One-Pot Preparation of Dimethyl Isosorbide from d-Sorbitol via Dimethyl Carbonate Chemistry

Article abstract of DOI:10.1002/cssc.201601382

Direct synthesis of dimethyl isosorbide (DMI) from d-sorbitol via dimethyl carbonate (DMC) chemistry is herein first reported. High yield of DMI was achieved using the nitrogen superbase 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as catalyst and performing the reaction in a stainless steel autoclave by increasing the temperature from 90 to 200 °C. In this procedure, DMC features its full capacity acting in the different steps of the process as carboxymethylating, leaving-group (cyclization), and methylating agent; DMC is also employed as the reaction media.

Full text of DOI:10.1002/cssc.201601382

Accepted Article
Title: One-pot Preparation of Dimethyl Isosorbide from D-Sorbitol via
Dimethyl carbonate Chemistry
Authors: Fabio Arico', Pietro Tundo, and Alexander Aldoshin
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10.1002/cssc.201601382
ChemSusChem
COMMUNICATION
One-pot Preparation of Dimethyl Isosorbide from D-Sorbitol via
Dimethyl carbonate Chemistry
F. Aricò, A. S. Aldoshin, P. Tundo*
Abstract: Direct synthesis of dimethyl isosorbide (DMI) from D-
sorbitol via dimethyl carbonate (DMC) chemistry is herein firstly
reported. High yield of DMI was achieved using nitrogen superbase
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as catalyst and performing
the reaction in a stainless steel autoclave by increasing the
temperature from 90 °C to 200 °C. In this procedure DMC features
its full capacity, acting in the different steps of the process as
carboxymethylating, leaving group (cyclization) and methylating
agent; DMC is also employed as the reaction media.
mono- and di-substituted isosorbide used as surfactants.[8]
Isosorbide and its derivates have also been exploited as
monomers in the manufacture of polymers, i.e., poly-(ethylene-
co-isosorbide)terephthalate (PEIT), poly(isosorbide oxalate) and
poly(isosorbide carbonate) [9] such as DURABIO® and
PLANEXT®.
Another very interesting derivate is dimethyl isosorbide (DMI), a
bio-based high-boiling green industrial solvent (b.p. 235 °C) that
has also found applications as pharmaceutical additives and in
personal care products. [10-11]
In this prospect, we have recently investigated the synthesis of
isosorbide and therefore its derivatization via green reagent and
solvent dimethyl carbonate (DMC).[12]
D-sorbitol is considered one of the top-ten bio-based platform
chemicals especially due to the numerous applications of its
anhydro sugar cyclic derivative isosorbide, namely 1,4:3,6-
dianhydro-D-glucitol (Figure 1). [1]
Nowadays, cyclization of D-sorbitol to achieve isosorbide is
mainly carried out by a twofold dehydration acid-catalyzed
reaction via 1,4-sorbitan intermediate. [2]
DMC is an extensively investigated green substitute of
phosgene in carboxymethylation reactions (base-catalysed
2
bimolecular acyl cleavage mechanism, BAc
) and dimethyl
sulphate (DMS) or methyl halides in methylation reactions
2
(base-catalysed
bimolecular
alkyl
cleavage,
BAl )
Isosorbide has
a
characteristic V-shaped structure [3]
mechanism).[13-14] Besides DMC has recently found
applications as cyclization agent for the synthesis of several
heterocycles, i.e. 5- and 6-membered cyclic ethers, pyrrolidines,
indolines and 1,3-oxazin-2-ones.[14]
constituted by two cis-connected tetrahydrofuran where each
hydroxyl group is in the β-position to both furanic oxygens.[4]
The OH directed toward the V-shaped cavity is labeled as endo
whereas the exo OH group is the one pointing outside of the
sugar cavity (Figure 1). The configuration of the two hydroxyl
groups drives the reactivity of the cyclic sugar as confirmed by
isomannide and isoidide, the two epimers of isosorbide that
incorporate only endo or exo hydroxyl groups, respectively. As
a consequence these epimers show diverse reactivity of the
hydroxyl groups (Figure 1).
The synthesis of isosorbide and its further functionalization
employing dialkyl carbonate, and in particular DMC, are
appealing processes as they encompass the preparation, as
well as, the transformation of a bio-based chemical via a
chlorine-free sustainable approach. In particular, the synthesis of
isosorbide was efficiently achieved by reacting D-sorbitol and
DMC in the presence of sodium methoxide. In this approach
DMC constitutes the leaving group which is generated in situ
and acts as a sacrificial molecule for the synthesis of five-
membered heterocycles (Scheme 1).
Epimers
en
do
exo
HO
endo
HO
H
H
HO
H
O
O
O
O
O
O
H
H
H
OH
OH
exo
endo
OH
exo
Isosorbide
Isomannide
Isoidide
Figure 1. Molecular structure of isosorbide, isomannide and isoidide.
Isosorbide has, in fact,
a considerable potential for the
production of versatile new chemicals as its hydroxyl groups can
be easily functionalized or directly processed. Examples of
industrial applications include mono- and dinitrate isosorbide
commonly used as vasodilators [5], isosorbide alkyl esters
investigated as plasticizers [6], short-chain aliphatic isosorbide
ethers employed as coalescent in the paint industry [7] and
Scheme 1. Synthesis of cyclic ethers via DMC chemistry.
2
The cyclization reaction proceeds via carboxymethylation (BAc
)
followed by an intramolecular alkylation reaction (BAl2). Using
this approach, isosorbide was synthesized in high yield and the
pure product recovered without any time consuming purification
technique. [11a]
[a]
Prof. F. Aricò, Dr. A. S. Aldoshin, Prof. P. Tundo
Department of Environmental Science, informatics and Statistics,
Ca’ Foscari University
More recently the cyclization of D-sorbitol was carried out in the
Campus Universitario, Via Torino 155, 30170 Venezia mestre (Italy)
E-mail: tundop@unive.it
presence of catalytic amount of
a
nitrogen base 1,8-
diazabicycloundec-7-ene (DBU) resulting in the quantitative
formation of the cyclic sugar. [11c]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cssc.201601382
ChemSusChem
COMMUNICATION
Table 1. D-sorbitol direct conversion into DMI[a]
DMC was also employed for the synthesis of DMI by methylation
of isosorbide both at reflux conditions (90 °C) in the presence of
a large excess of a strong base [10] and in autoclave (>180 °C)
using hydrotalcite as catalyst. [12] The methylation of isosorbide
in both reactions was quantitative. This result is particularly
relevant as the hydroxyl group of isosorbide are secondary
Base
(equiv.)
Temp.
(°C)
P.
(bar)
DMI
#
(%)[b]
1
K2CO3
(3)
(3)
(3)
(3)
(1)
(3)
(3)
(3)
(3)
180
180
180
180
180
180
180
180
180
180
10
10
12
50
20
12
12
10
10
10
2
0
2
3
4
5
6
5
7
8
9
[a]
NaOMe
KOBut
Et3N
alcohols
generally very difficult to alkylate even at high
temperature.[15]
16
24
18
11
7
Et3N
DMAP
DBU
Scheme 2. Methylation of isosorbide via DMC chemistry
TBD
22
0
The greenness and the bio-based properties of cyclic sugar D-
sorbitol and the valuable application of DMI prompted us to
investigate a new one-pot route to this compound starting
directly from its cheap and easy available parent alcohol. In fact,
according to the reported procedures, the synthesis of
isosorbide and its subsequent methylation (Scheme 1 and
Scheme 2) required different reaction conditions and
catalysts/bases. In this work for the first time we aim at
Al2O3
KW2000 (1/1 w/w)
23
Reaction conditions: D-sorbitol:DMC:catalyst 1:50:3 equiv. at
[b]
180 °C in autoclave for 24 hours.
curve on GC-MS.
Calculated via calibration
investigating
a single catalyst able to promote both the
In this view, it should be pointed out that the modest yield of DMI
is not surprising considering the complexity of the reaction
pathway. In fact, in order to achieve DMI, D-sorbitol has to
undergo a double carboxymethylation (BAc2) followed by a
double intramolecular alkylation (BAl2) where the carboxymethyl
group acts as the leaving group leading to the formation of
isosorbide (Scheme 4).
preparation and the derivatization of isosorbide in one-pot.
In this synthetic approach DMC would be used at its full extent
acting as carboxymethylating, leaving group in the cyclization
reaction and methylating agent; furthermore DMC is the
reaction media (Scheme 3).
OH OH
HO
H
OH
OH
HO
H3COOCO
OCOOCH3
OH OH
HO
H
OH
D-Sorbitol
HO
H
H
O
O
Scheme 3. One-pot synthesis of DMI starting from D-sorbitol.
OH
Isosorbide
In a first set of experiments D-sorbitol was dissolved in DMC and
the mixture was placed into a stainless steel autoclave in the
presence of a base or a catalyst. The synthesis was conducted
at 180 °C under autogenic pressure and by continuous stirring of
the solution. After 24 hours the reaction was stopped and the
resulting mixture analyzed via GC-MS; the concentration of DMI
was determined using a calibration curve (internal standard).
Results are reported in Table 1.
H
H
H
H
MeOOCO
MeOOCO
MeOOCO
HO
MeO
O
O
O
O
O
O
O
O
H
OCOOMe
OH
OH
OCOOMe
H
H
H
MMI1
MC1
DC
MeO
MC2
H
H
H
HO
O
O
O
O
O
O
OCOOMe
OMe
MMI2
OMe
H
H
H
MCE1
MCE2
Several catalysts were investigated including a weak base
(K2CO3), strong bases (NaOMe, KOBut), linear and cyclic
nitrogen bases (Et3N, 4-dimethylaminopyridine (DMAP)),
superbases (DBU and 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD)), basic (Al2O3) and amphoteric (hydrotalcite KW2000)
catalysts. Formation of dimethyl isosorbide was observed in all
the reactions (Table 1) except when sodium methoxide or
alumina were used. DMI yield ranged from 2 to 24%; the latter
result achieved when triethyl amine was used as a base.
H
O
MeO
O
OMe
H
DMI
Scheme 4. Simplified reaction pathway for the synthesis of DMI starting from
D-sorbitol via DMC chemistry. Reaction intermediates includes monomethyl
derivatives (MMI1, MMI2), carboxymethyl derivatives MC1, MC2, DC) and
methyl carboxymethyl derivatives (MCE1, MCE2).
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Besides, as reported in the literature,[10] the methylation of
isosorbide via DMC leads to the formation of seven
intermediates as a result of numerous succeeding reactions
where carboxymethylations are equilibrium reactions, meanwhile
methylations are kinetically driven irreversible reactions. Thus,
once formed, DMI accumulates in the reaction mixture as it
cannot undergo any further transformation.
Simplifying the methylation reaction we should, in any case,
account for two further intermolecular BAl2 reactions in order to
form the DMI molecule from isosorbide. Therefore, the one pot
synthesis of DMI takes place through, at least, six subsequent
reactions (Scheme 4).
point temperature) and then the temperature was increased to
200 °C.
In this reaction condition we aimed to ensure a higher efficiency
of the cyclization step before increasing the temperature
required for the methylation reaction. A test reaction was
conducted to prove this hypothesis; D-sorbitol (1.0 equiv.) and
TBD (1.0 equiv.) were dissolved in 50 mL of DMC and the
mixture was heated at 90 °C. After 48 hours the solution was
cooled to room temperature and p-xylene was added as external
standard. GC-MS analysis of the solution showed that, under
this reaction condition, isosorbide was formed in 85 % yield
(calculated via calibration curve).
Results reported in Table 1 show also that among the base
investigated Et3N is the most promising one (entry 4, Table 1).
The use of Et3N is quite interesting since, despite being a
homogenous base, it can be easily removed by evaporation at
the end of the reaction. However, in the triethylamine catalyzed
reaction, it was also detected an almost linear increasing of the
pressure up to 50 bar. Most probably this might be ascribed to
the continuous quaternization of Et3N performed by DMC [16]
that finally leads to the formation of four products, i.e.,
trimethylamine and ethylene due to Hoffman elimination;
methanol and CO2 (Scheme 5). The formation of these volatile
or low boiling side-products enhances the reaction pressure. In
order to validate this hypothesis, the one-pot synthesis of DMI
was also attempted with a reduced amount of Et3N (1.0 equiv.).
As a result the autogenic pressure was more than halved, albeit
the yield of DMI slightly diminished (entries 4-5, Table 1).
Table 2. D-sorbitol direct conversion into DMI[a]
Base
Temp.
(°C)
P.
(bar)
DMI
DMIm
DMIi
#
yield %[b]
yield %[b]
yield %[b]
1
Et3N
TDB
90/200
90/200
90/200
90/200
85
26
58
50
60
69
59
41
14
14
19
0
26
17
22
0
2
3
DBU[c]
4[d]
KW2000[e]
[a]
Reaction conditions: D-sorbitol:DMC:catalyst 1:50:1 equiv. in autoclave at
[b]
[c]
90 °C for 48h and then at 200 °C for 24 hours.
Calculated via GC-MS;
Purification via column chromatography led to isolation of DMI in 43% yield
[d]
amd DMIm in 9% yield.
In this case it was observed also the presence of
monomethyl derivatives MMI1 and MMI2 (16% and 11% respectively) and
methyl carboxymethyl derivatives MCE1 and MCE2 derivatives 32% (Scheme
4); [e] (1/1 w/w).
Table 2 reports the results observed for the most efficient
catalysts previously investigated, i.e., Et3N, TBD and hydrotalcite
showing an evident increase of the DMI yield. The best result,
69 %, was achieved when TBD was used as catalyst (entry 2,
Table 2).
In some experiments (entries 1-3, Table 2), the presence of
dimethyl isomannine (DMIm) and isoidide (DMIi) was also
detected [17] possibly due to the epimerization of residual
isosorbide carbonate precursor (Scheme 4) that takes place
when the temperature is increased at 200 °C.[18]
Scheme 5. Quaternization of triethyl amine by DMC with consequent
formation of several gaseous by-products.
The high pressure observed in all the experiments can be
ascribed to the decarboxylation of DMC over a long period of
time. Under this reaction condition, the use of Et3N resulted once
again in the highest autogenic pressure (entry 1, Table 2).
When hydrotalcite was used as catalyst, although the observed
yield was only modest, i.e. 40%, the formation of O-methylated
epimers DMIm and DMIi was not observed. Besides, GC-MS
showed also the presence of a good percentage of several
isosorbide derivatives in the reaction mixture, i.e., monomethyl
derivatives (MMI1, MMI2) and methyl carboxymethyl derivatives
(MCE1, MCE2) (entry 4, Table 2, note c). This result can be
ascribed to the catalyst that due to the presence of both acidic
and basic sites might lead to a different reaction mechanism
compared to the other base investigated.
In all the experiments reported in Table 1, GC-MS analysis of
the reaction mixture did not show the presence of any other
derivatives of isosorbide which were previously observed in the
methylation reaction of this cyclic sugar.[8] This led us to the
consideration that, under these reaction conditions, the limiting
step
was
most
probably
the
cyclization
reaction
(carboxymethylation of the primary alcohols followed by
intramolecular nucleophilic attack of the secondary hydroxyl
group) rather than the subsequent methylation of isosorbide,
which is an easier reaction in comparison.
Thus, in a second set of experiments the synthesis of DMI was
carried out modifying the reaction conditions. A mixture of D-
sorbitol, DMC and the catalyst (1 equiv.) was charged into the
autoclave. The reaction was first heated at 90 °C (DMC boiling
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10.1002/cssc.201601382
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COMMUNICATION
yield of DMI was calculated using a calibration curve (biphenyl was used
as internal standard).
Hydrotalcite is, in fact, a well known catalyst for decarboxylation
reaction that might improve the reaction outcome, but can also
lead to the faster decomposition of DMC into dimethyl ether.
For all the experiments (entries 1-4, Table 2), purification of the
reaction mixtures was conducted via column chromatography
resulting in the isolation of pure sample of DMI (see
experimental section).
General procedure for experiments reported in Table 2: In an autoclave,
equipped with a magnetic stir bar, was prepared a solution of D-sorbitol
(2.0 g, 11.0 mmol), a base (11.0 mmol) and DMC (50.0 g, 555.6 mmol).
Biphenyl (1.7 g, 11.0 mmol) was added to the reaction mixture and the
autoclave was hermetically sealed under a nitrogen atmosphere and then
heated to 90 °C. After 48 hours the mixture was heated at 200 °C for
other 24 hours. Then the reaction was cooled, filtered on paper and the
eventual catalyst residue (in the case of experiments with KW2000)
washed with DMC. The reaction mixture was the injected on the GC-MS
and the yield of DMI was calculated using a calibration curve.
In conclusion, it is herein reported the first example of direct
synthesis of DMI starting from cheap and easy available D-
sorbitol. Several bases have been investigated showing a
discrete conversion of the linear sugar into DMI. The relatively
modest yield was ascribed to the low efficiency in the cyclization
step. In order to address this issue the reaction was then
conducted in two sequential steps; first at 90 °C (atmospheric
pressure, boiling point of DMC) and thus increasing the
temperature to 200 °C. As a result the yield of DMI drastically
increased, up to 69% when TBD was employed as catalyst.
The direct synthesis of DMI from D-sorbitol encompasses a
quite complicated reaction pathway that includes two
carboxymethylations and two intramolecular cyclizations for the
synthesis of isosorbide followed by two methylations that are
most probably preceded by carboxymethylation reaction.
Purification of DMI can be conducted via gradient column
chromatography using as elution system CH2Cl2:MeOH (98:2). As for
entry 3; Table 2 DMI was isolated as colourless liquid in 43% yield:
C8H14O4; M=174.09 gmol-1; 1H NMR (300 MHz, CDCl3): d= 4.64 (t, 1H),
4.50 (d, 1 H), 3.88–3.99 (m, 4 H), 3.85 (m, 1 H), 3.53–3.61 (m, 1 H), 3.45
(s, 3H), 3.36 ppm (s, 3 H). All spectroscopic features of this product
correspond to those reported in the literature.
Keywords: Isosorbide • Dimethyl carbonate • Cyclization •
Methylation • Cyclic sugar
This work demonstrates that it is possible to synthesize DMI in a
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optimization of the procedure is still needed.
It is noteworthy that this reaction is the first example in which
DMC is used as carboxymethylating, leaving group, methylating
agent and reaction media at the same time. The result achieved
confirm the versatility of DMC as green reagent and solvent for
bio-based platform chemical synthesis and derivatization leading
in our case at the synthesis of DMI a valuable industrially
relevant product.
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tetramethylsilane (TMS). 13C NMR spectra were recorded at 75 MHz on a
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autoclave with a capacity of 220 mL equipped with a thermostat and
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General procedure for experiments reported in Table 1: In an autoclave,
equipped with a magnetic stir bar, was prepared a solution of D-sorbitol
sugar (2.0 g, 11.0 mmol), a base (33.0 mmol) and DMC (50.0 g, 555.6
mmol). Biphenyl (1.7 g, 11.0 mmol) was added to the reaction mixture
and the autoclave was hermetically sealed under a nitrogen atmosphere
and then heated to 200 °C. After 24 hours the mixture was cooled,
filtered on paper and the eventual catalyst/base residue (in the case of
experiments with K2CO3, NaOMe, KOBut, Al2O3 and KW2000) washed
with DMC. The reaction mixture was the injected on the GC-MS and the
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COMMUNICATION
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[17] Pure samples of dimethyl isoidide and dimethyl isomannide are
available in our laboratory and have been used for comparison in GC-
MS analysis.
[18] Most probably the residual carboxymethyl derivatives of D-sorbitol that
did not form isosorbide at 90 °C can undergo cyclization when the
temperature is increased to 200 °C forming either isosorbide or its
epimers. In order to prove this hypothesis, isosorbide was reacted with
TBD (1.0 equiv.) at 200 °C in the presence of an excess of DMC (50.0
equiv.) for 24 hours. GC-MS analysis of the reaction mixture showed
mainly DMI and small amount of MCE. Epimerization products were not
detected.
Another possibility would be a SN2 reaction of the methoxide anion on
the carbon bearing the carboxymethyl moiety of DCI leading to the
inversion of the corresponding chiral center configuration.
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10.1002/cssc.201601382
ChemSusChem
COMMUNICATION
COMMUNICATION
Dimethyl isosorbide is synthesized for
the first time via one-pot reaction
starting from its parent alcohol D-
sorbitol via dimethyl carbonate
chemistry.
F. Aricò, A. Aldoshin, P. Tundo*
Page No. – Page No.
One-pot Preparation of Dimethyl
Isosorbide from D-Sorbitol via
Dimethyl carbonate Chemistry
This article is protected by copyright. All rights reserved.