Use of glycerol carbonate in an efficient, one-pot and solvent free synthesis of 1,3-sn-diglycerides

Article abstract of DOI:10.1007/s11746-012-2165-0

An efficient solvent-free synthesis of a variety of highly pure 1,3-sn-diglycerides (1,3-sn-diacylglycerols) in a two-step one pot process is described. Heating glycerol carbonate (4-hydroxymethyl-1,3-dioxolan-2-one) with fatty acid anhydrides 2a-d affords 1:1 mixtures of glycerol carbonate fatty esters 3a-3d and the corresponding fatty acids. Further heating the reaction mixtures in the presence of catalytic amounts of 1,4-diazabicyclo[2.2.2]octane (DABCO) at 195-200 °C yields highly pure 1,3-sn-diglycerides 4a-4d.

Full text of DOI:10.1007/s11746-012-2165-0

J Am Oil Chem Soc (2013) 90:259–264
DOI 10.1007/s11746-012-2165-0
ORIGINAL PAPER
Use of Glycerol Carbonate in an Efficient, One-Pot and Solvent
Free Synthesis of 1,3-sn-Diglycerides
Mojgan Kargar
Mehdi Ghandi
•
Rahim Hekmatshoar
AbdolJalil Mostashari
•
•
Received: 23 April 2012 / Revised: 26 September 2012 / Accepted: 17 October 2012 / Published online: 3 November 2012
AOCS 2012
ꢀ
Abstract An efficient solvent-free synthesis of a variety
of highly pure 1,3-sn-diglycerides (1,3-sn-diacylglycerols)
in a two-step one pot process is described. Heating glycerol
carbonate (4-hydroxymethyl-1,3-dioxolan-2-one) with
fatty acid anhydrides 2a–d affords 1:1 mixtures of glycerol
carbonate fatty esters 3a–3d and the corresponding fatty
acids. Further heating the reaction mixtures in the presence
of catalytic amounts of 1,4-diazabicyclo[2.2.2]octane
They are used in bakery and confectionary dough [5], ice
cream coating [6], chewing gum [7], fried food [8], potato
chips and French fries [9], cocoa butter substitutes for the
chocolate industry [10] and shortening [11]. Kao Corpo-
ration and associates have marketed high diglyceride
(HiDi) edible oils in Japan and elsewhere, with several
attributed nutritional benefits [12]. Favorable nutritional
properties of 1,3-diglycerides in comparison with normal
fats and oils is believed to be due to their different meta-
bolic pathways. [13].
(DABCO) at 195–200 ꢁC yields highly pure 1,3-sn-digly-
cerides 4a–4d.
In addition to their use in the food industry, 1,3-
sn-diglycerides can be functionalized in the second position
directly with a drug bearing a carboxylic group such as the
anti-inflammatory niflumic acid or through a dicarboxylic
linker binding an alcohol such as bupranolol [14]. Similar
processes are used to produce lipid soluble prodrugs [15].
Diglycerides are also used as drug carriers, delivering drugs
with better absorption, improved bioavailability and reduced
side effects of the original drugs [16, 17].
Keywords Glycerol carbonate Á Glycerol carbonates fatty
esters Á Fatty acid anhydrides Á DABCO Á
1
,3-sn-Diglycerides Á Low HLB surfactants
Introduction
,3-sn-Diglyceride rich fatty compositions, are popular in
1
1
the food industry as benign low HLB [1] (co)emulsifiers
2], rheological modifiers [3] and dietary fat and oils [4].
Diglycerides are traditionally produced by processes
such as glycerolysis of natural fats and oils [18, 19] or
direct esterification of glycerol with fatty acids [20, 21].
These processes can be catalyzed chemically or enzymat-
ically [22, 23] especially by 1,3-selective lipase e.g.
[
Electronic supplementary material The online version of this
article (doi:10.1007/s11746-012-2165-0) contains supplementary
material, which is available to authorized users.
‘‘Lilipase A-10’’ [24, 25]. Naturally these processes lack full
positional selectivity and produce fatty mixtures enriched
in 1,3-diglycerides, containing 1,2-diglycerides as well as
mono and triglycerides. Due to commercial unavailability
of pure 1,3-diglycerides, even major pharmacopeias
describe diglycerides as mixtures containing mono and
M. Kargar (&) Á R. Hekmatshoar
Department of Chemistry, School of Sciences,
Alzahra University, Vanak, Tehran, Iran
e-mail: chemmojgan@yahoo.com
M. Ghandi
School of Chemistry, College of Science,
University of Tehran, Tehran, Iran
1
The hydrophilic-lipophilic balance (HLB) of a surfactant is a
measure of the degree to which it is hydrophilic or lipophilic,
determined by calculating values for the different regions of the
molecule, as described by Griffin in 1949.
A. Mostashari
Industrial Chemical R&D Organization, Tehran, Iran
1
23

2
60
J Am Oil Chem Soc (2013) 90:259–264
triglycerides. For many applications, multistep and at times
tedious processes [25] for the separation of pure symmet-
rical 1,3-sn-diglycerides from such mixtures is often
unnecessary. Nonetheless commercial availability of a
variety of pure symmetrical or unsymmetrical 1,3-sn-
diglycerides, shall allow predesigned and precise formu-
lations for more demanding applications in surfactant and
drug delivery areas.
one-pot reaction of appropriate pure fatty acids with acetic
anhydride while distilling the co-produced acetic acid and
excess acetic anhydride (Scheme 2).
Experimental Procedures
Chemicals and Measurements
Earlier multistep and low yield synthesis of pure 1,3-sn-
diglycerides using expensive dihydroxyacetone or allyl
alcohol as starting materials [26] are clearly wasteful,
hence uneconomical for industrial applications.
Glycerol carbonate (95 % purity) was prepared by a pre-
viously reported procedure [36]. All chemicals and
reagents including fatty acids (lauric 99 %, myristic 98 %,
palmitic 98 %, stearic 97 %) and acetic anhydride were
purchased from Merck and used without further purifica-
tion. Melting points were determined with an Electrother-
Pure 1,3-diglycerides were traditionally obtained by
acylation of 1-monoacylglycerides with fatty acid chlorides
[
27]. Use of noxious reagents (Such as thionyl chloride),
1
13
for the production of acid chlorides as well as handling
problems of fatty acid chlorides themselves, do not favor
industrialization of this process.
mal model 9100 apparatus. The H- and C-NMR spectra
were recorded on a Bruker DRX-500 AVANCE Spec-
trometer. Mass spectra of the products were obtained on an
Agilent Technology (HP) 5937 Mass Selective Detector,
with Electron Impact (EI) 70 eV, and Quadrupole
Analyzer.
An improved synthesis of pure 1,3-sn-diglycerides has
been reported by reacting pure fatty acids with glycidyl
fatty esters [28], which are themselves prepared from fatty
acid salts and epichlorohydrin [29] a highly toxic, corrosive
and more importantly carcinogenic chemical [30].
A clean synthesis of pure symmetrical 1,3-sn-diglycerides
by reacting fatty acid anhydrides with glycidol has been
reported [31]. However, the high cost of intermediate glyc-
idol and its transportation as well as possible spontaneous
self-polymerization on storage [32] makes techno-economi-
cal feasibility of the process for industrial application very
doubtful.
Synthesis of Fatty Acid Anhydrides 2a–d:
General Procedure
Fatty acid 1a–d (0.10 mol) was placed in a magnetically
stirred 100-mL three-neck round-bottom flask equipped
with a thermometer and a pressure-equalizing addition
funnel. The middle neck of the flask was connected to a
distillation set via a 20-cm vacuum-jacketed Vigreux col-
umn. Temperature was raised to 140 ꢁC and excess acetic
anhydride (12.24 g, 0.12 mol) was added drop-wise to the
molten fatty acid within 30 min while distilling the co-
produced acetic acid at a head temperature of 115–125 ꢁC.
When the distillation slowed down, the temperature of the
boiling mixture was raised to 165–185 ꢁC and the mixture
was kept at this temperature until acetic acid (by product)
and excess acetic anhydride were mostly distilled off under
normal pressure. A vacuum (200 mm Hg) was then applied
to remove all volatile materials. The reaction mixture was
cooled to 45 ꢁC and light petroleum ether (100 mL) was
added. The mixture was refluxed for 15 min. Pure fatty
acid anhydrides 2a–d were obtained as colorless crystalline
We have previously reported use of glycerol carbonate
as a glycerol synthon for the selective production of pure
a-monoglycerides [33]. We now report the synthesis of
highly pure symmetrical 1,3-sn-diglycerides in good yields
by condensation of fatty acid anhydrides with glycerol
carbonate. This solvent free, two-step and one-pot process
uses DABCO as catalyst (Scheme 1).
This type of reaction is not unprecedented. Reactions of
ethylene carbonates with benzoic anhydride at 240–250 ꢁC
to produce ethylene dibenzoate has previously appeared in
patent literature [34].
Food grade fatty acid anhydrides were synthesized using
a simplified version of the reported processes [35]; by a
OH
O
DABCO
O-CO-R
0
8
0 C
O
O
OH + R-CO-O-CO-R
a-d
O
R-OC-O
O-CO-R
O
7
h
O
0
1
95-200 C
2
3a-d
1.5-2 h
4a-d
+
RCOOH
R = C H -C H
1
1 23 17 35
Scheme 1
1
23

J Am Oil Chem Soc (2013) 90:259–264
261
0
(2-Oxo-1,3-dioxolan-4-yl) Methyl Laurate 3a (1.7 g,
1
65-185 C
0 min
(
CH CO) O RCOOH
R-CO-O-CO-R
a-d
3
2
+
3
5
7 %), White solid, MP 57–59 ꢁC, IR (KBr) mmax: 2,950,
2
-1 1
R = C H -C H
2,852, 1,784, 1,736, 1,475 cm , H NMR (CDCl ): d 0.9
1
1
23 17 35
3
(
t, J 6.8 Hz, 3H, CH ), 1.3 (m, 16H, 8CH ), 1.62 (m, 2H,
3 2
Scheme 2
CH ), 2.38 (t, J 7.5 Hz, 2H, CH CO), 4.26 (dd, J 4.1,
2
2
12.6 Hz, 1H, CH OCO ), 4.31 (dd, J 7.3 Hz, 1H,
2 2
materials upon cooling the petroleum ether solution followed
by filtration.
CH OCO), 4.38 (dd, J 3.3,12.6 Hz, 1H, CH OCO ), 4.57
2 2 2
1
3
(t, J 8.6 Hz, 1H, CH OCO), 4.94 (m, 1H, CH), C NMR
2
(
CDCl ) d 14.5, 23.8, 25.1, 29.4–29.9, 32.3, 34.3, 63.2,
3
?
Lauric Acid Anhydride 2a (18.7 g, 98 %), colorless
crystalline solid, MP 42–44 ꢁC, IR (KBr) mmax: 2,910,
66.4, 74.2, 154.8, 173.6, MS calculated for C H O
6 28 5
=
1
300; found: 300.
-
1 1
2
,830, 1,810, 1,730, 1,460 cm , H NMR (CDCl ) d: 0.90
3
(
t, J 7.1 Hz, 6H, 2CH ), 1.30 (m, 32H, 16CH ), 1.67 (m,
3
(2-Oxo-1,3-dioxolan-4-yl) Methyl Myristate 3b (2 g,
62 %), White solid, MP 67–69 ꢁC, IR (KBr) mmax; 2,921
2
4
H, 2CH ), 2.47 (t, J 7.5 Hz, 4H, 2CH CO).
2
2
-1 1
CH), 2,910, 1,784, 1,736, 1,472 cm , H NMR (CDCl ):
(
3
Myristic Anhydride 2b (21.7 g, 98 %), colorless crystal-
line solid, MP 54–55 ꢁC, IR (KBr) mmax: 2,910, 2,830,
d 0.9 (t, J 6.6 Hz, 3H, CH ), 1.3 (m, 20H, 10CH ), 1.63 (m,
3
2
2H, CH ), 2.39 (t, J 7.5 Hz, 2H, CH CO), 4.28 (dd, J 4.1,
2
2
-
1
1
1
,810, 1,735, 1,460 cm
,
H NMR (CDCl ) d: 0.90
12.6 Hz, 1H, CH OCO ), 4.31 (dd, J 7.3 Hz, 1H,
2 2
3
(
t, J 7.0, 6H, 2CH ), 1.30 (m, 40H, 20CH ), 1.67 (m, 4H,
2
CH OCO), 4.39 (dd, J 3.3, 12.6 Hz, 1H, CH OCO ), 4.58
2 2 2
3
1
3
2
CH ), 2.47 (t, J 7.5, 4H, 2CH CO).
2
(t, J 8.6 Hz, 1H, CH OCO), 4.94 (m, 1H, CH), C NMR
2
2
(
CDCl ): d 14.5, 23.1, 25.1, 29.4–30.0, 32.3, 34.3, 63.2,
3
?
Palmitic Anhydride 2c (24.7 g, 98 %), colorless crystal-
line solid, MP 62–64 ꢁC, IR (KBr) mmax: 2,920, 2,825,
66.4, 74.1, 154.7, 173.6, MS calculated for C H O
8 32 5
=
1
328; found: 328.
-
1
1
1
,800, 1,740, 1,470 cm
,
H NMR (CDCl ): d 0.90
3
(
t, J 7.0, 6H, 2CH ), 1.30 (m, 48H, 24CH ), 1.67 (m, 4H,
3
(2-Oxo-1,3-dioxolan-4-yl) Methyl Palmitate 3c (2.3 g,
66 %), White solid, MP 70–72 ꢁC, IR (KBr) mmax; 2,921,
2
2
CH ), 2.47 (t, J 7.5, 4H, 2CH CO).
2
2
-
1 1
2
,850, 1,784, 1,735, 1,475 cm , H NMR (CDCl ): d 0.9
3
Stearic Anhydride 2d (27.5 g, 98 %), shiny white crys-
talline solid, MP 71–72 ꢁC, IR (KBr) mmax: 2,920, 2,830,
(t, J 6.7 Hz, 3H, CH ), 1.29 (m, 24H, 12CH ), 1.63 (m, 2H,
3 2
CH ), 2.39 (t, J 7.5 Hz, 2H, CH CO), 4.28 (dd, J 4.1,
2
2
-
1
1
1
,810, 1,740, 1,470 cm
,
H NMR (CDCl ): d 0.90
12.6 Hz, 1H, CH OCO ), 4.32 (dd, J 7.3 Hz, 1H,
2 2
3
(
t, J 7.0, 6H, 2CH ), 1.32 (m, 54H, 28CH ), 1.67 (m, 4H,
3
CH OCO), 4.39 (dd, J 3.3, 12.6 Hz, 1H, CH OCO ), 4.58
2 2 2
2
1
3
2
CH ), 2.47 (t, J 7.5, 4H, 2CH CO).
2
(t, J 8.5 Hz, 1H, CH OCO), 4.92 (m, 1H, CH), C NMR
2
2
(
CDCl ): d 14.5, 23.1, 25.1, 29.4–30.1, 32.3, 34.3, 63.2,
3
?
Synthesis of Glycerol Ester Carbonates 3a–d:
General Procedure
66.4, 74.2, 154.7, 173.6, MS calculated for C H O
0 36 5
=
2
356; found: 356.
Fatty acid anhydride 2a–d (10 mmol) and glycerol car-
bonate (1.2 g, 10.5 mmol) were placed in a 100-ml three-
necked round-bottom flask, equipped with a thermometer,
magnetic stirrer and a condenser connected to a gas bubble
counter. The temperature was then raised to 80 ꢁC and kept
at this temperature for 7 h. After completion of the reac-
tion, the mass was cooled to 25–30 ꢁC and dissolved in
dichloromethane (200 mL). A dispersion of calcium
hydroxide (0.6 g) per 100 mL water was added. The
mixture was stirred at ambient temperature for 15 min and
filtered. Organic layer was separated from the filtrate. The
aqueous layer was re-extracted with dichloromethane
(2-Oxo-1,3-dioxolan-4-yl) Methyl Stearate 3d (2.7 g,
70 %), White solid, MP 79–81 ꢁC, IR (KBr) mmax: 2,958,
-
1 1
2,850, 1,784, 1,736, 1,472 cm , H NMR (CDCl ): d 0.9
3
(t, J 7.1 Hz, 3H, CH ), 1.29 (m, 28H, 14CH ), 1.63 (m, 2H,
3
2
CH ), 2.39 (t, J 7.6 Hz, 2H, CH CO), 4.28 (dd, J 4.1,
2
2
12.6 Hz, 1H, CH OCO ), 4.32 (dd, J 7.3 Hz, 1H,
2
2
CH OCO), 4.39 (dd, J 3.3, 12.6 Hz, 1H, CH OCO ), 4.58
2
2
2
1
(t, J 8.6 Hz, 1H, CH OCO), 4.94 (m, 1H, CH), C NMR
3
2
(CDCl ): d 14.5, 23.1, 25.1, 29.5–30.1, 32.3, 34.3, 63.2,
3
?
66.4, 74.1, 154.7, 173.7, MS calculated for C H O
2 40 5
=
2
384; found: 384.
(
100 mL). The combined dichloromethane layers were
One-Pot Synthesis of 1,3-sn-Diglycerides
4a-d from 2a-d: General Procedure
washed with water (200 mL) and the solvent was distilled
under reduced pressure. Recrystallization of the residue
from light petroleum ether afforded the pure products
Fatty acid anhydrides 2a–d (20 mmol) and glycerol
carbonate (2.5 g, 95 %, 20 mmol) were placed in a
3
a–3d as white powder in 57–70 % yield.
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J Am Oil Chem Soc (2013) 90:259–264
magnetically stirred 100 mL three necked round bottom
flask equipped with a thermometer, and a condenser
connected to a gas bubble counter. Temperature was
raised to 80 ꢁC and kept at this temperature for 7 h after
which time DABCO (6 mol %, 0.13 g) was added. The
temperature was raised to 195–200 ꢁC to start the con-
densation reaction as CO2 evolution observed in the
bubble counter. The mixture was kept at this temperature
Glycerol 1,3-distearate 4d (10.3 g, 83 %), White solid,
MP 77–79 ꢁC, IR (KBr) mmax: 3,490, 3,438, 2,954, 2,850,
-
1
1
1,731, 1,710, 1,473 cm
(t, J 7.0 Hz, 6H, 2CH ), 1.29 (m, 56H, 28CH
2CH ), 2.35 (t, J 7.5 Hz, 4H, 2CH ), 2.54 (s, 1H, OH), 4.12
(m, 1H, CH), 4.17 (dd, J 5.7, 11.5 Hz, 2H, CH CHOH), 4.21
CHOH), C NMR (CDCl ): d
14.53, 23.11, 29.5–30.1, 32.3, 34.5, 65.4, 68.8, 174.3, MS
,
H NMR (CDCl
): d 0.90
3
), 1.64 (m, 4H,
2
3
2
2
2
1
3
(dd, J 4.3, 11.4 Hz, 2H, CH
2
3
?
5
for an appropriate time (see Table 2) until CO evolution
2
calculated for C39H O
76
= 624; Found: 623.
ceased. The reaction mixture was then cooled to 45 ꢁC
and light petroleum ether (60 mL) was added. The
mixture was refluxed for 15–20 min and allowed to stand
for 30 min at 40–45 ꢁC without stirring. A thin viscous
liquid film, which was difficult to analyze, was deposited
at the bottom of the flask, but was assumed to consist
of polyglycerol derivatives. The upper hot petroleum
ether layer was then separated by decantation. Crude
Result and Discussion
The quantities of glycerol produced in the world oleochem-
ical industries exceed the market demand for this compound.
Production of biodiesel also generates a large amount of
crude glycerol. Recently conversion of this by-product to
glycerol carbonate has been suggested as an outlet for this
oversupply [37]. However, utilization of glycerol carbonate
itself is of great importance in this respect. This report
demonstrates a simple process for the production of higher
valued derivatives of glycerol, such as diglycerides, using
glycerol carbonate. This process may indeed improve the
economic viability of the biodiesel production.
1
,3-sn-diglycerides were obtained upon cooling the petro-
leum ether solution and filtration under vacuum. Pure
products 4a–d were obtained as colorless crystals by
recrystallization from light petroleum ether using decol-
orizing clay.
Glycerol 1,3-dilaurate 4a (8 g, 88 %), White solid, MP
5
5–57 ꢁC, IR (KBr) m : 3,500, 3,438, 2,914, 2,850,
On the other hand, due to inaccessibility of industrial
commercial quantities of individual 1,3-sn-diglycerides in
pure form, considerable industrial, pharmaceutical and
synthetic potentials of 1,3-sn-diglycerides have not been
exploited or even examined to any great extent.
max
-
1
1
1
,735, 1,710, 1,471 cm
,
H NMR (CDCl ): d 0.90
3
(
t, J 7.1 Hz, 6H, 2CH ), 1.30 (m, 32H, 16CH ), 1.65
3 2
(
m, 4H, 2CH ), 2.37(t, J 8.0 Hz, 4H, 2CH ), 2.51(s, 1H, OH),
2 2
4
.12 (m, 1H, CH), 4.16 (dd, J 5.7, 11.5 Hz, 2H, CH CHOH),
2
1
.21 (dd, J 4.3, 11.4 Hz, 2H, CH CHOH), C NMR (CDCl ):
3
4
Presently no facile, efficient and benign process to
produce individual 1,3-sn-diglycerides in pure form and
industrially useful quantities is available. Therefore, pre-
sentation of a novel and practical method using easily
available and eco-friendly starting materials in this field is
desirable.
2
3
d 14.5, 23.1, 29.5–30.0, 32.3, 34.5, 65.4, 68.8, 174.3, MS
calculated for C H O = 456; Found: 457.
?
2
7 52 5
Glycerol 1,3-dimyristate 4b (8.9 g, 87 %), White solid,
MP 64–66 ꢁC, IR (KBr) m : 3,498, 3,438, 2,954, 2,850,
max
-
1
1
1
,731, 1,709, 1,471 cm
,
H NMR (CDCl ): d 0.90
Controlled dehydration of fatty acids 1a–d with excess
acetic anhydride (Scheme 2) while removing acetic acid
and excess acetic anhydride, afforded the corresponding
fatty anhydrides as distillation residues. Distillation of
volatile acetic acid and anhydride was performed at
165–185 ꢁC reducing the pressure gradually from atmo-
spheric pressure to 200 mm Hg.
3
(
t, J 7.0 Hz, 6H, 2CH ), 1.29 (m, 40H, 20CH ), 1.64 (m, 4H,
3
2
2
CH ), 2.37 (t, J 7.6 Hz, 4H, 2CH ), 2.52 (s, 1H, OH), 4.10
2 2
(
m, 1H, CH), 4.15 (dd, J 5.7, 11.5 Hz, 2H, CH CHOH), 4.21
2
1
3
dd, J 4.3, 11.4 Hz, 2H, CH CHOH), C NMR (CDCl3):
(
2
d 14.5, 23.1, 29.5–30.0, 32.3, 34.5, 65.4, 68.8, 174.3, MS
calculated for C H O = 512; Found: 512.
?
3
1 60 5
Pure fatty acid anhydrides 2a–d were obtained as col-
orless crystalline materials in almost quantitative yields by
recrystallization from light petroleum ether (See ‘‘Experi-
mental Procedure’’). The results are presented in Table 1.
Identification of 2a–d was carried out using melting points,
Glycerol 1,3-dipalmitate 4c (9.6 g, 85 %), White solid,
MP 72–74 ꢁC, IR (KBr) m : 3,490, 3,438, 2,954, 2,850,
max
-
1
1
1
,731, 1,709, 1,473 cm
,
H NMR (CDCl ): d 0.90
3
(
t, J 7.0 Hz, 6H, 2CH ), 1.30 (m, 48H, 24CH ), 1.64 (m,
3
2
1
4
H, 2CH ), 2.37 (t, J 7.6 Hz, 4H, 2CH ), 2.51 (s, 1H,
2
IR and H-NMR spectral data. For example, IR spectrum of
-
2a shows two absorption bands at 1,810 and 1,730 cm
2
1
OH), 4.12 (m, 1H, CH), 4.16 (dd, J 5.7, 11.5 Hz, 2H,
CH CHOH), 4.21 (dd, J 4.4, 11.4 Hz, 2H, CH CHOH),
characteristic of anhydrides. The presence of a triplet and a
multiplet at d 1.67 (4H) and 1.30 (4H) together with a
triplet at d 0.9 (6H) and a multiplets at d 1.27–1.67 (32H)
2
2
1
3
C NMR (CDCl ): d 14.5, 23.11, 29.5–30.1, 32.3, 34.5,
3
?
5.4, 68.8, 174.3, MS calculated for C H O = 567;
6
3
5 67 5
1
Found: 568.
in H NMR of 2a is in agreement with lauric acid
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J Am Oil Chem Soc (2013) 90:259–264
263
Table 1 Reaction condition and results obtained for fatty acid
anhydrides (2a–2d) prepared from fatty acids (1a–1d) with acetic
anhydride
R
O
O
O
_
O
O
O
Route 1
O-CO-R
O
-CO2
RCOO
4a-d
Fatty acid
Time
min)
Temperature
(ꢁC)
MP
(ꢁC)
Yield
(%)
N
+
OH
(
N
R
O
H
O
O
Lauric (1a)
Myristic (1b)
Palmitic (1c)
Stearic (1d)
30
30
30
30
165–185
165–185
165–185
165–185
45
57
64
72
98
99
_
RCOO
O
O
Route 2
4
a-d
-
CO2
100
100
O-CO-R
Scheme 3
1
anhydride structure. The IR and H NMR spectra of 2b–d
were similar to that of 2a.
In the mass spectra of 4a–d, base peaks were assigned to
the acylinium moiety. The purity of these products was
confirmed by high-field NMR spectroscopy. It has previ-
ously been shown that the glycerol backbone protons of
acylglycerols can be highly useful in their identification
and determination of their purity [39, 40].
Lauric anhydride 2a served for our early exploration of
conversion into 4a. Condensation of the lauric anhydride
2
a with glycerol carbonate was subsequently carried out
initially at 80 ꢁC to form a 1:1 mixture of ester carbonate
and lauric acid. To this mixture was then added a catalytic
amount of DABCO and was heated at 195–200 ꢁC for
In order to ascertain the intermediacy of carbonate
esters, we tried to isolate these intermediates. But all
attempts to isolate pure ester carbonate in good yield by
fractional crystallization from various solvents were
unsuccessful. We were able to isolate the carbonate esters
in moderate yields by removing the free carboxylic acids
from the solution of the mixture in dichloromethane using
calcium hydroxide suspension. This method is inefficient
due to extensive saponification of the carbonate ester.
The second stage of the reaction to produce diglycerides
must be prevented till all the anhydride has been con-
sumed. Otherwise a side reaction of diglyceride with the
anhydride would result in the production of triglyceride.
This is done by keeping the reaction temperature below
1
.5 h (Scheme 1). Progress in the second step of the
reaction was followed by observing the liberation of carbon
dioxide as well as by withdrawing reaction samples peri-
odically and taking their IR spectra. The formation of the
product was monitored by the disappearance of the car-
-
1
bonyl peak of glycerol carbonate ester at 1,785 cm
.
Recrystallization of the crude product from light petroleum
ether afforded the crystalline 1,3-sn-diglyceride 4a in 88 %
yield. Based on the obtained results, fatty acid anhydrides
2
b, 2c and 2d were also transformed into 4b, 4c and 4d
Scheme 1, Table 2). The results are shown in Table 2.
(
Identification of 4a was carried out using IR and
1
H-NMR spectral data. The IR spectrum (KBr) of 4a
exhibited two double absorption bands at 3,500, 3,438 and
90 ꢁC till completion of anhydride consumption.
To obtain the effect of temperature on the next stage, the
-1
1
,735, 1,710 cm due to OH and CO stretchings respec-
1
tively [38]. The characteristic peaks of 4a in H NMR appear
reaction of fatty acid anhydrides 2a and 2d with glycerol
carbonate were carried out at 145–150, 165, 195 or 230 ꢁC.
It was observed that increasing the reaction temperature not
only speeds up the reaction rate, but also promotes the
disproportionation reaction of the generated diglyceride to
the relevant monoglyceride and triglyceride. Therefore,
keeping the reaction temperature maximum at 195–200 ꢁC
was expected to safely afford the pure 1,3-sn-diglycerides.
A plausible mechanism for the transformation of 2a–d
into 4a–d is shown in Scheme 3. The in-situ generated
as two AB systems at d 4.21 (2H, J 4.4, 11.4 Hz, CH CHOH)
2
and 4.16 (2H, J 5.7, 11.5 Hz, CHCHOH), a multiplets at 4.12
(
1H, CHOH) together with a broad singlet at d 2.51 (1H, OH)
and two triplets at d 2.37 (4H J 8.0 Hz–CH CO ), 0.90 (6H,
J 7.1 Hz–CH ). The MS of 4a showed the M ? 1 peak at 457
3
2
2
consistent with the molecular structure. In the mass spectrum,
compound 4a shows a base peak at m/z 183, assignable to the
?
acylinium moiety C H O .
1
2 23
Table 2 Reaction conditions and results obtained for diglycerides (4a–4d) prepared from condensation of fatty acid anhydrides (2a–2d) with
glycerol carbonate in the presence of DABCO
Fatty acid anhydride
Time (h)
Temperature (ꢁC)
MP (ꢁC)
Yield (%)
Acid number
Lauric (2a)
Myristic (2b)
Palmitic (2c)
Stearic (2d)
1.5
1.5
2
195–200
195–200
195–200
195–200
58
67
74
82
88
87
85
83
1.2
1.5
2
2
1.8
1
23

2
64
J Am Oil Chem Soc (2013) 90:259–264
3
a–d from the initial condensation of glycerin carbonate
18. Jacobs L, Lee I, Poppe G (2006) Chemical Process for the Pro-
duction of 1,3-Diglyceride Oils. US Patent 7,081,542 B2
with fatty acid anhydrides undergoes a reaction with the
fatty acid salt obtained via the reaction of the liberated fatty
acid with DABCO. As indicated in Scheme 3, the car-
boxylate anion might attack either the alkylene carbon
1
9. Zhong N, Li L, Xu X, Cheong L-Z, Zhao X, Li B (2010) Pro-
duction of diacylglycerols through low-temperature chemical
glycerolysis. Food Chem 122:228–232
20. Maruyama E, Shibata K, Yamaguchi H (2008) Preparation Pro-
cess of Diglyceride-Rich Fat or Oil. US Patent 7,375,240 B2
(
Paths 1) or the carbonyl group of the glycerol ester car-
2
1. Kotwal M, Deshpande SS, Srinivas D (2011) Esterification of
fatty acids with glycerol over Fe–Zn double-metal cyanide cat-
alyst. Catal Commun 12:1302–1306
bonates (Path 2), affording the desired 4a–4d.
The striking advantage of the reported work in this
manuscript is the utilization of the in-situ liberated fatty
acid in the esterification step without introducing any fresh
fatty acid.
22. Sugiura M, Kase M, Yamaguchi H, Yamada N (2003) Solid-
liquid fractionation process of oil composition. US Patent
6
,630,189 B2
2
3. Guo Z, Sun Y (2007) Solvent-free production of 1,3-diglyceride
of CLA: strategy consideration and protocol design. Food Chem
100:1076–1084
In summary, we have described an easy and benign
solvent-less method for the synthesis of highly pure 1,3-
sn-diglycerides of lauric, myristic, palmitic, and stearic
acids. The process can be commercialized easily.
2
2
2
4. Yamada Y, Shimizu M, Sugiura M, Yamada N (2001) Process for
producing diglycerides. US Patent 6,261,812 B1
5. Kase M, Shibata K, Komatsu T (2010) Process for producing fat
or oil. US Patent 7,709,667 B2
6. Barry PJ, Craig BM (1955) Synthesis of symmetrical diglycerides
from dihydroxy acetone and allyl alcohol. Can
3:716–721
J Chem
References
3
2
7. Mattson FH, Volpenhein RA (1962) Synthesis and properties of
glycerides. J Lipid Res 3:281–296
1
2
. Griffin WC (1949) Classification of surface-active agents by
HLB. J Soc Cosmet Chem 1:311–326
‘
28. Lok CM (1980) Preparation of glyceride esters. US Patent
4,234,498
29. Brown AB, Whitlock HW (1989) Novel preparation of 1,3-pro-
panediyl Bis[2-hydroxy-5-(2-propynyloxy)benzoate]: a one-step
nucleophilic synthesis of symmetric 1,3-diglycerides. Synth
Commun 19:3497–3507
30. Laskin S, Sellakumar AR, Kuschner M, Nelson N, La Mendola S,
Rusch GM, Katz GV, Dulak NC, Albert RE (1980) Inhalation
carcinogenicity of epichlorohydrin in noninbred Sprague-Dawley
rats. J Natl Cancer Inst 65:751–757
31. Lok CM, Mank APJ, Ward JP (1985) Synthesis of glycidol esters
and mono/di-acylglycerols from glycidol. Chem Phys Lipids
36:329–334
32. Maerker G, Saggese EJ, Port WS (1961) Glycidyl esters. II.
Synthesis of esters of commercial and pure fatty acids. J Am Oil
Chem Soc 38:194–197
33. Ghandi M, Mostashari AJ, Kargar M, Barzegar M (2007) Effi-
cient synthesis of a-monoglycerides via solventless condensation
of fatty acids with glycerol carbonate. J Am Oil Chem Soc
84:681–685
. Skogerson L, Boutt e´ T, Robertson J, Zhang F (2010) Non- hydro-
genated vegetable oil based margarine for puff pastry containing an
elevated diglyceride emulsifier. US Patent 7,687,096 B2
. Kayacier A, Singh RK (2003) Effect of mono- and diglyceride
addition on baked tortilla chips and their storage properties.
J Food Process Pres 27:1–8
3
4
5
. Koike S, Yasumasu T, Hase T, Murase T, Katsuragi Y, Takei A
(2006) Oil/fat composition. US Patent 7,008,661 B2
. Azizi MH, Rajabzadeh N, Riahi E (2003) Effect of mono-
diglyceride and lecithin on dough rheological characteristics and
quality of flat bread. Lebensm-Wiss U-Technol 36:189–193
. Cain FW, Struik HGAM, Quinalan PT, Moore ST (1999)
Ice-cream coating fats. US Patent 5,891,495
. Comollo AJ (1976) Non-tack chewing gum composition. US
Patent 3,984,574
. Mori H, Sakai H, Tanka Y, Yasukawa T (2000) Fried food and
shortening. US Patent 6,106,879
6
7
8
9
. Kudo N, Kameo Y, Mizuno W (2005) Oil-cooked or baked
potatoes. US Patent 6,896,922 B2
1
1
0. Higashioka H, Tanaka Y (1994) Chocolates. US Patent 5,326,581
1. Cottrell T, Dantuma P (2008) Zero-trans fat shortening for lami-
nated dough application. US Patent Application 2008/0063782 A1
2. Yanai H, Yoshida H, Tomono Y, Hirowatari Y, Kurosawa H
34. Windholz TB (1962) Preparation of esters by reacting an anhy-
dride with carbonic acid diesters. US Patent 3,056,827
35. Stipp GK, Kluesener BW (1995) Fatty acid anhydride process.
US Patent 5,387,705
36. Rokicki G, Rakoczy P, Parzuchowski P, Sobiecki M (2005)
Hyperbranched aliphatic polyethers obtained from environmen-
tally benign monomer: glycerol carbonate. Green Chem 7:529–
539
37. www.international.inra.fr/…/1/…/Inra_live_from_the_labs_N7.pdf
Developing a by-product—glycerol—to promote the sustainable
lipid chemistry sector. Accessed 22 Nov 2006
38. Chapman D (1962) The Polymorphism of Glycerides. Chem Rev
62:433–456
1
1
1
1
(2008) Effects of diacylglycerol on glucose, lipid metabolism,
and plasma serotonin levels in lean Japanese. Obesity 16:47–51
3. Yanai H, Tomono Y, Ito K, Furutani N, Yoshida H, Tada N
(
6
2007) Diacylglycerol oil for the metabolic syndrome. Nutr J
:43. doi:10.1186/1475-2891
4. Mantelli S, Speiser P, Hauser H (1985) Phase behaviour of a
diglyceride prodrug: spontaneous formation of unilamellar vesi-
cles. Chem Phys Lipids 37:329–343
5. Kihel E, Bourass J, Richomme P, Petit J, Yand LY (1996) Syn-
thesis and evaluation of the anti-inflammatory effects of niflumic
acid lipophilic prodrugs in brain edema. Drug Res 46:1040–1044
6. Shulman A, Pelled D, Choen T, Farkash O (2007) Treatment
methods requiring phyto-ingredients. US Patent 2007/0196440 A1
7. Niemiec SM, Ramachandran C, Weiner N (1995) Influence of
nonionic liposomal composition on topical delivery of peptide
drugs into pilosebaceous units: an in vivo study using the hamster
ear model. Pharm Res 8:1184–1188
39. Haraldsson GG, Halldorsson A, Kul E (2000) Chemoenzymatic
synthesis of structured triacylglycerols containing eicosapentae-
1
1
noic and docosahexaneoic acids.
77:1139–1145
J Am Oil Chem Soc
40. Haraldsson GG, Gudmundsson BO, Almarsson O (1995) The
synthesis of homogeneous triglycerides of eicosapentaenoic acid
and docosahexaenoic acid by lipase. Tetrahedron 51:941–952
1
23