Efficient synthetic protocols in glycerol under heterogeneous catalysis

Article abstract of DOI:10.1002/cssc.201100106

The massive increase in glycerol production from the transesterification of vegetable oils has stimulated a large effort to find novel uses for this compound. Hence, the use of glycerol as a solvent for organic synthesis has drawn particular interest. Dra

Full text of DOI:10.1002/cssc.201100106

DOI: 10.1002/cssc.201100106
Efficient Synthetic Protocols in Glycerol under
Heterogeneous Catalysis
Giancarlo Cravotto,*[a] Laura Orio,[a] Emanuela Calcio Gaudino,[a] Katia Martina,[a]
Dorith Tavor,[b] and Adi Wolfson[b]
Dedicated to Professor Vittorio Mortarini on the occasion of his 70th Birthday
The massive increase in glycerol production from the transes-
terification of vegetable oils has stimulated a large effort to
find novel uses for this compound. Hence, the use of glycerol
as a solvent for organic synthesis has drawn particular interest.
Drawbacks of this green and renewable solvent are a low solu-
bility of highly hydrophobic molecules and a high viscosity,
which often requires the use of a fluidifying co-solvent. These
limitations can be easily overcome by performing reactions
under high-intensity ultrasound and microwaves in a stand-
alone or combined manner. These non-conventional tech-
niques facilitate and widen the use of glycerol as a solvent in
organic synthesis. Glycerol allows excellent acoustic cavitation
even at high temperatures (70–1008C), which is otherwise neg-
ligible in water. Herein, we describe three different types of ap-
plications: 1) the catalytic transfer hydrogenation of benzalde-
hyde to benzyl alcohol in which glycerol plays the dual role of
the solvent and hydrogen donor; 2) the palladium-catalyzed
Suzuki cross-coupling; and (3) the Barbier reaction. In all cases
glycerol proved to be a greener, less expensive, and safer alter-
native to the classic volatile organic solvents.
Introduction
The need for clean processes, in which energy and waste are
minimized and costs are reduced, is of general concern. To
reach this goal in organic synthesis, the use of sustainable re-
action media, for example, an environmentally friendly solvent
with suitable chemico-physical and biological properties that
allows for reactants and catalysts to be dissolved, reactions to
be worked-up, and catalysts to be recycled easily, is a crucial
feature.[1–3]
syntheses, its use has several drawbacks, including a high vis-
cosity and a low solubility of highly hydrophobic compounds
and gases, such as hydrogen and oxygen. These factors limit
its mass transport capabilities. These limitations can be over-
come by using high-intensity ultrasound (US)[13,14] and micro-
waves (MW) in a stand-alone[15] or combined manner,[16,17] to
enhance momentum, heat, and mass transfer and hence to ac-
celerate reaction rates. In recent years both techniques have
emerged as new and irreplaceable tools in organic synthe-
sis.[18,19] Although dielectric heating and sonication save
energy, they strongly accelerate chemical transformations and
often improve selectivity and strongly reduce the amount of
catalyst required.[20] Preliminary results from the MW-promoted
Wolff–Kishner reduction of benzaldehyde to toluene[21] and CÀ
C coupling reactions (Heck and Suzuki) in glycerol[5] were re-
ported.
Glycerol is a non-toxic, non-hazardous, non-volatile, biode-
gradable, and recyclable liquid that is produced as a byproduct
of the transesterification of oil from renewable sources. It has
recently gained increased attention as an alternative sustain-
able solvent for catalytic and non-catalytic organic transforma-
tions.[4–9] Although its use as a solvent goes back to the middle
of the last century,[10] it has only recently been found that glyc-
erol can dissolve many organic and inorganic compounds, in-
cluding transition-metal complexes. It also allows products to
be easily separated by extraction with glycerol-immiscible sol-
vents, such as ethers, esters,[4–8] and supercritical carbon diox-
ide.[9] Moreover, employing glycerol as a solvent has often re-
sulted in improved product yields and selectivity.[7,8] Glycerol
can also be reused and enables transition-metal complexes to
be recycled in a simple way.[4,5] In the catalytic transfer hydro-
genation of various unsaturated organic compounds[11] and in
the transesterification of alcohols[12], glycerol was simulta-
neously used as a solvent and reactant. Owing to its very low
toxicity, glycerol can also be a suitable solvent in the synthesis
of active pharmaceutical ingredients, in which the level of sol-
vent residue is strictly controlled.
So far, we have not been able to find comprehensive studies
of organic reactions in glycerol under US and/or MW in litera-
ture. In the present work, both US and MW irradiation, stand-
alone or combined techniques, were employed for the first
time for organic transformations in glycerol. Three representa-
[a] Prof. G. Cravotto, L. Orio, Dr. E. C. Gaudino, Dr. K. Martina
Dipartimento di Scienza e Tecnologia del Farmaco
Universitꢀ degli Studi di Torino
Via P. Giuria 9, 10125 Torino (Italy)
Fax: (+39)0116707684
E-mail: giancarlo.cravotto@unito.it
[b] Prof. D. Tavor, Prof. A. Wolfson
Green Processes Center, Chemical Engineering Department
Sami Shamoon College of Engineering
Bialik/Basel Sts. Beer-Sheva, 84100 (Israel)
Although glycerol exhibits promising features as a sustaina-
ble solvent for liquid-phase catalytic and non-catalytic organic
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ChemSusChem 2011, 4, 1130 – 1134

Synthetic Protocols in Glycerol
tive reactions have been investigated, including selective trans-
fer hydrogenation and metal-catalyzed CÀC couplings.
Results and Discussion
Scheme 1. Benzaldehyde transfer hydrogenation reaction.
Table 1. Transfer hydrogenation of benzaldehyde in glycerol.[a]
The aim of this work was to demonstrate that glycerol can be
successfully used as a solvent of choice in several types of or-
ganic reactions and that the use of non-conventional tech-
niques, such as US and MW, may solve problems of solubility
and high viscosity by enhancing heat and mass transfer.
An important application of glycerol is in the transfer hydro-
genation reaction, a reaction that is usually performed by
using a hydrogen donor, which can also fulfill the role of the
solvent.[22–25] The most commonly used hydrogen sources are
simple alcohols, such as 2-propanol.[26,27] As mentioned above,
glycerol can be used both as a solvent and a hydrogen donor
in the catalytic transfer hydrogenation of various unsaturated
organic molecules.[11,28] Various catalysts, such as Raney-Ni or
Ru and Rh complexes, have been tested,[29,30] and a few MW-
assisted reactions have been reported.[31] In this study, we ex-
ploited the dual effect of glycerol in the MW- and US-promot-
ed transfer hydrogenation of benzaldehyde, which was cata-
lyzed by using a Ru(p-cumene)Cl2 dimer under varying reaction
temperatures, base concentrations, and irradiation power
values.
Entry
Base
Method
T [8C]
t [h]
Yield [%]
1
2
3
4[c]
5[c]
6a[c]
6b[c]
6c[c]
7
KOH
NaOH
OB[b]
OB
OB
OB
MW/UP[d]
US/OB
US/OB
US/OB
US/MW
70
70
70
70
70
60
60
60
60
24
24
24
12
1.5
1
2
3
1.5
–
3
69
66
49
68
77
100
84[e]
KOH+NaOH
KOH+NaOH
KOH+NaOH
KOH+NaOH
KOH+NaOH
KOH+NaOH
KOH+NaOH
[a] Reaction conditions: benzaldehyde (1 mmol), base (0.01–0.02 mmol),
Na2CO3 (1.2 mmol), Ru(p-cumene)Cl2 dimer (0.01 mmol), glycerol
(21 mmol, 2 g). [b] OB=oil bath. [c] Presonication by using cup-horn
(100 W; 19.0 kHz) for 15 min. [d] MW/UP=microwaves under pressure.
[e] With longer reaction times the yield did not improve.
We also focused our attention on metal-catalyzed CÀC cou-
pling reactions in which glycerol also proved itself to be a suit-
able solvent. Suzuki couplings have long been the subject of
intensive work in the area of transition-metal synthesis (reac-
tion conditions, media, and techniques). These transformations
have been performed in several green media such as water,
ethanol, polyethylene glycol, supercritical carbon dioxide, ionic
liquids, and in the absence of a solvent.[32] Few promising re-
sults have been obtained in glycerol.[5] Several papers have re-
ported on the palladium-catalyzed Suzuki couplings carried
out under MW and US irradiation,[33] even in a combined fash-
ion,[34] with several advantages. Glycerol dissolved organic sub-
strates, inorganic bases, and palladium complexes as a polar
organic solvent, and allowed for the reaction product to be
easily isolated through a simple extraction process using glyc-
erol-immiscible solvents, such as diethyl ether, and also permit-
ted catalyst recycling.
yielded similar benzyl alcohol yields in half the reaction time
(entry 4) as compared to the conventional method. Even the
combined US/MW irradiation by means of a pyrexꢁ horn
(entry 7) could not compete with the US irradiation (titanium
horn) in a thermostated oil bath (US/OB) with 100% yield after
3 h (entry 6c).
We studied a series of metal-catalyzed CÀC couplings in
glycerol, including the Suzuki reaction (Scheme 2). We com-
pared conductive heating in an oil bath (OB), MW irradiation
Scheme 2. Suzuki cross-coupling reaction in glycerol.
Barbier-type reactions, historically performed in anhydrous
solvents, have been widely studied in aqueous media using
tin, zinc, indium, and other metals.[35] On the basis of our previ-
ous experience with sonochemical Barbier reactions,[36,37] we
tested this reaction in glycerol. Experiments were carried out
in triplicate and in duplicate for a few cases (conventional con-
ditions). As with the transfer hydrogenation of benzaldehyde
(Scheme 1, Table 1), a first set of experiments was performed
in an oil bath (OB). Surprisingly, yields were negligible if only
KOH or NaOH were used (entries 1 and 2) and could be im-
proved by combining the two bases (entry 3). Under sono-
chemical conditions, base dispersion in glycerol was optimal
(entries 4–7) resulting in a shorter reaction time.
(MW), US horn irradiation combined with conductive heating
in a thermostated oil bath (US/OB), and simultaneous US/MW
irradiation (US/MW) (Table 2). The coupling between 4-iodoani-
sole and phenylboronic acid using ligand-free palladium salts
or palladium on charcoal was used as a model reaction.
Preliminary sonochemical trials performed at room tempera-
ture using a probe system with a titanium horn gave poor
yields. For this reason, all the reactions were performed at
808C. This is one of the great advantages of glycerol; it allows
excellent acoustic cavitation even at high temperatures. We
observed that in all cases palladium chloride and palladium
acetate were more efficient than palladium on charcoal
(Table 2). US/OB, MW, and simultaneous US/MW irradiation
strongly improved the reaction rate. The latter (entry 5) and
The crucial role of sonication was shown in the transfer hy-
drogenation of benzaldehyde, in which short pre-sonication
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1131

G. Cravotto et al.
hyde as a substrate (Scheme 3). We compared the classical sol-
vent system THF/NH4Cl with glycerol/NH4Cl (Table 4). The
effect of a US cleaning bath on the reaction rate was negligi-
ble, whereas using a US horn at room temperature yielded
80% alcohol in only 15 min, and 100% conversion after 1 hour
without byproduct formation (entries 4–6).
Table 2. Cross-coupling yields in glycerol using different techniques.
Entry
Method[a]
t [min]
Yield [%]
PdCl2
Pd(OAc)2
Pd/C
1
2
3
4
5
OB[b]
US/OB
MW
MW
US/MW
60
60
15
60
60
85
99
57
74
100
75
98
70
92
98
44
86
60
67
94
[a] Reaction conditions: 4-iodomethoxbenzene (2 mmol), phenylboronic
acid (2.4 mmol), Na2CO3 (2.4 mmol), ligand-free catalyst (0.04 mmol), glyc-
erol (42 mmol, 4.0 g), 808C. [b] OB=oil bath.
the US/OB method (entry 2) gave the best results due to en-
hanced heat and mass transfer.
Scheme 3. Barbier reaction in glycerol.
The conditions and yields of reactions using bromo- and
chloroarenes in glycerol and ligand-free catalysts are reported
in Table 3. In addition to classical palladium salts, we used a
Table 4. Barbier reaction using benzaldehyde and propargyl bromide.[a]
Entry Solvent
Method T [8C] t [min] Yield [%] Byproduct [%]
1
2
3
4
5
6
THF/NH4Cl st.
RT
40
RT
RT
RT
RT
90
90
90
15
30
60
81
72
80
80
89
3
10
12
–
–
–
Table 3. Suzuki cross-coupling using different substrates.
THF/NH4Cl st.
Glyc/NH4Cl st.
Glyc/NH4Cl US[b]
Glyc/NH4Cl US[b]
Glyc/NH4Cl US[b]
Entry Substrate
Catalyst
Method[a] t [min] T [8C] Yield [%]
1
2
3
4
5
6
7
8
4-Br-anisole PdCl2
4-Br-anisole PdCl2
OB[b]
US/OB
MW
US/MW
OB
US/OB
MW
US/MW
MW/UP[c] 30
OB
US/OB
MW
60
60
30
30
60
60
30
60
80
80
80
80
80
80
90
90
140
80
80
80
80
80
80
90
90
140
90
90
36
75
70
73
71
89
78
83
79
62
77
69
78
64
86
10
38
41
48
61
100
4-Br-anisole PdCl2
4-Br-anisole PdCl2
4-Br-anisole Pd(OAc)2
4-Br-anisole Pd(OAc)2
4-Br-anisole Pd(OAc)2
4-Br-anisole Pd(OAc)2
4-Br-anisole Pd(OAc)2
3-Br-anisole PdCl2
3-Br-anisole PdCl2
3-Br-anisole PdCl2
3-Br-anisole Pd(OAc)2
3-Br-anisole Pd/C
[a] Reaction conditions: benzaldehyde (1 mmol), propargyl bromide
(2 mmol), zinc powder (2 mmol). [b] Titanium US horn.
A set of different aldehydes and halides was also tested in
glycerol/NH4Cl at room temperature under magnetic stirring in
US using a cleaning bath or a US horn at 408C (Table 5). No re-
action occurred with 5-chloropent-1-yne, whereas 3-bromopro-
pene reacted very quickly with benzaldehyde (entries 1 and 2,
respectively).
9
10
11
12
13
14
15
16
17
18
19
20
60
60
30
30
30
60
60
60
60
60
60
MW
US/MW
3-Br-anisole Supp-Pd[d] US/MW
4-Cl-acet.[e]
4-Cl-acet.
4-Cl-acet.
4-Cl-acet.
4-Cl-acet.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Supp-Pd
OB
Thus, 3-bromopropene was also reacted with a series of dif-
ferent aldehydes, giving high yields in all reactions (entries 3–
6). The reaction with propargyl bromide generated a byprod-
uct (entry 7). Byproducts were also detected when 3-bromo-
propene was employed together with 2,4-dimethoxybenzalde-
hyde (entry 8). It was demonstrated that the Barbier reaction in
glycerol under high-intensity US (horn) is extremely efficient
and fast.
US/OB
MW/UP
US/MW
US/MW
[a] Reaction conditions: see Table 2. [b] OB=oil bath. [c] MW/UP=MW
under pressure (closed vessel). [d] Supp-Pd=palladium-cross-linked chito-
san. [e] 4-Cl-acet.=4-Cl-acetophenone.
palladium-loaded cross-linked chitosan,[38] which gave the best
results using both 3-bromoanisole and 4-Cl-acetophenone (en-
tries 15 and 20, respectively). This polymeric catalyst was also
used during conventional heating (OB) in the case of 3-bro-
moanisole; however, the reaction yield was close to 80% after
12 h stirring at 808C. The weight content of PdII in cross-linked
chitosan, analyzed by using inductively coupled plasma mass
spectrometry (ICP-MS), was 0.39%. No advantages were ob-
served at higher MW power and temperature values in closed
vessels under pressure (entry 9). Lower yields were observed
with 4-chloroacetophenone (entries 16–20), although US, MW-
UP, and US/MW irradiation markedly increased the yield.
Conclusions
Glycerol proved to be a very attractive, non-volatile, polar sol-
vent for several organic reactions under heterogeneous cataly-
sis. We have observed a mutual advantage working under
MW- or US-irradiation. Glycerol was successfully employed
both as a solvent and as a hydrogen donor in the transfer hy-
drogenation of benzaldehyde, and US dramatically increased
the reaction yields. Improved dispersion of a base in glycerol
was obtained with efficient presonication, reducing reaction
times even when the reaction was performed in an oil bath or
MW oven.
Another striking example of a reaction in glycerol is the
Barbier reaction, which was first studied by using benzalde-
1132
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ChemSusChem 2011, 4, 1130 – 1134

Synthetic Protocols in Glycerol
Methods
Table 5. Barbier reaction using different substrates.[a]
Benzaldehyde transfer hydrogena-
tion: In a typical procedure, ben-
zaldehyde (1 mmol), a base (0.01–
0.02 mmol), and Ru(p-cumene)Cl2
dimer (0.01 mmol) were added to
glycerol (21 mmol, 2 g). In some
procedures (Table 1), the mixture
was pre-sonicated by using a US
cup-horn (100 W; 19.0 kHz) for
15 min. For reactions under con-
ventional heating, the mixture was
placed in a preheated oil bath at
708C and magnetically stirred for
24 h. For MW-assisted reactions,
the mixture was irradiated at a
Entry
Method
Aldehyde
Halide
Yield[%]
1[b]
2[b]
3[b]
4[b]
5[b]
6[c]
7[c]
8[c]
9[c]
OB
OB
OB
OB
benzaldehyde
benzaldehyde
(E)-3-(4-(Me2-phenyl)acrylaldehyde
ethyl vanillin
4-methoxybenzaldehyde
4-methoxybenzaldehyde
4-methoxybenzaldehyde
2,4-dimethoxybenzaldehyde
benzaldehyde
5-chloropentyne
3-bromopropene
3-bromopropene
3-bromopropene
3-bromopropene
3-bromopropene
propargyl bromide
3-bromopropene
3-bromopropene
–
70
5
77
99
99
19
91
99
OB
US/OB
US/OB
US/OB
US/OB
[a] Reaction conditions: aldehyde (1 mmol), halide (2 mmol), zinc powder (2 mmol), 408C. [b] Time reaction:
90 min. [c] Time reaction: 30 min.
fixed temperature (708C) in a MW oven (maximum power 40–
45 W) for 2 h. For US-assisted reactions, the mixture was heated to
608C in an oil bath and sonicated by using a titanium horn (30 W)
for up to 4 h. The reaction mixture was then cooled down to room
temperature, the product was extracted by using ethyl acetate and
dried under vacuum. Product conversions were determined by
using GC–MS.
Enhanced reaction rates were detected for the palladium-
catalyzed Suzuki cross-coupling reactions in glycerol in the
order MW/US>US>MW. Both US- and MW-irradiation greatly
improved the reaction of halobenzenes, such as chloroaceto-
phenone, which are poorly reactive toward CÀC coupling. Out-
standing catalytic activity was achieved using a solid ligand-
free catalyst, a palladium-loaded cross-linked chitosan. Good
yields were also obtained in the Barbier reaction, proving that
the use of glycerol as a solvent maintains the conversion yield
in the same range as other organic solvents, while enabling a
greener procedure and easier work up of the products through
a simple extraction process using ethyl acetate.
Suzuki cross-coupling reaction: In a typical procedure, 4-iodoani-
sole (1 mmol), phenylboronic acid (1.2 mmol), Na2CO3 (1.2 mmol),
and either the palladium salt (0.02 mmol) or the corresponding
amount of solid catalysts (5% Pd/C or palladium-cross-linked chito-
san) were added to a flask with glycerol (21 mmol, 2 g). For reac-
tions under conventional heating, the mixture was placed in a pre-
heated oil bath at 808C and magnetically stirred for 60 min under
N2. For MW-assisted reactions, the mixture was irradiated at a fixed
temperature (808C) in a MW-reactor (max power 40–45 W) under a
nitrogen atmosphere. For US-assisted reactions, the mixture was
heated to 808C in an oil bath and sonicated under nitrogen by
using a titanium horn (30 W) for 60 min. The simultaneous US/MW
irradiation experiments were performed in glycerol (109 mmol,
10 g), irradiated in a MW oven, and sonicated by using a pyrex
horn under N2 at a fixed temperature (808C) for 60 min. The reac-
tion mixture was then cooled down to room temperature, the
product was extracted with diethyl ether, filtered on a Hirsh funnel
(paper filter) and dried under vacuum. Product conversions were
determined by using GC–MS.
We believe that using glycerol as a solvent for organic trans-
formations not only improves reaction performance in terms
of yields and costs, but also offers an attractive way to conduct
green and sustainable processes. Applications of glycerol in
other organic reactions are ongoing in our laboratory.
Experimental Section
Materials
Barbier reaction: In a typical procedure, aldehyde (1 mmol), allyl (or
propargyl) halide (2 mmol), and zinc powder (2 mmol) were added
to a mixture of a saturated aqueous ammonium chloride solution
which was added to an equal amount of glycerol or alternatively
THF. The mixture was stirred for 90 min at room temperature or
stirred in an oil bath at 408C. For US-assisted reactions the mixture
was sonicated in a US bath for 90 min or sonicated by using a tita-
nium horn (60 W) for 30 min. The reaction mixture was then
cooled down to room temperature and the product was extracted
by using ethyl acetate and dried under vacuum. Product conver-
sions were determined by using GC–MS.
All reagents were obtained from commercial sources and used
without further purification. Reactions were monitored by using
thin layer chromatography (TLC) carried out on precoated, glass-
backed plates (thickness 0.25 mm, Merck 60 F254), which were vi-
sualized by UV inspection and/or by heating after being sprayed
with H2SO4 (5%) in ethanol. Gas chromatography–mass spectrosco-
py (GC–MS) analyses were carried out by using an Agilent 6890
gas chromatograph (Agilent Technologies-USA) fitted with an Agi-
lent Network 5973 mass detector. Sonochemical reactions were
performed in commercially available probe systems equipped
either with an immersion horn or a cavitating tube, both made
from titanium (Danacamerini, Italy). The working frequency was
19.5–19.6 kHz and the power 30–45 W. MW-promoted reactions
were carried out in a professional oven (Microsynth-Milestone,
Italy); this oven was also used for combined MW/US irradiation
after a probe equipped with a pyrex horn was inserted. The palla-
dium content in solution was determined by using inductively cou-
pled plasma mass spectroscopy (ICP-MS) performed by using a
Quadrupole-ICP-MS X Series II (Thermo Fisher Scientific) after di-
gestion in HNO3.
Acknowledgements
Financial support from MIUR (PRIN 2008 “A Green Approach to
Process Intensification in Organic Synthesis”) is gratefully ac-
knowledged.
ChemSusChem 2011, 4, 1130 – 1134
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