antioxidant defenses.
However, when the rate of free radical generation exceeds the capacity of antioxidant defenses,
oxidative stress ensues, with severe damage to the cell [1]. Therefore, the use of radical scavengers
should be of critical importance to prevent and cure many diseases such as ischemia-reperfusion
injury, neurodegenerative disorders and surgical organ transplantation [2]. Recent evidence has

Molecules 2009, 14
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demonstrated that ferulic acid is a scavenger of hydroxyl and peroxyl radicals in both brain cells and
macrophages and easily forms a resonance-stabilized phenoxy radical [3-5]. However, ferulic acid has
only limited solubility in hydrophobic media, which reduces its antioxidant effects in inhibiting auto-
oxidation of fats and oils [6]. The strategy of esterification of hydrophilic ferulic acid with lipophilic
molecules, such as aliphatic alcohols, could be employed to alter its solubility in a hydrophobic
medium. Indeed, it has been found that the hydrophobic alkyl ferulate derivatives have a higher
antioxidative activity than ferulic acid for the prevention of oxidation of linoleic acid in a bulk
system [7].
In the classical method of esterification ferulic acid was refluxed with alcohols in the presence of
various catalysts, such as concentrated sulfuric acid, hydrogen chloride, boron trifluoride, aluminum
chloride, trifluoroacetic anhydride, polyphosphate ester, neodymium oxide, dicyclohexylcarbodiimide,
graphite bisulfate, etc [8-10], but it was difficult to avoid the disadvantages of using these catalysts,
such as long reaction times, low yield, expensive reagents and tedious operation. For instance, in 2007,
Rault’s group [11] described a classical esterification of ferulic acid in the presence of methanol and
sulfuric acid (95%) to afford methyl ferulate, and the same procedure was used in the presence of
ethanol to afford ethyl ferulate, however, the reaction required 24 h in this procedure.
Ferulic acid is heat-sensitive and susceptible to oxidation, which has made enzymatic syntheses of
its esters more attractive than chemical syntheses. However, enzymatic syntheses also have many
disadvantages including low yields, time consumption, solvent requirements, etc [12-13]. For example,
in 2006, Yoshida and co-workers [14] continuously synthesized 1-pentyl, 1-hexyl and 1-heptyl
ferulates at 60-90 ºC, however, the reactor system they used, in which a column packed with ferulic
acid powder and another column packed with immobilized Candida antarctica lipase particles were
connected in series, was very special and the reaction must continue for at least 40 h in order to obtain
the alkyl ferulates in high yield.
In recent years, microwave-assisted reactions have received a great deal of attention, because
reactions under microwave irradiation are in general not only faster than with conventional heating
methods, but also potentially more efficient, clean, and safe [15-16]. Further improvements have also
been reported whereby microwave-assisted reactions can offer enhanced reaction rates, higher yields,
and greater selectivity for the targeted product under milder reaction conditions [17]. In 2002, Lee’s
group reported a facile and efficient method for the conversion of ferulic acid to the corresponding
alkyl carboxylates with trialkyl orthoacetate under microwave irradiation under solvent-free and
neutral reaction conditions [18], but their method could only be applied to trimethyl orthoacetate and
triethyl orthoacetate because trialkyl orthoacetates with long lined carbon chains or branched carbon
chains could not be easily synthesized. Because alcohols are a type of polar solvent, they can absorb
microwaves very efficiently [17], so we have therefore attempted the use of alcohols as alkylation
reagents for the esterification of ferulic acid under the microwave irradiation. The aim of this study
was to establish an efficient strategy of synthesizing alkyl ferulates under the microwave irradiation,
and to evaluate its efficiency in comparison with the traditional method.

Molecules 2009, 14
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2. Results and Discussion
2.1. Optimization of the catalyst for the synthesis of ethyl ferulate
In our research, we selected ethanol (2b) as a representative alcohol to optimize the reaction
conditions (cf. Scheme 1A). First, we tried this esterification without any catalysts, and ferulic acid (1)
was reacted with the ethanol (2b) directly under microwave irradiation with the power set at 200 W
(Table 1, Runs 1-2). Unfortunately, there was no indication of product formation even when the
reaction time was extended for 10 mins. To make this reaction proceed easily, we added conc. sulfuric
acid to the reaction mixture as catalyst. This time the esterification in the presence of 10 mol% H2SO4
in ethanol was found to be complete after 5 mins at 88 ºC, giving the corresponding ethyl ferulate (3b)
in 94% yield (Table 1, Run 7). When the amount of H2SO4 was increased to 12 mol%, the yield of the
product was reduced to 86% (Table 1, Runs 8); this could be because the ethyl ferulate was hydrolyzed
if the amount of H2SO4 used was excessive. However, when the amount of H2SO4 was decreased
(2, 4, 6, 8 mol%), the reaction proceeded more slowly, and the yields of ethyl ferulate (3b) were
reduced to 56, 70, 86 and 90%, respectively, even when the reaction was carried out for 5 mins at
88 ºC (Table 1, Runs 3-6).
Scheme 1. Syntheses of alkyl ferulates.
R=a: CH3
b: CH2CH3
OR
OH
O
c: (CH2)2CH3
d: CH(CH3)2
e: (CH2)3CH3
f : CH2CH(CH3)2
g: (CH2)4CH3
h: (CH2)2CH(CH3)2
O
H3CO
HO
H3CO
HO
convertional heating (A)
+
ROH
or microwave irradiation (B)
1
2
3
Table 1. Optimization of the catalyst concentration for the synthesis of ethyl ferulate (3b)a.
Run
1
2
3
4
5
6
7
8
Cat. (mol %)
Timec (min)
Yieldd (%)
0
0
5
10
5
5
5
5
5
5
0
0
2b
56
70
86
90
94
4b
6b
8b
10b
12b
86
b
a Reaction conditions: Ferulic acid (1, 1 mmol), ethanol (2b, 5 mL), temperature 88 °C; Conc.
sulfuric acid as the catalyst; c Monitored by TLC; d Isolated yield, purity confirmed by MS and 1H-
NMR.
2.2. Optimization of the temperature for the synthesis of ethyl ferulate
Reaction temperature played a crucial role in this microwave-assisted esterification. We found that
the increase of the temperature remarkably accelerated the reaction (Table 2, Runs 1-5). A high yield

Molecules 2009, 14
2121
was obtained within 5 mins when the esterification was carried out in ethanol at 88 °C (20°C higher
than the boiling point of ethanol) (Table 2, Run 5). The esterification at 48 °C for 5 mins gave only a
40% yield of desired product (Table 2, Run 1). However, for this esterification, a higher temperature
was unfavorable as the desired ethyl ferulate (3b) was hydrolyzed (Table 2, Runs 6-7).
Table 2. Optimization of the temperature for the synthesis of ethyl ferulate (3b)a.
Run
1
2
3
4
5
6
7
Temp. (ºC)
Timeb (min)
Yieldc (%)
48
58
68
78
88
5
5
5
5
5
5
5
40
54
76
86
94
90
83
98
108
a Reaction conditions: Ferulic acid (1, 1 mmol), ethanol (2b, 5 mL), Conc. sulfuric acid (10 mol%);
b Monitored by TLC; c Isolated yield, purity confirmed by MS and 1H-NMR..
2.3. Optimization of the reaction time for the synthesis of ethyl ferulate
The effect of the reaction time was also examined (Table 3, Runs 1-6). From the results we could
see that as the reaction time was extended from 2 to 7 mins, the yield of the desired product ethyl
ferulate (3b) improved from 56% to 94% (Table 3, Runs 1-4). However, when the reaction time
exceeded 4 mins, the yield was not affected so much (Table 3, Runs 5-6).
Table 3. Optimization of the reaction time for the synthesis of ethyl ferulate (3b)a.
Run
1
2
3
4
Timeb (min)
Yieldc (%)
2
3
4
5
6
7
56
94
94
93
94
94
5
6
a Reaction conditions: Ferulic acid (1, 1 mmol), ethanol (2b, 5 mL), Conc. sulfuric acid (10 mol%),
Temperature (88 ºC); b Monitored by TLC; c Isolated yield, purity confirmed by MS and 1H-NMR.
2.4. Optimization of the molar ratio of ferulic acid to ethanol for the synthesis of ethyl ferulate
Finally, we investigated the effect of the molar ratio of ferulic acid to ethanol in this esterification
(Table 4, Runs 1-8). It was found that when the molar ratio was more than 1:6, the targeted product of
ethyl ferulate was obtained in almost quantitative yield (Table 4, Runs 6-8). Decreasing the molar ratio
to 1:1, the ethyl ferulate was obtained in only 30% after this esterification was continued for 3 mins
(Table 4, Run 1), and as the molar ratio of ferulic acid to ethanol increased, the yield of ethyl ferulate
was also enhanced (Table 4, Runs 2-6).

Molecules 2009, 14
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Table 4. Optimization of the molar ratio of ferulic acid to ethanol for the synthesis of ethyl
ferulate (3b)a.
Run
1
2
3
4
5
6
7
8
Molar Ratio (1 : 2b)
Timeb (min)
Yieldc (%)
1 : 1
1 : 2
1 : 3
1 : 4
1 : 5
1 : 6
1 : 7
1 : 8
3
3
3
3
3
3
3
3
30
54
83
88
92
94
94
93
a
Reaction conditions: Ferulic acid (1, 1 mmol), Conc. sulfuric acid (10 mol%), Temperature
(88ºC); b Monitored by TLC; c Isolated yield, purity confirmed by MS and 1H-NMR.
2.5. Synthesis of alkyl ferulates under conventional heating and microwave irradiation
After we have optimized the catalyst, temperature, reaction time and the molar ratio of ferulic acid
to alcohol for this esterification, we applied this methodology to the reactions between ferulic acid and
other alcohols, and compared the efficiency of microwave-assistance with conventional heating (Table
5). The result showed that the reaction times for conventional heating were always very long, the
longest reaction time being 28 h, as in the case of 3h (Table 5, Run 8). The reaction time became much
longer as the number of atoms in the alcohol increased, such as in the case of 3b (Table 5, Run 2) and
3c (Table 5, Run 3), where the reaction times were 8 h and 14 h, respectively. For alcohols with same
atom numbers, the reaction time for alcohols with branched carbon chains was much longer than those
with linear carbon chains, for instance, the reaction time of 3c was 14 h (Table 5, Run 3), while the
reaction time of 3d was 20 h (Table 5, Run 4). Another interesting phenomenon was that similarly the
yields of the alkyl ferulates turned to be much lower as the atom numbers of the alcohol became more,
such as in the case of 3e (73%) (Table 5, Run 5) and 3a (79%) (Table 5, Run 1), and the yield of the
alkyl ferulates with branched alkyl chains was much lower than those with linear alkyl chains, which
could be observed from the case of 3g (58%) (Table 5, Run 7) and 3h (46%) (Table 5, Run 8). These
differences in the reaction time and yields between reactions with branched and linear alcohols may be
due to steric hindrance in the alcohols with branched carbon chains [19]. When microwave irradiation
was applied to these esterifications of ferulic acid, all the reaction times decreased to several minutes,
even for the alcohols with long carbon chains or branched chains, such as in the case of 3g (Table 5,
Run 7) and 3h (Table 5, Run 8), where the reaction time for synthesis of these two ferulates was only 5
min under the microwave irradiation, especially for 3h, the reaction time was reduced from 28 h to 5
min, while the yield increased from 46% to 91%, and furthermore, all the yields achieved in the
synthesis of ferulates under microwave irradiation were above 90% (Table 5). This interesting
phenomenon may be attributed to an increased equilibrium constant under microwave irradiation, as in
the reaction vessel, the reactive pressure must be very high under microwave irradiation when the
vessel is sealed, so the equilibrium constant might be increased because this equilibrium constant is in
directly proportional to pressure [20].

Molecules 2009, 14
Table 5. Synthesis of alkyl ferulates under conventional heating and microwave irradiation.
2123
Conventional heatinga
Temp.
Microwave irradiationb
Run
Sub.
Prod.
Timec
8 h
Yieldd
Temp.
75 ºC
88 ºC
107 ºC
92 ºC
128 ºC
118 ºC
148 ºC
142 ºC
Timec
3 min
3 min
4 min
4 min
4 min
4 min
5 min
Yieldd
95
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
79
81
77
69
73
63
58
46
8 h
94
94
93
93
92
93
91
14 h
20 h
18 h
24 h
22 h
28 h
2g
2h
3g
3h
5 min
a
b
Reaction conditions: 1 (1 mmol), alcohol (5 mL), Conc. sulfuric acid (10 mol%); Reaction
c
conditions: 1 (1 mmol), alcohol (6 mmol), Conc. sulfuric acid (10 mol%); Monitored by TLC;
dIsolated yield, purity confirmed by MS and 1H-NMR.
3. Experimental
3.1. General
All reagents were commercially available and used directly. The 1H-NMR spectra were recorded on
a Bruker AV 300 spectrometer using CDCl3 as the solvent and TMS as the internal standard. Chemical
shifts are reported in parts per million (ppm). The ESI-MS were obtained on Agilent 1946A-MSD. IR
spectra were recorded on a Nicolet Impact 410 instrument. Elemental analysis was performed on an
Elementar Vario EL III analyzer.
3.2. General procedure for the esterification of ferulic acid with conventional heating
To a stirred mixture of ferulic acid (1, 970 mg, 5 mmol) in alcohol (5 mL) was added concentrated
sulfuric acid (0.027 mL, 0.5 mmol), and the reaction mixture was refluxed until the ferulic acid had
completely reacted, as indicated by TLC. After cooling to 25°C, ethyl acetate was added and the
mixture washed with water and brine. The ethyl acetate layer was dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by silica gel column chromatography
eluted with petroleum ether-EtOAc (8:1, v/v) to afford the corresponding ferulates.
3.3. General procedures for the esterification of ferulic acid with microwave irradiation
Concentrated sulfuric acid (0.027ml, 0.5 mmol) was added dropwise to a stirred mixture of ferulic
acid (970 mg, 5 mmol) in alcohol (30 mmol) and the reaction mixture was refluxed in a sealed
Discover (CEM, USA) reaction vessel under microwave irradiation; the power was set at 200W, and
the temperature was set at some 20°C above the boiling point of the alcohol, and the pressure was set
at 180 psi.

Molecules 2009, 14
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3.4. Analytical and Spectroscopic Data for Some Representative Compounds and New Compounds
1
(E)-Methyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (3a) [11]: White solid. H-NMR δ 3.80 (s, 3H),
3.91 (s, 3H), 6.29 (d, J = 15.9 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 7.04 (m, 2H), 7.62 (d, J = 15.9 Hz,
1H); ESI-MS m/z: 209 [M +H]+ (100); IR (KBr) 3383, 2950, 2844, 2645, 2356, 1599, 1169, 816, 567
cm-1; Anal. Calcd for C11H12O4: C, 63.45; H, 5.81; Found: C, 63.41; H, 5.85.
(E)-Ethyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (3b) [11]: White solid. 1H-NMR δ 1.31 (t, 3H), 3.92
(s, 3H), 4.25 (q, 2H), 6.29 (d, J = 15.9 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.06 (m, 2H), 7.61 (d, J =
15.9 Hz, 1H); ESI-MS m/z:223 [M +H]+ (100); IR (KBr) 3401, 2979, 2357, 1699, 1599, 1518, 1456,
1378, 1169, 1033, 816, 569 cm-1; Anal. Calcd for C12H14O4: C, 64.85; H, 6.35; Found: C, 64.82; H,
6.39.
1
(E)-Propyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (3c) [19]: White solid. H-NMR δ 1.01 (t, 3H),
1.75 (m, 2H), 3.94 (s, 3H), 4.15 (q, 2H), 6.31 (d, J = 15.9 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 7.05 (m,
2H), 7.63 (d, J = 15.9 Hz, 1H); ESI-MS m/z: 237 [M +H]+ (100); IR (KBr) 3366, 2965, 2638, 2355,
1698, 1519, 1261, 816, 568 cm-1; Anal. Calcd for C13H16O4: C, 66.09; H, 6.83; Found: C, 66.01; H,
6.88.
(E)-Isopropyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (3d) [19]: Light brown solid. 1H-NMR δ 1.32 (d,
J = 6.2Hz, 6H), 3.92 (s, 3H), 5.14 (m, 1H), 6.27 (d, J = 15.9 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.03 (m,
2H), 7.60 (d, J = 15.9 Hz, 1H); ESI-MS m/z: 237 [M +H]+ (100); IR (KBr) 3383, 2978, 2359, 1692,
1597, 1514, 1462, 1426, 1375, 1275, 1180, 902, 810, 656, 566 cm-1; Anal. Calcd for C13H16O4: C,
66.09; H, 6.83; Found: C, 66.02; H, 6.89.
1
(E)-Butyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (3e) [19]: Light brown oil. H-NMR δ 0.97 (t, 3H),
1.45 (m, 2H), 1.69 (m, 2H), 3.93 (s, 3H), 4.20 (t, 2H), 6.29 (d, J = 15.9 Hz, 1H), 6.92 (d, J = 8.0 Hz,
1H), 7.04 (m, 2H), 7.61 (d, J = 15.9 Hz, 1H); ESI-MS m/z: 251 [M +H]+ (100); IR (KBr) 3559, 2849,
2331, 2066, 1955, 1859, 1063 cm-1; Anal. Calcd for C14H18O4: C, 67.18; H, 7.25; Found: C, 67.11; H,
7.20.
(E)-Isobutyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (3f) [19]: Light brown oil. 1H-NMR δ 0.98 (d, J =
6.8Hz, 6H), 2.03 (m, 1H), 3.92 (s, 3H), 3.98 (d, J = 6.6 Hz, 2H), 6.30 (d, J = 15.9 Hz, 1H), 6.91 (d, J =
8.0 Hz, 1H), 7.05 (m, 2H), 7.62 (d, J = 15.9 Hz, 1H); ESI-MS m/z: 251 [M +H]+ (100); IR (KBr) 3440,
2975, 2657, 2353, 2069, 1953, 1859, 1634, 1443, 1223, 1130, 982, 819, 571 cm-1; Anal. Calcd for
C14H18O4: C, 67.18; H, 7.25; Found: C, 67.13; H, 7.28.
(E)-Pentyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (3g) [19]: Light brown oil. 1H-NMR δ 0.88 (t, 3H),
1.36 (m, 4H), 1.70 (m, 2H), 3.91 (s, 3H), 4.20 (t, 2H), 6.28 (d, J = 15.9 Hz, 1H), 6.90 (d, J = 8.0 Hz,
1H), 7.04 (m, 2H), 7.60 (d, J = 15.9 Hz, 1H); ESI-MS m/z: 265 [M +H]+ (100); IR (KBr) 3422, 2335,
2065, 1860, 1636, 1447, 1049, 819, 571 cm-1; Anal. Calcd for C15H20O4: C, 68.16; H, 7.63; Found: C,
68.11; H, 7.68.

Molecules 2009, 14
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1
(E)-Isopentyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (3h) [19]: Yellow oil. H-NMR δ 0.95 (d, J =
6.6 Hz, 6H), 1.56 (m, 2H), 1.81 (m, 1H), 3.91 (s, 3H), 4.22 (t, 2H), 6.29 (d, J = 15.9 Hz, 1H), 6.91 (d, J
= 8.0 Hz, 1H), 7.07 (m, 2H), 7.61 (d, J = 15.9 Hz, 1H); ESI-MS m/z: 265 [M +H]+ (100); IR (KBr)
3373, 2958, 2356, 1699, 1519, 1163, 816, 569 cm-1; Anal. Calcd for C15H20O4: C, 68.16; H, 7.63;
Found: C, 68.19; H, 7.66.
4. Conclusions
In summary, an efficient microwave-assisted esterification of ferulic acid with alcohols was
developed for the first time. The reported procedure affords high yields in shorter reaction times, and
the results of the present study should be of value to synthesize other esters.
Acknowledgements
This work was supported by Key Research Project in Basic Science of Jiangsu College and
University (NO. 06KJA36022, 07KJA36024), the Natural Science Foundation of the Jiangsu Higher
Education Institutions of China (NO. 08KJD350001), and 2006’ Training Program of Scientific and
Technological Innovation Team for “Qinglan Project” of Jiangsu College and University.
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Sample Availability: Samples of the compounds 3a-h are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).