Green synthesis of dimethyl isosorbide

Article abstract of DOI:10.1002/cssc.201000011

A green synthetic approach for dimethyl isosorbide (DMI) with dimethylcarbonate (DMC) in the presence of a base is reported. The easy methylation of isosorbide may be due to its unique structure (which enhances the nucleophilicity of the hydroxyl groups), and to the effect of the hydrogen bonding which increases the reactivity of the molecule towards DMC.

Full text of DOI:10.1002/cssc.201000011

DOI: 10.1002/cssc.201000011
Green Synthesis of Dimethyl Isosorbide
Pietro Tundo,*[a, b] Fabio Aricꢀ,[a, b] Guillaume Gauthier,[c] Laura Rossi,[d] Anthony E. Rosamilia,[a]
Hanamanthsa S. Bevinakatti,[e] Robert L. Sievert,[e] and Christoper P. Newman[f]
In the last twenty years, new categories of solvents have been
investigated in order to deal with safety and environmental
issues;[1] that is, water,[2] supercritical fluids,[3] ionic liquids,[1a]
[1b,4]
solvents derived from CO2
or from renewables.[5] The ad-
vantage of using solvents derived from renewables is that nat-
ural products are present in large amounts, although only a
small fraction (ca. 4%) is used for this purpose.
Scheme 1. Synthesis of dimethyl isosorbide.
d-sorbitol is a good example of biofeedstock and has several
applications in food and non-food industries. Besides, its cyclic
derivate, isosorbide, is widely used in the pharmaceutical and
hygiene industries. The methyl derivative of isosorbide, di-
methyl isosorbide (DMI), is also extensively used in cosmetics
and as a thinning agent.[6] Furthermore, due to its renewable
starting materials and high boiling point (2468C), DMI is also a
suitable substitute of the more toxic currently used solvents,
such as dimethylsulfoxide (DMSO), dimethylformamide (DMF),
and dimethylacetamide (DMAc).[7] However, currently DMI is
synthesized by common methylation reactions, which employ
dimethyl sulfate (DMS) or methyl halides. Herein, it is reported
an improved green synthesis of DMI by reaction of isosorbide
with dimethyl carbonate (DMC) as reagent and solvent, in the
presence of a base at reflux temperature of 908C. (Scheme 1).
DMC, nowadays produced by a clean and halogen-free pro-
cess,[8] is an environmentally benign substitute of phosgene,
DMS, and methyl halides and it is a well-known nontoxic sol-
vent and reagent.[9,10] In general DMC, as a methylating agent
(bimolecular, base-catalyzed, alkyl cleavage, nucleophilic substi-
tution, BAl2, mechanism)[4c] requires temperatures higher than
1508C in the presence of a base. However, we previously re-
ported that under similar conditions the reaction of hard alkox-
ides and DMC gave exclusively the transesterified methylcar-
bonates derivatives (via BAc2 mechanism), also at high temper-
atures.[11] On the contrary, other softer nucleophiles such as
anilines, phenols and methylene-active compounds were easily
methylated by DMC via a BAl2 mechanism.[4,12] Methyl ethers of
primary alcohols can be obtained through two steps: a BAc2
transesterification followed by the decarboxylation of the re-
sulting methylcarbonate. However, methylation of secondary
alcohols was never obtained quantitatively due to the forma-
tion of elimination products.[11] On the other hand, this is not
the case in the present work; the secondary hydroxyls groups
of isosorbide are efficiently methylated at reflux temperature
(908C) by reaction with DMC in the presence of a range of
bases (Table 1). This is quite surprising, especially in consider-
ation of all the possible products that could be formed by re-
acting isosorbide with DMC, which include three classes of
compounds (Figure 1): carboxymethyl derivates (MC-1, MC-2,
dicarboxymethyl isosorbide (DC)), carboxymethyl methyl deri-
vates (MCE-1, MCE-2), and methyl derivates (MMI-1, MMI-2 and
DMI). In particular, it was possible to isolate all these isosorbide
derivatives as pure compounds except MMI-2 and MC-2 due to
their low amount in the reaction mixture. The isolated com-
pounds were identified by GS–MS analysis and NMR spectros-
copy (see the Experimental Section).
[a] Prof. P. Tundo, Dr. F. Aricꢀ, Dr. A. E. Rosamilia
Consorzio Interuniversitario Nazionale “La Chimica per l’Ambiente”
(INCA - Interuniversity Consortium “Chemistry for the Environment“)
Via delle Industrie 21/8 30175, Marghera Venice (Italy)
Fax:(+39)0412346650
E-mail: tundop@unive.it
[b] Prof. P. Tundo, Dr. F. Aricꢀ
Table 1 shows that the reaction of isosorbide with DMC in
the presence of weak bases (entries 1–2), which led mostly to
the formation of carboxymethylated products MC-1, MC-2, and
DC.
Ca’ Foscari Universitꢁ di Venezia, Dipartimento Scienze Ambientali
Dorsoduro 2137-30123, Venice (Italy)
[c] G. Gauthier
ꢂcole Nationale Supꢃrieure de Chimie de Paris (ENSCP-Chimie ParisTech)
11 rue Pierre et Marie Curie, 75005 Paris (France)
However, reactions conducted in the presence of a strong
base led to the formation of DMI with yields up to 40%
(Table 1, entries 3–4). Increasing the amount of base (Table 1,
entries 5–6), enhanced the yield of DMI. Quantitative conver-
sion to DMI could be achieved using 3 equivalents of sodium
methoxide. It is also interesting to point out that the methyl
carboxymethyl derivative of isosorbide MCE-1 was formed in
higher yields compared to MCE-2 (Table 1, entries 3–5). This
result shows that the OH in endo position is more reactive to-
wards methylation compared to the OH in exo position.
[d] Prof. L. Rossi
Instituto de Investigaciones en Fisicoquꢄmica de Cꢅrdoba (INFIQC)
Facultad de Ciencias Quꢄmicas, Departamento de Quꢄmica Orgꢆnica
Universidad Nacional de Cꢅrdoba, Ciudad Universitaria
CP 5000, Cꢅrdoba (Argentina)
[e] Dr. H. S. Bevinakatti, R. L. Sievert
Uniqema Ltd Wilton Centre, Room T425 Wilton, Redcar TS10 4R (United
Kingdom)
[f] C. P. Newman
Quest International, Ashford, Kent TN24 0 LT (United Kingdom)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201000011.
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ChemSusChem 2010, 3, 566 – 570

NaOMe using either DMF or di-
glyme as solvents (see the Sup-
porting Information). In both sol-
vents, methylation of isosorbide
did not occur. These results
prove that the methylation reac-
tion does not proceed via a de-
Table 1. Reactions of isosorbide with DMC, Scheme 2, path a[a]
Entry Base
Equivalents
or w/w
Product distribution
Carbonates
MC-2 DC
Carbonate ethers
MCE-1
Ethers
MMI-1 MMI-2 DMI
MC-1
MCE-2
1
2
3
4
5
6
K2CO3
Cs2CO3 1 w/w
NaOMe 1.5
tBuOK
NaOMe
NaOMe
1.5
30 (23)[a]
19
-
-
1
-
7
4
1
-
1
-
59 (47)[b]
2
3
30
37
36
-
-
1
12
18
8
-
-
-
-
6
2
1
-
-
-
73 (65)[b]
6
-
11
-
11 (8)[b]
26 (20)[b]
40
carboxylation
reaction
(Scheme 2, path c), but the
mechanism operating in this
case is BAl2 substitution on the
DMC molecule. Noteworthy, the
pathways a, b, and c (methyla-
tion, carboxymethylation, and
decarboxylation reactions) did
not involve the chiral centers
1.5
2
3
2
1
-
41 (32)[b]
100 (98)[b]
-
[a] Isosorbide (2 g)/DMC (1:50); Reaction time: 20 h; Reaction conditions: 105 Pa, 908C. [b] Isolated yield.
which
remained
unaffected
during the reactions.
The remarkable reactivity of
isosorbide towards methylation
with DMC could be assigned to
its unique structure. In fact,
within isosorbide V-like configu-
ration, each hydroxyl group is in
the b-position to both furanic
oxygens and this vicinity might
enhance its reactivity towards
DMC. Besides, the hydrogen of
the endo hydroxyl group can
form a strong intramolecular hy-
drogen bond (Figure 2a).[13] To
understand the influence of the
molecule backbone of secondary
alcohols in a BAl2 reaction, a
number of substrates of similar
structure were selected and their
methylation was investigated.
Table 2 shows the results ob-
tained when the alcohols were
reacted with an excess of
NaOMe in refluxing DMC.
Among the selected alcohols,
isosorbide showed modified
higher selectivity towards meth-
ylation. The other secondary al-
cohols formed methyl derivates
in low to modest yields. In par-
ticular, 2-octanol gave only the
carboxymethyl derivative where-
as both propylene glycol propyl
ether and 3-hydroxy-tetrahydro-
furan methylated, but only in 9
and 14% yield, respectively.
Figure 1. Carboxymethyl and methyl derivatives of isosorbide.
To gain some insights into the unusual reactivity of isosor-
bide, the dicarboxymethyl isosorbide (DC) was isolated as a
pure compound and its involvement as intermediates in the
synthesis of DMI was investigated. Thus, DC was reacted with
To confirm this trend, a set of competition reactions was
also performed using the same conditions (Table 3). In this
case, isosorbide and the competing secondary alcohol were re-
acted in the same vessel in the presence of a base in DMC
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567

uct.[14] The different reactivity among the investigated secon-
dary alcohols is remarkable especially because the methylation
of isosorbide involves two hydroxyl groups. This effect can be
clearly ascribed to the rigidity of the structure that follows the
trend: 2-octanolꢀpropylene glycol propyl ether<3-hydroxy-
tetrahydrofuran !isosorbide. Along this trend, the reaction
pathway is modified (from BAc2 to a BAl2) and the yield of the
methylated product is enhanced.
The easy methylation of isosorbide could be attributed in a
first instance to the acidity of the hydroxyl groups. However,
the hydroxyl group in the exo position, which is more acidic
than the endo hydroxyl group involved in a strong hydrogen
bonding (Figure 2), showed to methylate at a slower rate as
demonstrated by the lower yield of MCE-2 compared to MCE-1
(Table 1, entries 3–5).[15] Further investigations on the structure
of isosorbide and on the effect of the hydrogen bonding are
ongoing in order to understand its complex and unexpected
reactivity.
Scheme 2. Possible reaction pathways for the methylation of isosorbide.
In conclusion, the work herein is an example of efficient
transformation of a renewable source into a product through
free-halogen chemistry and opens up the way to further ex-
ploitation of DMI, as well as other carboxymethyl and methyl
derivates of isosorbide. In general, halogen chemistry is charac-
terized by an intensive use of energy and, in substitution reac-
tions, by a fast reaction rate. To exploit chemistry without halo-
gens and therefore to save energy,[16] we need to find alterna-
tive methods of molecular activation. These new reaction path-
ways should have low activation energy, being high yielding
and as selective as in enzymatic reactions. From this point of
view, the result on DMC and isosorbide reactivity is a step for-
ward in this direction. Finally, this reaction is fascinating from a
theoretical point of view for its complexity and also because it
links nicely the idea of green chemistry with the exploitation
of renewables resources.
Figure 2. a) Isosorbide molecule. b) The reactivity of the endo hydroxyl
group of isosorbide.
Table 2. Reactions of secondary alcohols with DMC and sodium methox-
ide at reflux conditions.[a]
Entry
Starting Reagent
Product Distribution
Conv.
Carbonate Ether
1
2
100 (95)[b]
100 (95)[b]
91 (68)[b]
-
Experimental Section
100 (70)[b]
100 (86)[b]
9 (2)[b]
General information: 1H NMR spectra were recorded at 300 MHz
on a Bruker 300 Ultra Shield apparatus. 13C NMR spectra were re-
corded at 75 MHz on a Bruker apparatus 300 Ultra Shield. Chemi-
cal shifts are reported in ppm from the solvent resonance as an in-
ternal standard (CDCl3). Analytical chromatography, TLC, was per-
formed on Merck precoated TLC plates (silica gel 60 GF254,
0.25 mm). Flash column chromatography was performed on silica
gel 60 ꢂ grade 9385 (Merck 230–400 mesh). GC–MS analyses were
performed on a Agilent 6890N gas chromatograph equipped with
HP-5MS 30 m ꢃ 0.25 mm column and Agilent 5973 network mass
selective detector. All the reactions were performed using dime-
thylcarbonate (Aldrich, 99% purity) dried on molecular sieves 4 ꢂ.
3
4
86 (75)[b]
14 (11)[b]
-
100 (100)[b]
100 (40 DMI)[b,d]
(30)[b,c]
[a] Alcohol/DMC (1:50); NaOMe (3 equiv.); Reaction time: 20 h; Reaction
conditions: 105 Pa, 908C. [b] Product distribution after 8 h. [c] 30% of car-
bonates calculated as the sum of MCE-1 (23%); MCE-2 (7%). [d] Also ob-
tained MMI-1 (18%); MMI-2 (10%).
Example of a reaction at reflux condition (Table 1): In a two-necked
round bottom flask equipped with a dephlegmator, isosorbide
(2.0 g, 0.014 mol, 1 equiv.), DMC (61.7 g, 0.658 mol, 50 equiv.), and
sodium methoxide (2.2 g, 0.041 mol, 3 equiv.) were heated at reflux
while stirring continuously under a nitrogen atmosphere. After
20 h, the reaction was stopped, the mixture was filtrated over
Gooch n84, and the DMC evaporated. The residual solution was
distilled under vacuum to recover the crude reaction mixture. A
sample was analyzed by GC–MS. The reaction mixture was subject-
under reflux (Table 3). The results collected confirmed the
trend of reactivity towards methylation reported in Table 2.
The selection of secondary alcohols mainly gave carboxymeth-
yl derivates whereas isosorbide led to DMI as the major prod-
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ChemSusChem 2010, 3, 566 – 570

Table 3. Competition reaction with selected secondary alcohols.[a]
Entry
Alcohols
Alcohol [equiv.]
Product distribution of isosorbide
Carbonate ethers
Product distribution of alcohol
Carbonates
MC1 MC2 DC
Ethers
Isosorbide [equiv.]
ROH
ROCO2Me
ROMe
MCE1
21
MCE2
20
4
MMI1 MMI2 DMI
1
2
3
(1)
(1)
(1)
2-Octanol (1)
3-OH-tetrahydrofuran (1)
Propylene glycol
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
59
73
83
-
-
-
100
96
91
-
4
9
23
17
-
propyl ether (1)
[a] Isosorbide (0.5 g)/DMC (1:50); NaOMe (6.0 equiv.); Reaction time: 20 h; Reaction conditions: 105 Pa, 908C.
ed to column chromatography. The gradient elution chromatogra-
phy with DCM/MeOH (98:2) on silica gel allowed several of deri-
vates to be isolated as pure compounds:
distilled under vacuum to recover the crude reaction mixture that
was then analyzed by GC–MS.
1
MC-2: C8H12O6; M=204.06 gmolÀ1; H NMR (300 MHz, CDCl3): d=
Acknowledgements
5.12 (d, 1H), 4.64 (t, 1H), 4.52 (d, 1H), 4.31 (q, 1H), 4.12 (d, 1H),
3.99 (dd, 1H), 3.88 (dd, 1H), 3.80 (s, 3H,), 3.56 (dd, 1H),
2.59 ppm(d, 1H,); 13C NMR (75 MHz, CDCl3): d=154.6, 85.3, 81.9,
81.5, 73.5, 73.2, 72.2, 55.1 ppm.
We want to acknowledge the Imperial Chemical Industries Ldt
(ICI) for the support and funding.
1
DC: C10H14O8; M=262 gmolÀ1; H NMR (300 MHz, CDCl3): d=5.09
(d, 1H), 5.05 (t, 1H), 4.88 (t, 1H), 4.53 (d, 1H), 3.98–4.05 (m, 2H),
3.88–3.91 (m, 2H), 3.80 (s, 3H), 3.79 ppm(s, 3H,)
(75 MHz, CDCl3): d=155.0, 154.6, 85.7, 81.0, 80.7, 76.5, 73.1, 70.3,
Keywords: carbohydrates · carbonates · green chemistry ·
methylation · renewable resources
;
13C NMR
55.0, 54.9 ppm.
1
MCE-1: C9H14O6; M=218.08 gmolÀ1; H NMR (300 MHz, CDCl3): d=
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5.04 (t, 1H), 4.68 (t, 1H), 4.54 (d, 1H), 4.04 (d, 2H), 3.88–3.96 (m,
2H), 3.76 (s, 3H), 3.57–3.60 (m, 1H), 3.43 ppm (s, 3H,); 13C NMR
(75 MHz, CDCl3): d=154.7, 85.6, 81.6, 81.5, 80.4, 73.3, 69.9, 58.2,
54.9 ppm.
1
MCE-2: C9H14O6; M=218.08 gmolÀ1; H NMR (300 MHz, CDCl3): d=
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4.96 (t, 1H), 4.73 (t, 1H), 4.38 (d, 1H), 3.88–3.96 (d, 1H), 3.74–3.84
(m, 4H), 3.72 (s, 3H), 3.29 ppm (s, 3H,); 13C NMR (75 MHz, CDCl3):
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1
MMI-1: C7H12O4; M=160.07 gmolÀ1; H NMR (300 MHz, CDCl3): d=
4.71 (t, 1H), 4.43 (d, 1H), 4.29 (t, 1H), 3.86–3.98 (m, 4H), 3.55 (t,
1H), 3.45 (s, 3H), 2.56 ppm (s, OH,).
DMI: C8H14O4; M=174.09 gmolÀ1 1H NMR (300 MHz, CDCl3): d=
;
4.64 (t, 1H), 4.50 (d, 1H), 3.88–3.99 (m, 4H), 3.85 (m, 1H), 3.53–3.61
(m, 1H), 3.45 (s, 3H), 3.36 ppm (s, 3H). All spectroscopic features of
this product correspond to those reported in the literature.
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Example of a reaction with DMC at reflux condition (Table 2): In a
two-necked round bottom flask equipped with a dephlegmator, 3-
hydroxy-tetrahydrofuran (2.0 g, 0.022 mol, 1 mol. equiv), DMC
102 g (1.13 mol, 50 mol. equiv), and sodium methoxide (7.3 g,
0.136 mol, 3 equiv.) were heated at reflux while stirring continuous-
ly under a nitrogen atmosphere. After 20 h the reaction was
stopped, the mixture was filtrated over Gooch n84, and the DMC
evaporated. The residual solution was distilled under vacuum to re-
cover the crude reaction mixture that was then analyzed by GC–
MS.
Example of a reaction with DMC at reflux condition (Table 3): In a
two-necked round bottom flask equipped with a dephlegmator,
isosorbide (0.5 g, 0.0034 mol, 1 equiv.), DMC (16 g, 0.171 mol,
50 equiv.), 3-hydroxy-tetrahydrofuran (0.3 g, 0.0034 mol, 1 equiv.),
and sodium methoxide (2.2 g, 1.1 mol, 3 equiv.) were heated at
reflux while stirring continuously under a nitrogen atmosphere.
After 20 h the reaction was stopped, the mixture was filtrated over
Gooch n84, and the DMC evaporated. The residual solution was
[13] a) F. J. Hopton, G. H. S. Thomas, Can. J. Chem. 1969, 47, 2395; b) Y. Zhu,
M. Durand, V. Molinier, J. M. Aubry, Green Chem. 2008, 10, 532–540.
[14] The yield of DMI in this case is not quantitative due to the lower
amount of base used (ca. 30% equivalents less compared to Tables 1
and 2)
ChemSusChem 2010, 3, 566 – 570
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569

[15] In this case study, the OH group labeled as endo refers to the OH point-
ing toward the isosorbide V-shaped cavity, whereas the exo OH group
refers to the OH pointing out of the V-shaped cavity of isosorbide.
[16] European production of chlorine is 20 million tonnes per year in 80
plants which in turn generates 5.21 trillion tonnes of CO2 equivalents
per year with a primary energy consumption of 55 trillion GJ per year;
in Europe, chlorine use accounts for 0.45% of the global warming po-
tential.
Received: January 19, 2010
Revised: February 17, 2010
Published online on April 16, 2010
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ChemSusChem 2010, 3, 566 – 570