Scalable synthesis of oleoyl ethanolamide by chemical amidation in a mixed solvent

Article abstract of DOI:10.1007/s11746-015-2749-6

Oleoyl ethanolamide is a lipid mediator that exhibits biological activity in animal and cell models. In this study, an effective process is described to synthesize oleoyl ethanolamide by chemical amidation with native oil used as an acyl donor in the presence of sodium methoxide. Reaction conditions were optimized. When the amidation reaction was conducted in a mixed solvent, by reacting 2 mmol high oleic sunflower oil and 20 mmol ethanolamine in the presence of 1.5 % sodium methoxide with agitation, >90 % fatty acid ethanolamide was formed after 3 h of reaction time. The fatty acid ethanolamide product was purified by a two-step crystallization process to prepare oleoyl ethanolamide. Highly pure oleoyl ethanolamide was obtained in a 70.3 % molar yield. The novelty of the work is the use of native oil as acyl donor and the mixed solvent used as the reaction media. The use of native oil avoids the formation of ion pairs with ethanolamine that can occur in other synthesis routes.

Full text of DOI:10.1007/s11746-015-2749-6

J Am Oil Chem Soc (2016) 93:125–131
DOI 10.1007/s11746-015-2749-6
ORIGINAL PAPER
Scalable synthesis of oleoyl ethanolamide by chemical amidation
in a mixed solvent
Xiaosan Wang1 · Zhengyang Han1 · Yang Chen1 · Qingzhe Jin1 · Xingguo Wang1
Received: 28 October 2014 / Revised: 16 October 2015 / Accepted: 2 November 2015 / Published online: 12 November 2015
© AOCS 2015
Abstract Oleoyl ethanolamide is a lipid mediator that
exhibits biological activity in animal and cell models. In
this study, an effective process is described to synthesize
oleoyl ethanolamide by chemical amidation with native oil
used as an acyl donor in the presence of sodium methox-
ide. Reaction conditions were optimized. When the amida-
tion reaction was conducted in a mixed solvent, by reacting
2 mmol high oleic sunflower oil and 20 mmol ethanola-
mine in the presence of 1.5 % sodium methoxide with agi-
tation, >90 % fatty acid ethanolamide was formed after 3 h
of reaction time. The fatty acid ethanolamide product was
purified by a two-step crystallization process to prepare
oleoyl ethanolamide. Highly pure oleoyl ethanolamide was
obtained in a 70.3 % molar yield. The novelty of the work
is the use of native oil as acyl donor and the mixed solvent
used as the reaction media. The use of native oil avoids the
formation of ion pairs with ethanolamine that can occur in
other synthesis routes.
Introduction
Fatty acid ethanolamides are an important class of non-
ionic surfactants, which are widely used as lubricants,
surfactants, detergents, and cosmetics [1–3]. Their phys-
icochemical properties can differ depending on the length
of the hydrocarbon chain. Typically, these compounds are
used as anti-slip and anti-block additives for polyethylene
films, coatings for paper, lubricant additives, printing ink
additives, water repellants for textiles, mold release agents,
defoaming agents and flow improvers [3].
In addition to use as nonionic surfactants, studies con-
ducted over the last 20 years suggest that fatty acid ethan-
olamides are a class of endogenous signaling molecules
and lipid mediators in animal and plant tissues [4–6]. The
most important ethanolamides in this regard are palmitoyl,
stearoyl, oleoyl and arachidonoyl ethanolamides. Palmitoyl
and stearoyl ethanolamides are most abundantly found in
nature while arachidonoyl ethanolamide is usually a minor
component [4]. Palmitoyl ethanolamide has been noted to
reduce allergic reactions, inhibit mast cell degranulation
[7], exhibit anti-inflammatory activity and attenuate pain
sensation [8], and exert neuroprotective effects in rats and
mice [9]. Similarly, stearoyl ethanolamide has been found
to exhibit anti-inflammatory activity. In addition, some
studies have reported anorexic effects with stearoyl etha-
nolamide [10]. Oleoyl ethanolamide is a natural analog of
the endogenous cannabinoid arachidonoyl ethanolamide
and has also been found to exhibit biological activity. First,
oleoyl ethanolamide is thought to modulate feeding and
energy homeostasis by binding to peroxisome proliferator-
activated receptor-α (PPAR-α), where it affects the biosyn-
thesis of satiety signaling biomarkers [11]. In addition, the
compound can affect lipid metabolism by elevating lipolysis
Keywords Oleoyl ethanolamide · High oleic sunflower
oil · Sodium methoxide · Amidation · Mixed solvent
* Xiaosan Wang
wxstongxue@163.com
* Xingguo Wang
wxg1002@qq.com
1
State Key Laboratory of Food Science and Technology,
Synergetic Innovation Center of Food Safety and Nutrition,
School of Food Science and Technology, Jiangnan
University, 1800 Lihu Road, Wuxi, Jiangsu 214122, People’s
Republic of China
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J Am Oil Chem Soc (2016) 93:125–131
in adipocytes and simultaneously increase intestinal fatty
acid uptake by modulating the expression of FAT/CD36
(fatty acid translocase) in adipose tissue [11, 12]. Thus, ole-
oyl ethanolamide is a focus of considerable pharmaceutical
interest to treat diseases, such as obesity and cancer.
AgroSciences (Guangzhou, China). The average molecu-
lar weight of the fatty acids from HOSO was 281.5 g/
mol, whereas average triglyceride molecular weight was
882.6 g/mol.
Stearoyl ethanolamide standard was purchased from
Sigma-Aldrich Chemical (St. Louis, MO, USA). Ethanol-
amine and sodium methoxide were obtained from Sinop-
harm Chemical Reagent (Shanghai, China). All other rea-
gents, including solvents, were analytical grade and were
obtained from Sinopharm Chemical Reagent.
In general, these compounds are prepared by the reaction of
free fatty acids [13–16], fatty acid chlorides [17–19], or native
oil [20] with ethanolamine. The most common method is to
use a free fatty acid or its chloride as an acyl donor to pro-
duce a pure fatty acid ethanolamide. When the free fatty acid
is selected as the acyl donor, fatty acid ethanolamide is usu-
ally prepared by enzymatic amidation in solvent. Even though
enzymatic synthesis is effective, the reaction conducted in a
solvent generally requires at least 30 wt% lipase relative to the
weight of the reactants [13, 14, 16]. The high lipase load is
attributed to the formation of ion pairs between ethanolamine
and free fatty acid [15]. As a salt, the ion pair has a high melt-
ing point and cannot be dissolved in organic solvent. Lipase
does not effectively catalyze ion pairs, resulting in the need
to use a high lipase load. When a solvent-free system is used
for the reaction, the products palmitoyl, stearoyl and oleoyl
ethanolamides also have high melting points. Thus, the reac-
tion should be conducted at temperatures above their melting
points, which would inactivate the lipase [13]. Hence, a lipase-
catalyzed solvent-free system is not suitable for the synthesis
of high melting point ethanolamides.
For ethanolamide synthesis, chemical amidation is more
effective when a fatty acid chloride is used as the acyl donor.
However, fatty acid chlorides are expensive and less available
compared with free fatty acids or native oil. In addition, fatty
acid chlorides attend to be corrosive and relatively toxic.
The use of native oil as the acyl donor to synthesize fatty
acid ethanolamide has received little attention. Native oil is
beneficial because it is safe, cheap, and will not form ion
pairs with ethanolamine. However, native oil contains a dis-
tribution of fatty acids, and the purity of any specific fatty
acid ethanolamide will necessarily be low. Fatty acid eth-
anolamide obtained from the amidation of native oil with
ethanolamine would generally be used for industrial rather
than medicinal purposes [20].
Optimization of oleoyl ethanolamide synthesis
Four parameters were optimized to obtain maximum the
content of fatty acid ethanolamides in the crude reac-
tion mixtures. These factors included the reaction system
and solvent, the amounts of solvent and catalyst, and the
reaction time. To optimize the conditions, one factor was
changed at each step, while the other factors were fixed.
After each step of optimization, the optimal value was
used in the next optimization step. All reactions were
run in duplicate unless otherwise specified. Results were
expressed as mean standard deviation (SD).
The optimization reactions were conducted with 1.77 g
HOSO (2 mmol) and 1.22 g ethanolamine (20 mmol) and
magnetic stirring (250 rpm). For the initial study of solvent
systems, 1 % (relative to the weight of the reactants) sodium
methoxide was used and the reaction was allowed to proceed
for 3 h. The reaction was performed in 1 mL of one of a vari-
ety of solvents or in a solvent-free system. The selected sol-
vents included hexane, ethanol, hexane/ethanol 1:1 (v/v), and
acetone. At the end of the reaction, the solvents were removed
by evaporation at reduced pressure. The crude reaction prod-
uct was diluted to 1 mg/mL with hexane and subsequently
quantified by HPLC. All crude products obtained from the
optimization experiments were treated with the same process.
To study the effect of system dilution, the total solvent
volume was then varied between 0.5 and 2.0 mL. Next,
the amount of catalyst was varied between 1.0 and 2.5 %.
Finally, the reaction time was then studied on an hourly
basis.
In this study, high oleic sunflower oil (HOSO) was used
as the acyl donor to prepare oleoyl ethanolamide. The effects
of reaction system and solvent type, amounts of solvent and
sodium methoxide, and the reaction time were investigated. At
the end of the reaction, a separation method was developed to
obtain pure oleoyl ethanolamide based on the solubility differ-
ences of the crude product components in different solvents.
Larger scale synthesis of oleoyl ethanolamide (177 g
HOSO)
To test the scalability of the synthesis, the amidation reac-
tion was also conducted with 177 g (201 mmol) of HOSO
under the optimal conditions identified at the reduced scale.
Materials and methods
Purification of oleoyl ethanolamide
HOSO containing 87.5 % oleic acid, 8 % saturated fatty
acids and 3 % linoleic acid was purchased from Dow
To obtain highly pure oleoyl ethanolamide, crystallization
was used to remove impurities, i.e., excess ethanolamine,
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J Am Oil Chem Soc (2016) 93:125–131
127
small amounts of sodium methoxide, unreacted triglycer-
ides, and saturated and polyunsaturated fatty acid ethanola-
mides. The purification process included two basic steps.
First, the crude product was dissolved in hexane (1:10, v/v)
at 60 °C and the temperature was reduced to 4 °C. After
1 h, the precipitated material (crystal 1), containing fatty
acid ethanolamide, was collected by filtration, and the fil-
trate containing unreacted triglyceride (filtrate 1) was dis-
carded (Fig. 1). The process was repeated two times to
remove all of the unreacted triacylglycerol.
Subsequently, crystal 1 was then dissolved in methanol
(5:1, v/w) at 60 °C, and the solution was allowed to crys-
tallize at −15 °C. Once a precipitate began to form, the
sample was shaken and most of saturated fatty acid etha-
nolamides (crystal 2) then crystallized from the solution.
After filtration, crystal 2 was discarded, and the filtrate
(filtrate 2) was collected for further purification. Filtrate 2
was cooled to −15 °C again for about 40 min to produce
another precipitate (crystal 3). Crystal 3 containing oleoyl
ethanolamide was separated by filtration. The resulting
filtrate (filtrate 3) was again cooled to −15 °C for 40 min
after the volume ratio of methanol to fatty acid ethanola-
mide was decreased from 5:1 to 3:1, which resulted in a
further precipitate (crystal 4). Crystal 4 was composed of
oleoyl ethanolamide, whereas sodium methoxide, excess
ethanolamine, and polyunsaturated fatty acid ethanola-
mides remained in the filtrate (filtrate 4).
ethanolamide relative to the theoretical moles of oleoyl eth-
anolamide possible from the reaction conditions.
HPLC analysis of fatty acid ethanolamide
Amidation products were analyzed by HPLC-ELSD, using
a Waters 1525 liquid chromatographic system (Waters,
Milford, MA, USA) equipped with a LiChrospher Si col-
umn (25 cm × 0.46 cm, 5 μm particle size; Sigma-Aldrich,
Tokyo, Japan). The column was maintained at 35 °C, and
the compounds were eluted with a binary gradient of iso-
propanol/hexane (1:99 v/v) (solvent A) and isopropanol/
hexane/acetic acid (1:1:0.01 v/v/v) (solvent B) as follows:
B was increased from 0 to 10 % over 10 min then increased
to 20 % between 10 and 20 min; it was then held at 20 %
for 10 min. Total run time was 30 min. Samples were
diluted to 1 mg/mL and analyzed at a flow rate of 0.8 mL/
min.
Stearoyl ethanolamide was used as external standard and
the peak was identified by retention time (fatty acid ethan-
olamide: 22.95 min; triacylglycerol: 2.01 min). Since the
ethanolamine peak did not separate during the chromatog-
raphy, the purity of fatty acid ethanolamide was calculated
based on the peak area relative to the total peak area of a
particular sample except for the ethanolamine. The purity
of fatty acid ethanolamide was also calculated based on
mass ratio. To calculate the masses of HOSO and fatty acid
ethanolamide in the crude mixture, calibration curves were
determined by using triolein and stearoyl ethanolamide as
standards. The ratio of fatty acid ethanolamide peak area
to total peak area was converted to mass ratio based on the
calibration curves.
Purity of oleoyl ethanolamide in crystal 4 was confirmed
1
by H NMR. The yield of oleoyl ethanolamide was cal-
culated according to ratio of the moles of isolated oleoyl
Crude product
NMR analysis of oleoyl ethanolamide after purification
4 oC, 1 h
In hexane
1H NMR spectra was measured in CDCl3 with tetramethyl
silane (TMS) as the internal standard on a Bruker NMR
spectrometer (Avance III 400 MHz; Switzerland) operating
at 400 MHz.
The filtrate 1
Crystal 1
-15 oC, In methanol
Triglycerides
The filtrate 2
Crystal 2
Statistical analysis
-15 oC, In methanol
All data were analyzed by one-way ANOVA with Ori-
gin 8.0. Differences among the means were compared at
P = 0.05 by Tukey’s test.
Saturated ethanolamides
The filtrate 3
Crystal 3
-15 oC, Reduced
methanol volume
The filtrate 4
Crystal 4
Results and discussion
Catalyst, ethanolamine,
linoleoyl ethanolamide
The amidation reaction was performed both in a solvent-
free system and in different solvents. The solvent-free
system was selected based on a previous study [20]. How-
ever, we hypothesized that the solvent might decrease the
Oleoyl ethanolamide
Fig. 1 Purification of crude product by two-step crystallization
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J Am Oil Chem Soc (2016) 93:125–131
Fig. 2 Influence of reaction system and the type of solvent on the
formation of fatty acid ethanolamides. Reaction conditions described
in text
Fig. 3 Influence of solvent volume on the formation of fatty acid eth-
anolamides. Reaction conditions described in text
viscosity of the reaction system and reduce the potential for
solidification of the high melting products formed during
the reaction. In addition, the type of the solvent may affect
the amidation because the solvent interactions with ethan-
olamine and HOSO.
and the product. However, the solubility of HOSO in pure
alcohol is low. Thus, the mixture of ethanol and hexane was
suggested be the best solvent for the amidation reaction
since the mixture appeared to solubilize all the necessary
components and produced the most product. Based on the
analysis and the results, the mixed solvent was used for the
further reactions.
When the amidation was carried out in a solvent-free
system, a 57.6 % yield of fatty acid ethanolamide was
achieved (Fig. 2). In hexane, ethanol, hexane/ethanol 1:1
(v/v) and acetone, the yields were 64.1 74.9, 90.1 and
23.8 %, respectively. Significant differences were observed
in fatty acid ethanolamide content when reaction system
and the type of solvent were changed. In the solvent-free
system, the solution solidified after 30 min due to the for-
mation of high melting point ethanolamides, resulting in
incomplete reaction. Previously, Kolancilar [20] reported
the synthesis of fatty acid ethanolamide by amidation of
laurel oil and ethanolamine in a solvent-free system. How-
ever, we found the solvent-free system less suitable, most
likely because the melting points of some of the products
from HOSO are higher than the melting points of the prod-
ucts formed from laurel oil.
When the amidation reaction was conducted in hexane
and acetone, the solution was initially cloudy. Even though
hexane and acetone solubilizes HOSO, they did not not
readily dissolve ethanolamine or fatty acid ethanolamide,
which resulted in a poor interaction between HOSO and
ethanolamine and a low fatty acid ethanolamide content in
the crude reaction mixture.
The influence of solvent volume
The total volume of solvent affects the concentrations of
the product, reactants, and catalyst. Small amounts of sol-
vent may not fully dissolve the product and reactants. Large
amounts of solvent dilute the reactants and the catalyst, and
may result in reduced catalytic efficiency. The results show
that fatty acid ethanolamide content was not significantly
affected by additional solvent volume (Fig. 3). However,
fatty acid ethanolamide content produced in 0.5 mL of sol-
vent was significantly lower at the P = 0.1 level as com-
pared to fatty acid ethanolamide content in 1.0 or 1.5 mL.
The reduced product formation was probably because the
low solvent volume influenced the dissolution of the prod-
ucts, as the cloudy solution of this treatment suggested.
One milliliter solvent volume was chosen for further study.
The influence of sodium methoxide amount
In contrast, when amidation was conducted in ethanol
or the mixed hexane/ethanol solvent, the reaction solutions
were clear. Oleoyl ethanolamide and ethanolamine were
apparently more soluble in the polar alcohol compared with
the more nonpolar solvents. The observation suggests that
alcohol is a good solvent to dissolve both ethanolamine
Larger amounts of catalyst may increase reaction rate and
shorten reaction time. Otherwise, the reaction time may
need to be prolonged to reach equilibrium. We found that
fatty acid ethanolamide content was not changed with the
increase in sodium methoxide amount (Fig. 4). The results
suggested that the initial reaction time (3 h) was sufficient
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J Am Oil Chem Soc (2016) 93:125–131
129
Fig. 5 Influence of reaction time on the formation of fatty acid etha-
nolamides. Reaction conditions described in text
Fig. 4 Influence of catalyst amount on the formation of fatty acid
ethanolamides. Reaction conditions described in text
acid ethanolamide content between small-scale and large-
scale synthesis.
for completion of the amidation reaction at the levels of
catalyst studied. Even though 1.5 % sodium methoxide did
not give significantly higher fatty acid ethanolamide con-
tent compared with that of 1 %, a 1.5 % catalyst concentra-
tion was selected to ensure complete reaction. Under these
conditions, 90.1 % of fatty acid ethanolamide was formed
in the crude reaction mixture.
Purification of oleoyl ethanolamide by two‑step
crystallization
To obtain pure oleoyl ethanolamide from the crude product
mixture, a separation method was established. Generally,
column chromatography is used for the purification of the
product but the method limits the scalable synthesis of ole-
oyl ethanolamide. Thus, crystallization was investigated to
purify the crude product. The impurities included saturated
and polyunsaturated fatty acid ethanolamides, unreacted
HOSO, excess ethanolamine and small amounts of catalyst.
The purification of oleoyl ethanolamide was based on
solubility differences between oleoyl ethanolamide and the
various impurities in different solvents and at different tem-
peratures. Unreacted HOSO is soluble in hexane, whereas
the products are insoluble. Therefore, when the crude prod-
uct was dissolved in hexane at 60 °C and then crystallized
at 4 °C, fatty acid ethanolamide and sodium methoxide
precipitated but unreacted HOSO remained in solution.
The oleoyl ethanolamide was separated by filtration. Next,
saturated fatty acid ethanolamides are insoluble in most
solvents, whereas polyunsaturated fatty acid ethanolamides
have higher solubility in methanol. When the precipitate
was dissolved in methanol and the temperature lowered
at −15 °C, the precipitate initially formed contained satu-
rated fatty acid ethanolamides. Once this crystallization
started, the sample was agitated for 30 s to induce the full
precipitation of saturated fatty acid ethanolamides, which
were then removed by vacuum filtration. The remaining
filtrate was then crystallized further at −15 °C to obtain
crystals containing oleoyl ethanolamide, whereas linoleoyl
The influence of reaction time
Finally, the effect of reaction time was investigated.
The result showed that there was no significant increase
between 2 and 6 h (Fig. 5). Even though the maximum fatty
acid ethanolamide content was observed after 6 h reaction,
long reaction times increase operating costs. Therefore, 4 h
was selected as sufficient. Under these conditions, 90.2 %
fatty acid ethanolamide (area ratio) was formed in the
crude reaction mixture. Correspondingly, the purity of fatty
acid ethanolamide was 92.3 % based on the mass ratio. The
conversion of fatty acids was calculated based on the aver-
age molecular weights of fatty acids and HOSO, and the
corresponding conversion was 91.8 % (mol/mol).
Synthesis of fatty acid ethanolamide at a larger scale
To test the feasibility of scalable synthesis of oleoyl etha-
nolamide, the reaction conditions were run at the optimal
conditions obtained from the single-factor experiments.
The synthesis on a 201-mmol scale resulted in the forma-
tion of 90.3 % (w/w) fatty acid ethanolamide in the crude
reaction mixture. The conversion of fatty acids in the sys-
tem into fatty acid ethanolamides was 89.6 % (mol/mol).
There were no significantly differences observed in fatty
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J Am Oil Chem Soc (2016) 93:125–131
Fig. 6 1H NMR spectrum of synthetic oleoyl ethanolamide
ethanolamide, a minor amount of sodium methoxide, and
excess ethanolamine remained in the methanol phase
(Fig. 1). Therefore, after two basic steps, pure oleoyl ethan-
olamide was obtained in a 70.3 % (mol/mol) overall yield.
1H NMR spectroscopy of oleoyl ethanolamide showed
the following peaks: δ 0.88 (t, 3H, –CH3), 1.27 (m, 20H,
10 × –CH2–), 1.62 (q, 2H, –CH2CH2CONH–), 2.00
(m, 4H, –CH2CH=CHCH2–), 2.20 (t, 2H, –CH2CH-
2CONH–), 3.41 (p, 2H, HOCH2CH2NH–), 3.70 (t, 2H,
HOCH2CH2NH), 5.34 (m, 2H, –CH2CH=CHCH2–),
prepared for sufactant use, a low purity product is accept-
able, and purification is not necessary [21]. Consequently,
we aimed to purify oleoyl ethanolamide from the product
mixture for pharmaceutical application and an effective
two-step crystallization method was established. This is
the first report noting the separation of fatty acid ethan-
olamide with different degrees of saturation and chain
length.
1
6.32 (s, 1H, –CH2CH2CONH–). No H NMR peak for –
Conclusions
COOCH2CH2NH2 (δ 4.2–4.4, 2H) or –COOCH2CH2NH2
(δ 1.1–1.5, 2H) were observed. Thus, we confirmed the
structure and purity of oleoyl ethanolamide (Fig. 6).
An effective method for the synthesis of oleoyl ethanola-
mide was established. Under the optimal conditions, >90 %
fatty acid ethanolamide was formed. After purification of
oleoyl ethanolamide by two-step crystallization, pure ole-
oyl ethanolamide was obtained in a 70.3 % overall yield. A
mixed solvent system and the use of native oil as the acyl
donor was advantageous over other approaches.
The biological activity of oleoyl ethanolamide makes
its synthesis interesting. However, commercial oleoyl
ethanolamide is very expensive. For example, 10 mg of
oleoyl ethanolamide from Sigma Chemical costs US$165.
Thus, it is beneficial to establish a simpler and more eco-
nomic approach. To date, one publication has reported the
synthesis of fatty acid ethanolamide using a native oil as
the acyl donor [20]. This report used a solvent-free sys-
tem to synthesize fatty acid ethanolamide that was to be
used as a surfactant. We found that a solvent-free system
was not suitable due to precipitation of the products, but
that a mixed solvent system (hexane/ethanol) was best to
promote the reaction. Finally, when fatty acid amide was
Acknowledgments This work was financially supported by
“The Natural Science Foundation of Jiangsu Province (Grants No
BK20150137)” and “National Natural Science Foundation of China
(31401525)”.
Compliance with ethical standards
Conflict of interest The authors have declared no conflict of interest.
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13. Wang X, Wang X, Wang T (2012) Synthesis of oleoylethanola-
mide using lipase. J Agric Food Chem 60:451–457
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