Straightforward selective synthesis of linear 1-O-alkyl glycerol and di-glycerol monoethers

Article abstract of DOI:10.1016/j.tetlet.2009.09.134

1-O-Alkyl glycerol and di-glycerol monoethers are, respectively, obtained in high yields and selectivity by catalytic reductive etherification of mono- and di-glycerol with linear aldehydes in the presence of 0.5 mol % of Pd/C under 10 bars of hydrogen us

Full text of DOI:10.1016/j.tetlet.2009.09.134

Tetrahedron Letters 50 (2009) 6891–6893
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Straightforward selective synthesis of linear 1-O-alkyl glycerol and di-glycerol
monoethers
Yan Shi a,b, Wissam Dayoub a, Alain Favre-Réguillon a,c, Guo-Rong Chen b, Marc Lemaire a,
*
a Laboratoire de Catalyse et Synthèse Organique, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS UMR5246, Université Lyon 1,
Bâtiment Curien-CPE, 3° étage, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
b Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, PR China
c Laboratoire de Transformations Chimiques et Pharmaceutiques, UMR7084,CNAM, 2 Rue Conté, 75003 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2009
Revised 21 September 2009
Accepted 23 September 2009
Available online 27 September 2009
1-O-Alkyl glycerol and di-glycerol monoethers are, respectively, obtained in high yields and selectivity by
catalytic reductive etherification of mono- and di-glycerol with linear aldehydes in the presence of
0.5 mol % of Pd/C under 10 bars of hydrogen using a Brønsted acid as co-catalyst.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Reductive alkylation
Glycerol
Di-glycerol
1-O-Alkyl mono- and di-glycerol
monoethers
Glycerol is one of the main co-products of the vegetable oil
industry. Recently, a new trend influenced the glycerol production
since renewable oils have been used for energy applications. ‘Bio-
diesel’, that is, fatty acid methyl esters, has been widely implanted
in the EU and US and as a consequence, the output of glycerol has
risen. There are already a great number of applications of glycerol
as an additive, as a raw material and for energy production.1,2
However, as fossil raw material stocks irrevocably diminish and
environmental awareness increases, there are opportunities to pro-
duce valuable chemicals, using renewable resources such as glyc-
erol.3 The conversion of glycerol into useful chemicals is a topic
of great industrial interest.3,4
glycerol ethers is easily realizable in acidic catalysis, the direct syn-
thesis of linear ones is not.9
We report herein that the catalytic reductive alkylation is suit-
able for the synthesis of linear 1-O-alkyl mono- and di-glycerol
ethers in one step (Scheme 1). More than 10 years ago, our group
discovered an alternative method to Williamson etherification
from linear alcohols and carbonyl compounds using Pd/C as a cat-
alyst under hydrogen pressure.10 However, to the best of our
knowledge, this method has never been applied to polyfunctional
alcohols in mild conditions. The few examples that can be found
report two-step procedures, high pressures and temperatures.11
Glycerol monoether (GME) is one of the most valuable deriva-
tives of glycerol. A lot of applications were patented in personal
care, cosmetic, laundry, and cleaning formulations,5 as well as in
the pharmaceutical field.6 GME could also be used as building
blocks for the synthesis of bioactive molecules.7 Traditionally,
ethers are prepared via the Williamson ether synthesis despite
the need for a strong base and for the formation of a stoichiometric
amount of salts.8 Since glycerol has three hydroxyl groups with
similar pKas, the control of the regioselectivity is the main key of
the process to minimize waste and by-products production.
Moreover, even though the direct synthesis of branched saturated
HO
OH
OH
OH
O
OH
R
2a-d
H2, Pd
R
CHO
1a-d
1-O-alkyl glycerol ether
OH
acid
OH
O
O
OH
R
3b-d
1-O-alkyl diglycerol ether
HO
O
OH
OH
OH
a: R= C6H5-CH2- b: R = nC3H7 c: R = nC6H13 d: R = nC10H21
* Corresponding author. Tel.: +33 472 314 07; fax: +33 472 314 08.
E-mail address: marc.lemaire@univ-lyon1.fr (M. Lemaire).
Scheme 1. Direct etherification from mono- and di-glycerol with different
aldehydes.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.134

6892
Y. Shi et al. / Tetrahedron Letters 50 (2009) 6891–6893
Table 1
co-catalyst, 0.5 mol % of Pd and a ratio aldehyde/glycerol of 1/10, at
Acid Screening for reductive alkylation of aldehyde 1a
110 °C for 24 h. The conversion could be improved to 37% by
increasing the temperature to 140 °C and diluting the medium to
a ratio aldehyde/glycerol of 1/40. Nevertheless, the conversion of
the acetals to the corresponding monoethers was still generally
low, that is, 37%. (Table 1, entry 4). Finally, the best yield was ob-
tained when camphorsulfonic acid (CSA) was used and the glycerol
monoether 2a was obtained in 57% GC yield (Table 1, entry 5).
Taking into account these encouraging results, we employed the
optimized reductive alkylation conditions for the synthesis of lin-
ear, saturated 1-O-alkyl glycerol monoethers. After 24 h of reac-
tion, ethers 2b–d were separated from glycerol by extraction
with toluene, and pure GMEs 2b–d were isolated by column chro-
matography.13 Thus, GMEs 2b–d were obtained in high yields and
selectivities (Table 2, entries 1–3).
O
Pd/C, 10% acid,
10bar H2
H
O
OH
HO
OH
OH
OH
1a
2a
Entry
Acid
2a GC yield
Selectivityc
1a
2a
3a
4b
5b
HCOOH
TFA
PTSAÁH2O
PTSAÁH2O
CSAd
Traces
9
25
37
57
nd
>25/1
>25/1
>25/1
>25/1
a
b
C
110 °C, 0.5 mol % Pd, 10% acid, 10 bar H2, 24 h.
140 °C, 0.5 mol % Pd, 10% acid, 10 bar H2, 24 h.
Selectivity between 1-O-alkyl glycerol monoether and 2-O-alkyl glycerol
Figure 1 discloses a GC spectrum of the obtained crude material
(entry 1). It can be observed that the selectivity of the process is
monoether.
d
(R)-10-Camphorsulfonic acid.
- 15.71
N L:
2.04E7
TIC F: MS
DSQ090417
-03
Using the reductive conditions reported in earlier publications8
with 3-phenylpropanal 1a as a substrate and glycerol as a solvent,
no traces of the expected 1-O-alkyl glycerol monoether 2a were
observed by GC/MS, after 24 h of reaction at 100 °C under 40 bars
of hydrogen. The only detected products were the four possible
corresponding acetals. The formation of these intermediates has al-
ready been reported in the literature.9,12 In order to reduce the C–O
bonds of acetals, we increased the amount of Pd to 5 mol % and
added different Brønsted acids as co-catalysts. First, with formic
acid, traces of ether 2a were observed (Table 1, entry 1). Then, with
trifluoroacetic acid, 9% of ether 2a was detected (Table 1, entry 2).
Considering this encouraging result, we continued our Brønsted
acids screening while optimizing the reaction conditions; the
amount of Pd, the nature and the amount of acid, the temperature,
and hydrogen pressure. Thus, the yield of 2a could be improved to
25% by using p-toluenesulfonic acid monohydrate (PTSAÁH2O) as a
OH
O
OH
HO
OH
2b
OH
O
OH
OH
0
2
4
6
8
10
12
14
Time (min)
Figure 1. GC/MS analysis of crude of the reductive etherification of glycerol with
valeraldehyde 1b (entry 1).
Table 2
Etherification of mono- and di-glycerol with different aldehydes
Entry
1a
Aldehyde
Alcohol/solvent
Product
Acid
CSAc
GC yield
94
Selectivityb
>25/1
OH
O
OH
Valeraldehyde
Glycerol
2b
OH
2a
3a
4a
5a
6a
Octanal
Glycerol
CSA
CSA
CSA
CSA
CSA
79
75
83
72
71
>12/1
>10/1
>9/1
O
OH
O
2c
OH
OH
Dodecanal
Valeraldehyde
Octanal
Glycerol
2d
OH
OH
O
O
OH
Di-glycerol
Di-glycerol
Di-glycerol
3b
OH
OH
OH
O
O
O
OH
O
>9/1
3c
OH
OH
Dodecanal
>9/1
3d
a
b
c
140 °C, 0.5 mol % Pd, 10% acid, 10 bar H2.
Selectivity between 1-O-alkyl glycerol monoether and 2-O-alkyl glycerol monoether.
(R)-10-Camphorsulfonic acid.

Y. Shi et al. / Tetrahedron Letters 50 (2009) 6891–6893
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very high since, in these conditions, the major product in the crude
is the expected GME 2b and a very small amount of 2-O-alkyl glyc-
erol ether is detected. In this case, the ratio of 1-O-alkyl glycerol/of
2-O-alkyl glycerol is about 25/1.
In order to test the versatility of our approach, we finally applied
these optimized conditions for the reductive alkylation of di-glyc-
erol. Thus, we obtained the desired 1-O-alkyl di-glycerol monoe-
thers 3b–d in high yields and selectivity (Table 2, entries 4–6).
In conclusion, we report herein a benign, eco-friendly process
for the synthesis of 1-alkyl mono- and di-glycerol monoethers with
high yields and selectivity without the production of unwanted
inorganic salts. Key features of the new process are the use of glyc-
erol or di-glycerol as solvent and reactant, a small amount of Pd/C
as a catalyst, and Brønsted acid as a co-catalyst. The linear 1-O-al-
kyl glycerol and di-glycerol ethers are recovered by a simple
extraction with toluene. This highly selective process opens up a
new alternative to the Williamson etherification for the synthesis
of linear glycerol monoethers with different hydrophilic–lipophilic
balances, which are of great interest in many research fields.
11. (a) Nakagawa, S.; Tottorinaka, H. S. EP Patent 0624563A1, 1994.; (b) Nagasawa,
A.; Okutsu, M.; Kitsuki, T. WO Patent 2001032306, 2001.
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13. Typical procedure for reductive etherification of glycerol with aldehyde using H2 as
a reducing agent: aldehyde (6 mmol) and glycerol (240 mmol) were mixed in a
100 mL steel autoclave. Pd/C (0.5 mol % Pd) and CSA (10 wt %) were added to
this solution. The autoclave was first flushed with argon, then with hydrogen
three times. The solution was then stirred (1500 rpm) at 140 °C under 10 bars
of hydrogen for 24 h. After the reaction was complete, the solution was
filtered off and extracted three times with toluene and the products were
purified by silica column chromatography (eluent: cyclohexane/ethyl
acetate = 4:1–1:1).
Acknowledgments
Financial support provided in the frame of the MIRA collabora-
tive program between Shanghai City (PR China) and Région Rhône-
Alpes is greatly appreciated. China Scholarship Council is also
gratefully acknowledged for Ph.D. grants to S.Y.
References and notes
1. (a) Pagliaro, M.; Rossi, M. The Future of Glycerol: New Uses of a Versatile Raw
Material; RSC Green Chemistry Book Series, 2008; (b) D’Hondt, E.; Van de