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Cite this: Chem. Commun., 2011, 47, 6208–6227
www.rsc.org/chemcomm FEATURE ARTICLE

Glycerol and derived solvents: new sustainable reaction media for
organic synthesis
Alba E. Dı́az-Álvarez, Javier Francos, Beatriz Lastra-Barreira, Pascale Crochet
and Victorio Cadierno*
Published on 30 March 2011 on http://pubs.rsc.org | doi:10.1039/C1CC10620A
Received 31st January 2011, Accepted 4th March 2011

DOI: 10.1039/c1cc10620a
Downloaded by University of Memphis on 24 September 2012
The rapid growth of the biodiesel industry has led to a large surplus of its major byproduct, i.e.
glycerol, for which new applications need to be found. Research efforts in this area have focused
mainly on the development of processes for converting glycerol into value-added chemicals and its
reforming for hydrogen production, but recently, in line with the increasing interest in the use of
alternative greener solvents, an innovative way to revalorize glycerol and some of its derivatives
has seen the light, i.e. their use as environmentally friendly reaction media for synthetic organic
chemistry. The aim of the present Feature Article is to provide a comprehensive overview on the
developments reached in this field.
Introduction of triglycerides with a short-chain aliphatic alcohol, typically

methanol, under basic conditions (Scheme 1).2 One major
Petroleum is the main energy source in the world, but its concern regarding the biodiesel production is the formation
availability is limited and the search for new renewable energy of glycerol (glycerine or 1,2,3-propanetriol) as a by-product
sources is of prime interest.1 Biodiesel, composed of long- (B10% by weight). In this sense, according to recent estimates,3
chain monoalkyl esters of fatty acids derived from vegetable world production of glycerol could have reached 1.2 million
oils or animal fats, is the most realistic alternative to effectively tonnes in 2010 and will grow in coming years due to the
reduce our current dependence on fossil fuels for transportation increasing demand for biodiesel.4
in the short-term.2 Production of biodiesel is a relatively There are over 2000 established uses for glycerol as a
simple process that involves the catalytic transesterification high-valued starting material in the drug, food, beverage,
chemicals and synthetic materials industries (see Fig. 1).5
Departamento de Quı´mica Orgánica e Inorgánica, It is used in cosmetics, toiletries, sweeteners, softening
Instituto Universitario de Quı´mica Organometálica ‘‘Enrique Moles’’ agents, cough syrups, surface coatings, paints and many other
(Unidad Asociada al CSIC), Universidad de Oviedo,
Julián Claverıá 8, 33006 Oviedo, Spain. E-mail: [email protected]; products. However, the large surplus of glycerol generated by
Fax: +34 985103446; Tel: +34 985103453 the biodiesel industry has recently led to a collapse in the
Alba E. Dıáz-Álvarez studied Javier Francos received his

chemistry at the University of BSc in Chemistry from the
Oviedo (Spain) and obtained University of Oviedo (Spain)
his PhD degree in 2007 in 2006. He is currently a PhD
working on homogeneous student working under the
catalysis under the supervision supervision of Dr V. Cadierno.
of Dr Pascale Crochet. After a In 2009 he conducted a three-
postdoctoral stay in the group month stay in the group
of Dr Diego Peña (University of Prof. J. M. J. Williams
of Santiago de Compostela, (University of Bath, UK).
Spain), developing new nano- His research interests include
structures based on polycyclic the preparation of new
aromatic hydrocarbons, she ruthenium catalysts and
returned to Oviedo in 2010 as their applications in green
Alba E. Dı́az-Álvarez a postdoctoral researcher. Her Javier Francos chemistry.
current work involves the
development of new catalytic transformations in water and
glycerol.
6208 Chem. Commun., 2011, 47, 6208–6227 This journal is c The Royal Society of Chemistry 2011
View Online
Scheme 1 Overall reaction for production of biodiesel. Fig. 1 The market of glycerol (industrial sectors and volumes).
prices, which has been accompanied by a growing imbalance

in the supply/demand of this chemical. The current inability of

Today, most of the efforts in this area are focusing on
the market to absorb all the glycerol produced in the biodiesel
the development of procedures to convert this highly
plants makes this renewable chemical become a mere waste.
functionalized molecule into value-added chemicals that have
This scenario could have negative implications on the

either been previously prepared from petrochemical sources or
economic viability of many biorefineries in the near future,
suffered from environmental problems during their preparation.
and also on the environment due to an improper disposal of
Several comprehensive review articles covering the current
glycerol. Consequently, new applications for this polyol as a
state-of-the-art have already appeared in the literature, and
low-cost raw material need to be developed and/or the existing
they are recommended to readers seeking a broader knowledge
ones need to be expanded.6
on this topic.3,6,7 Glycerol reforming for hydrogen production,8
and its transformation into fuel additives,9 are also extremely
active areas of research. However, in order to absorb all the
Beatriz Lastra-Barreira surpluses, new uses requiring large volumes of glycerol would
received his BSc in Chemistry be highly welcomed.
from the University of Oviedo Reaction solvents are used in huge amounts and are one of
(Spain) in 2006. She is the most important constituents in any chemical process.
currently a PhD student Synthetic organic chemistry is traditionally carried out in
working under the supervision solution to facilitate the intimate contact of reactants and
of Dr P. Crochet. In 2008 she catalysts. Although any liquid may be potentially used as a
conducted a two-month stay
solvent, the most widely employed in both academia and
in the group of Prof. D.
industry are the hydrocarbons (including halogenated and
Bourissou (Universite´ Paul
Sabatier, France). Her thesis aromatic ones), ethers and alcohols derived from fossil fuels.
is focused on the design of However, despite the obvious usefulness of these organic
new water-soluble ruthenium solvents, problems associated with their volatility, flammability
complexes and their catalytic and toxicity, as well as their increasing prices, advise against
Beatriz Lastra-Barreira applications. their use.
Pascale Crochet studied Victorio Cadierno studied

chemistry at the University of chemistry at the University of
Rennes I (France) and Oviedo and obtained his PhD
obtained her PhD in 1996 degree in 1996 working under
under the supervision of Prof. the supervision of Prof. J.
P. H. Dixneuf and B. Gimeno. He then joined the
Demerseman. After a two- group of Prof. J. P. Majoral
year post-doctoral stay in the at the LCC-CNRS (Toulouse,
group of Prof. M. A. Esteruelas France) for a two-year post-
(University of Zaragoza, doctoral stay. Thereafter, he
Spain) and one year as an returned to the University of
Assistant Professor at the Oviedo where he is currently
‘‘National High School of an Associate Professor of
Physics and Chemistry’’ of Inorganic Chemistry. In 2002
Pascale Crochet Bordeaux (France), she Victorio Cadierno he was awarded with the
moved in 1999 to the Spanish Royal Society of
University of Oviedo where she is currently an Associate Professor Chemistry (RSEQ) Young Investigator Award. His current
of Inorganic Chemistry. Her research interests deal with the design research interests cover the development of catalytic trans-
and synthetic applications of organometallic complexes, with a formations in green reaction media, being co-author of more
particular focus on hydrosoluble ruthenium catalysts. than 110 publications.
This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 6208–6227 6209
View Online
In recent years, safety and environmental concerns have Table 1 Some physicochemical properties and toxicity data of
been increasingly recognized by the chemical community glycerol
worldwide, and the twelve principles of the so-called ‘‘Green Melting point 17.8 1C
Chemistry’’ are nowadays considered as an essential driving Boiling point 290 1C
force in the quest for sustainable chemical processes.10 Viscosity (20 1C) 1200 cP
Solvents are a key component in making a process ‘‘green’’ Vapour pressure (20 1C) o1 mm Hg
Density (20 1C) 1.26 g cm3
and, consequently, one of the major challenges for today’s Flash point 160 1C (closed cup)
chemists is to move away from the classical volatile organic Autoignition temperature 400 1C
solvents.11 An ideal ‘‘green’’ solvent should have a high boiling Critical temperature 492.2 1C
Critical pressure 42.5 atm
point, a low vapour pressure, be non-toxic, be able to dissolve Dielectric constant (25 1C) 44.38
a great range of compounds, be inexpensive and, of course, Dipole moment (30–50 1C) 2.68 D
be recyclable. Although the universal green solvent for all LD50 (oral-rat) 12 600 mg kg1
situations does not exist, several alternatives have been evaluated LD50 (dermal-rabbit) >10 000 mg kg1
LC50 (rat-1 h) 570 mg m3

during the last years (water, ionic liquids, supercritical fluids,
perfluorinated solvents, etc.).12 Among them, water appears to
be the superior choice since it satisfies the aforementioned not needed) and the isolation of the final reaction products
considerations almost completely. Indeed, it is now well- through a simple distillation process, (ii) its low vapor pressure
accepted that water is a reliable alternative to the petroleum- and (iii) its high dielectric constant, all these properties
based solvents, a wide variety of highly efficient and selective facilitating its use as a suitable solvent for microwave-assisted
synthetic protocols conducted in aqueous media being already reactions.15 However, despite all these considerations,
available for practical uses.13 problems associated with its high viscosity, which could
As water, glycerol and some of its most direct derivatives provoke poor substrate diffusion in the medium, and the
meet the requirements needed to be considered as green presence of three reactive and metal-coordinating hydroxyl
solvents. In fact, their use as alternative media for organic groups should be taken into account prior to its utilization as
reactions has emerged as a promising new field of research, solvent for a particular reaction.
which opens a new way to revalorize this waste generated by For its part, crude glycerol generated in biodiesel plants is
the biodiesel industry. The aim of the present Feature Article is an impure material in which, depending on the feedstock and
to provide a comprehensive overview on the developments production process employed, glycerol accounts for 65–85 wt%
reached in this field. In particular, after a few brief comments of the total.16 Methanol and soaps are the major impurities
on the main properties of these new solvent systems, their contained in crude glycerol. The presence of methanol is due
applications in synthetic organic chemistry, catalysis and to the fact that biodiesel producers use excess of methanol to
biocatalysis will be discussed in detail. At this point, we must drive the chemical transesterification to completion, while
note that a recent, non-comprehensive and complementary, soaps originate from the reaction of free fatty acids present
article highlighting the utility of glycerol as solvent in different in the starting materials and the base employed as a catalyst.
areas has already appeared.14 In addition, although a large In addition to methanol and soaps, water, inorganic salts and
number of glycerol transformations take place in the absence unreacted mono-, di- and triglycerides are also present in
of any added solvent,6,7 only selected examples where glycerol varying proportions. Crude glycerol usually appears as a
is simultaneously used as a solvent and as a reagent are cloudy dark-brown liquid with a high pH value (11–12) and,
included here. unrefined, has only a marginal value. Purifying crude glycerin
is expensive and requires energy,6 so the possibility of developing
large-scale synthetic processes using crude glycerol as the
Solvent properties of glycerol and its derivatives solvent would be highly appreciated.
Glycerol Glycerol-based ethers, esters and carbonates

In pure form, glycerol is a sweet-tasting, colourless, odourless, The drawbacks outlined above for using glycerol as a solvent
viscous liquid which possesses a unique combination of can be overcome by the synthesis of a glycerol-based family of
physical and chemical properties (some key data are collected solvents whose properties can be tailored, tuned and adjusted
in Table 1).6 Thus, like water, glycerol is highly polar, according to the requirements of each reaction. The presence
biodegradable, immiscible with hydrocarbons and ethers of three reactive hydroxyl groups makes glycerol an excellent
(adequate therefore for biphasic catalysis and for product platform for chemical modification, giving the opportunity to
isolation by liquid–liquid extraction), able to form strong produce unlimited glycerol derivatives that can potentially be
hydrogen bonds and to dissolve inorganic compounds (salts, used as solvents. In this context, following classical synthetic
acids, bases and transition metal complexes). It is also virtually routes Garcı́a and Mayoral have prepared a family of alkyl
non-toxic and non-flammable. Moreover, in comparison glycerol ethers, consisting of over sixty 1,3-dialkoxy-2-propanols
with water, it presents the advantage to dissolve organic and 1,2,3-trialkoxypropanes, both symmetrically and unsym-
compounds usually insoluble in water. Another interesting metrically substituted at terminal positions, and evaluated
features of glycerol are (i) its high boiling point, which enables their possible role as substitutive solvents through measurements
the development of high-temperature organic reactions in a of their physico-chemical properties (Scheme 2).17 Nearly
technically easier way (the use of autoclaves or sealed tubes is 400 experimental data were collected for these species and
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Scheme 4 Preparation and derivatization of glycerol carbonate.
The hydrogen bond ability (a = 0.81) of solketal is typical for

an aliphatic alcohol.21c
Organic carbonates are becoming widely recognized as
Scheme 2 Synthetic routes to symmetrical and unsymmetrical alkyl
solvents for green organic synthesis due to their high biode-
glycerol ethers.
gradability and low toxicity.22 In this context, glycerol

carbonate A is a readily available compound that can be
compared with analogous properties of common organic
prepared by direct carbonation of glycerol with CO2,23 by
solvents. The molecular diversity of the derivatives prepared
metal-catalyzed oxidative carbonylation of glycerol,24 or by
results in significant variations of polarity, viscosity, hydrogen

catalytic transesterification with other carbonates (dimethyl,
bond ability and hydrophobicity, while maintaining in all
diethyl or propylene carbonate) or urea (Scheme 4).25 In
cases a high boiling point and low toxicity. Similarly, a variety
addition, derivatization of glycerol carbonate with carboxylic
of mono-, di-, and tri-esters are also accessible from glycerol
acid chlorides allows the access to high-boiling carbonates B
through catalytic esterification or transesterification
which are useful solvents for reactions under fine vacuum
reactions.18 Among them, triacetin (glycerol triacetate) is the
conditions at elevated temperatures.26
most popular representative due to its industrial applications
Despite the potential utility of all these glycerol-based
in cosmetics and as fuel additive. As the reader will see below,
ethers, esters and carbonates as solvents in organic synthesis,
this oily liquid has also found usefulness as a combined solvent
one should keep in mind that they contain reactive functional
and acyl donor in some catalytic and biocatalytic
groups and, even if they tolerate a broad range of experimental
transformations.
conditions and reagents, may not be suitable solvents for any
Glycerol can also be easily transformed into high value-
type of reactions.
added cyclic acetals and ketals by reaction with carbonyl
compounds.19 For example, acid-catalyzed direct acetalization
Glycerol-based ionic liquids and deep eutectic solvents
of glycerol with formaldehyde gives the well-known ‘‘glycerol
formal’’, which is composed of a mixture of 5-hydroxy-1,3- As already commented, ionic liquids (ILs), salts having a
dioxane and 4-hydroxymethyl-1,3-dioxolane in ca. 60 : 40 melting point below 100 1C, are receiving considerable
ratio (Scheme 3).20 Like glycerol, glycerol formal is a viscous attention as potential alternatives to conventional molecular
colorless liquid of high boiling point, which finds applications organic solvents.27 An ionic liquid generally consists of a large
as a low-toxic solvent in different areas (injectable prepara- nitrogen-containing organic cation and a smaller inorganic
tions, paints, plastifying agents, insecticide delivery systems, anion. The cation/anion asymmetry reduces the lattice energy
etc.). Note that, unlike glycerol, glycerol formal is completely of the crystalline structure and results in a low melting point
miscible with ethers and acetone. salt. Many ionic liquids are highly polar and non-coordinating,
Through a related condensation reaction with acetone, ideal for catalytic reactions, many are immiscible with water,
solketal (2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane) is also saturated hydrocarbons, dialkyl ethers, and a number of
accessible.21 As in the precedent case, the low toxicity of common organic solvents, thus providing flexibility for reaction
solketal has allowed its use as a solvent in several large-scale and separation schemes. In addition, by selecting anions and
applications. Moreover, its polarity and hydrophobicity para- cations, ILs can be easily tuned to provide a specific melting
meters have been determined, pointing out that its polarity lies point, viscosity, volatility, density, hydrophobicity, miscibility,
between those of acetonitrile and ethanol, whereas its hydro- etc. for specific chemical systems. However, despite all these
phobicity is halfway between those of ethanol and 2-propanol. promising properties, widespread application of ILs in process
chemistry is still hampered by doubts generally related to their
high cost, and possible biodegradability and toxicological
concerns.28
Although their green and sustainable nature is also doubtful,
some glycerol-based ILs have seen the light in recent years. In
this context, Bellina and Chiappe et al. have recently described
the preparation of a series of task-specific ILs based on
glycerylimidazolium cations (C and D in Fig. 2) by reaction
of 1-chloropropanediol, a compound readily obtainable from
glycerol,29 with the appropriate imidazolic base and subsequent
alkylation of the resulting 3-(1H-imidazol-1-yl)propane-1,2-
Scheme 3 Synthesis of glycerol formal and solketal. diol with chloroalkanes, bromoalkanes or alkyl mesylates.30
View Online
Scheme 5 Nucleophilic substitution and reduction reactions in

glycerol.
Fig. 2 Structure of some glycerol-based ionic liquids. and the reduction of benzaldehyde with sodium borohydride, in
this ‘‘green’’ medium (Scheme 5).38 Reactions performed at 80 1C

Alternatively, some (glycerol)borate-based ILs E have also been with stoichiometric amounts of KSCN and NaBH4 delivered the
prepared by neutralization of bis(glycerol)boric acid, generated desired benzyl thiocyanate and alcohol, respectively, in excellent
by treatment of boric acid with glycerol in refluxing toluene, with yields and short times. Further studies by the same group showed
alkali hydroxides.31 All these species are potential solvents for that other carbonyl compounds (aldehydes, ketones and
developing selective synthetic organic reactions. b-ketoesters) can be selectively reduced in glycerol with NaBH4.39
On the other hand, the so-called deep eutectic solvents (DESs) In general, reactions proceeded efficiently at room temperature
are eutectic mixtures of a solid ammonium salt and a hydrogen- with one equivalent of NaBH4, affording the final alcohols in
bond donor which, like the more classical ILs, often have melting good yields after quenching the reaction mixtures with diluted
points below room temperature, low vapor pressure, high acid and extraction with diethyl ether. Interestingly, almost
thermal stability and are usually water-miscible.32 DESs are quantitative conversion of ethyl acetoacetate into ethyl
readily prepared from low-cost starting materials, typically by 3-hydroxybutyrate could be reached using only 0.25 equiv. of
mixing choline chloride (ChCl) or ethylammonium chloride with NaBH4, i.e. the stoichiometrically correct amount of reductant
an organic hydrogen-bond donor such as acetamide, urea, based on hydride. Note that these atom-economical conditions
malonic acid, etc. Compared to ILs, DESs have the advantage are rarely found in the literature.
of being in general non-toxic and biodegradable. In addition, the As a solvent, glycerol also allowed the reduction of
solvent properties of these eutectic mixtures, in which both benzaldehyde to toluene with hydrazine under basic conditions,
anions and cations as well as neutral molecules are present, differ via the Wolff–Kishner reaction.39 Taking advantage of the
considerably from those of ILs since, in addition to the electro- high dielectric constant and boiling point of glycerol, the
static solvation, substrates can also establish a hydrogen-bond process was conveniently performed using microwave irradiation
network with the solvent.33 Glycerol is known to form eutectic heating (Scheme 6).
mixtures with quaternary ammonium salts, a property that has After these pioneering works, many other useful synthetic
been exploited for the purification of biodiesel.34 Quite recently, protocols in glycerol have been developed. Thus, Gu and Jérôme
the physical properties of DESs resulting from mixing choline have demonstrated that glycerol is an efficient promoting
chloride with glycerol have been quantified and it was shown that medium for the catalyst-free aza-Michael addition of amines to
they can circumvent some of the difficulties of using glycerol as a a,b-unsaturated carbonyl compounds and nitriles (Scheme 7).40
solvent.35 Thus, by adding ChCl to glycerol there is a marked Reactions performed at 80–100 1C afforded the corresponding
reduction in the viscosity (from 1200 to 400 cP by adding mono-adducts 1–2 in good yields after extraction of the crude
30 mol% of ChCl) and density (from 1.26 to 1.18 g cm3 by mixtures with ethyl acetate, and subsequent chromatographic
adding 30 mol% of ChCl). This is due to the 3D intermolecular work-up. In addition, the recovered glycerol phase could be
H-bond interactions in glycerol that are broken up on addition reused, with the yields obtained after three consecutive runs being
of ChCl, resulting in a less ordered system. Several polarity comparable to those reached in fresh glycerol.
parameters (ENT, a, b and p*)36 were also measured, the data Remarkably, classical organic solvents, such as toluene,
obtained suggesting that the relative polarity of these systems is DMF, DMSO or 1,2-dichloroethane, were completely ineffective
similar to the classical imidazolium-based ILs. for these reactions, and only trace amounts of 1–2 were
Although the ability of DESs to serve as solvents in the field
of synthetic organic chemistry has not been adequately
explored,37 as the reader will see below, glycerol eutectics have
already found some applications in biocatalysis.
Organic synthesis without transition metals

First examples demonstrating the utility of glycerol as solvent
for synthetic organic chemistry were described by Wolfson and
co-workers, who successfully accomplished the nucleophilic
substitution of benzyl chloride with potassium thiocyanate, Scheme 6 Wolff–Kishner reduction of benzaldehyde in glycerol.
View Online
Scheme 9 Base-catalyzed aldol condensation of n-valeraldehyde.

Scheme 10 Addition of thiophenol to citral in glycerol.

Scheme 7 Catalyst-free aza-Michael reactions in glycerol.
successfully employed by Wolfson’s group as a green solvent
formed in water or under solvent-free conditions. A similar in the KOH-catalyzed aldol condensation of n-valeraldehyde
trend was also observed when studying the Michael addition (Scheme 9). However, for this particular reaction lower
of indoles to b-nitrostyrene and 3-buten-2-one, in which only conversions compared to that reached in pure glycerol were
the use of glycerol (or water) afforded the desired products 3–4 observed (31–43% vs. 52%).42
in good yields without the assistance of any Brønsted or Lewis Michael addition of thiophenol to citral 5 was also studied
acid catalyst (Scheme 8).40,41 in glycerol (Scheme 10).43 In the absence of any catalyst
Although reasons behind the promoting effect of glycerol in a mixture of two products, 6 and 7, resulting from the
these addition reactions are not entirely clear, it is suspected conjugated 1,4- or double 1,2-addition, respectively, of PhSH
that the strong hydrogen bond network of glycerol might be to the enal unit was obtained. However, the selectivity of the
responsible, similarly to the well-known accelerating effect process could be finely tuned by using an appropriate acid or
exerted by water in many organic reactions. However, at base catalyst. Thus, over basic KF/Al2O3, the reaction was
present it cannot be totally ruled out that the presence of oriented towards the formation of the 1,4-adduct 6, whereas
trace amounts of impurities (acidic or basic derivatives) can in the presence of H2SO4 the 1,2-addition product 7 was
act as a possible catalyst.14 exclusively generated. In the presence of KF/Al2O3, other
Importantly, the Michael-type addition reactions depicted aliphatic and aromatic thiols were selectively added to citral,
in Schemes 7 and 8 also proceeded efficiently in technical grade and related electron-poor alkenes, in glycerol. Note that
glycerol,40 which is much more appealing from the viewpoint the catalyst and solvent could be effectively recycled after
of Green Chemistry since purification of crude glycerol from extraction of the reaction products with diethyl ether.
biodiesel production is a costly and energy consuming Glycerol was also an excellent promoting medium for the
process.6 In this context, we must note that crude glycerol, ring-opening of styrene oxide with p-anisidine (Scheme 11).40
generated from various vegetable oil sources, was also In this case no catalysts were needed to reach a good selectivity.
Indeed, it was remarkably higher to that observed when the
reaction was performed in aqueous medium under identical
conditions (8/9 ratio = 93/7 vs. 76/24). Good results were also
observed in the acid-catalyzed dehydrative dimerization of
Scheme 8 Catalyst-free Friedel–Crafts alkylations of indoles in

glycerol. Scheme 11 Ring-opening of styrene oxide with p-anisidine.
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Scheme 12 Acid-catalyzed dehydrative dimerization of alcohol 10.

Scheme 14 Catalyst-free condensations of aldehydes with 1,3-cyclo-

hexanedione in glycerol.
Scheme 13 Catalyst-free synthesis of bis(indolyl)methanes in
glycerol.
alcohol 10, where only the use of glycerol led to the formation
of the desired product 11 (Scheme 12).40
In the context of a broad study, Gu and co-workers have
demonstrated that glycerol is an advantageous solvent for the
electrophilic activation of aldehydes.44 Thus, as shown in
Scheme 13, several bis(indolyl)methane derivatives 12 could
be efficiently synthesized by a thermal reaction between
2-methylindole and aldehydes, without using any acid catalyst.
Aromatic, heteroaromatic and aliphatic aldehydes, including
the acid-sensitive furfural and 4-dimethylaminobenzaldehyde,
were tolerated and the process could be satisfactorily extended
to other indole derivatives (1-methylindole, 2-phenylindole,
2-methyl-5-methoxyindole, 1-methyl-2-phenylindole or indole Scheme 15 Thioacetalization of carbonyl compounds in glycerol.
itself).45 The only limitation was found in the reactions with
ketones, which were completely inoperative in the process. For
comparative purposes, the suitability of other solvents, such as and general catalyst-free thioacetalization protocol has been
toluene, DMF, DMSO, n-butyl acetate, n-butanol, ethylene recently described using glycerol as solvent.47 Thus, as
glycol, polyethylene glycol (PEG-400) and water, in these shown in Scheme 15, several aldehydes and ketones could be
catalyst-free coupling reactions was evaluated under the same successfully thioacetylated with benzenethiol or 1,2-ethanedithiol
experimental conditions. In all cases, the desired products just by heating in glycerol at 90 1C. The resulting thioacetals
were obtained either in a trace amount or in a significantly 15–16 were isolated in good yields after extraction of the crude
lower yield than in glycerol. Moreover, taking advantage of reaction mixtures with hexanes, and subsequent chromato-
the insolubility of bis(indolyl)methanes 12 in glycerol, at the graphic purification. In addition, glycerol could be reused
end of the reaction, they could be easily isolated by simple for further thioacetalizations maintaining its good level of
filtration. efficiency after four consecutive runs.
Glycerol also promoted the condensation of aromatic, Multicomponent reactions (MCRs), in which three or more
heteroaromatic and a,b-unsaturated aldehydes with 1,3-cyclo- reactants are combined in a single chemical step, comply with
hexanedione to generate selectively the corresponding most of the requirements for an ideal organic synthesis
xanthene-1,8(2H)-diones 13, or the isomeric 1-oxo-hexahydro- (structural complexity from readily available starting materials,
xanthenes 14 if salicylaldehydes are used as starting materials, atom economy, operational simplicity, resource effectivity,
reactions that are conventionally carried out using acid etc.).48 In this context, glycerol also proved to be a convenient
catalysts (Scheme 14).44 platform to perform this type of transformations. In particular,
Thioacetals are useful carbonyl protecting groups in organic many substrates, such as styrenes, primary amines,
synthesis due to their inherent stability towards ordinary acidic 2-naphthol, 4-hydroxy-6-methyl-2-pyrone and 4-hydroxy-1-
and basic conditions.46 As in the precedent transformations, methyl-2-quinolone, could be readily assembled with
thioacetalization reactions usually require the assistance of 1,3-cyclohexadiones and formaldehyde in glycerol, under
protic or Lewis acids. However, taking advantage of the catalyst-free conditions, to afford the elaborated polycyclic
activating effect of glycerol towards CQO bonds, an appealing compounds 17–21 in moderate to high yields (Scheme 16).49 In
View Online
Scheme 16 Multicomponent reactions of 1,3-cyclohexanediones and formaldehyde in glycerol.
these MCRs, glycerol not only showed a significant beneficial

effect on the reaction yields compared to more classical
organic solvents (toluene, nitromethane, DMF or DMSO)
and water, but also allowed easy separation of the products
17–21 by means of extraction with ethyl acetate.
The reaction of styrene with dimedone and paraformaldehyde
was studied in great detail and the positive effect of glycerol
could be attributed to two factors: (i) a restricted formation of
the oxo-diene intermediate 22 (Scheme 17), resulting from the
initial Knoevenagel condensation between dimedone and
formaldehyde, and (ii) the enhancing effect of glycerol on
the rate of the subsequent hetero-Diels–Alder reaction of 22
with styrene due to its polar character. In this sense, during the
reaction, the authors observed the formation of a thin shell,
mainly composed of the insoluble by-product 23 generated
at the beginning of the reaction, on the surface of solid Scheme 18 Four-component two-step sequential reactions in
paraformaldehyde (NMR analysis).49 This coating of glycerol.
paraformaldehyde by 23 in glycerol, not observed when water
and other organic compounds were used as solvents, inhibits The utility of glycerol in MCRs was further demonstrated in
its decomposition and controls the formation of the key the preparation of the polyheterocycles 25 through a one-pot
intermediate 22. Thus, 22 is formed gradually and it is two-step sequential coupling of phenylhydrazine, b-keto
immediately consumed in the Diels–Alder step without time esters, formaldehyde and styrenes (Scheme 18).50 In the first
to evolve into 23, the major reaction product observed using step a 1,3-disubstituted 5-pyrazolone 24 is selectively formed
other solvents. by condensation between phenylhydrazine and the b-keto
ester. Subsequent addition of the styrene derivative and
paraformaldehyde to the reaction mixture generates 25
through a tandem Knoevenagel/hetero-Diels–Alder reaction.
A related sequential transformation involving the coupling
of phenylhydrazine, a b-keto ester, formaldehyde and 1-ethyl-
2-phenylindole in glycerol has also been described, the process
allowing the preparation of the highly functionalized indole
derivative 26 in 42% yield (Scheme 19).50
Using the aminopolysaccharide 27 as a surfactant-combined
basic catalyst, chemoselective ring-opening of epoxides with
carboxylic acids to afford the corresponding esters 28 could be
achieved in glycerol (Scheme 20).51 Remarkably, the use of
conventional basic catalysts, such as ZnO, K2CO3 or secondary
Scheme 17 Reaction pathway involved in the formation of 17. amines, resulted in lower reaction rates and selectivities since
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Fig. 3 PPI dendrimer used in the catalytic ring-opening of epoxides.

Scheme 19 Synthesis of the functionalized indole 26.
Scheme 21 Hydrothiolation of 1,3-butadiynes in PEG-400 and

glycerol.
A green and general protocol for the synthesis of thio-

butenynes 30 in glycerol, through the heterogeneous
KF/Al2O3-catalyzed hydrothiolation of disubstituted 1,3-
butadiynes, was developed by Perin and co-workers
Scheme 20 Catalytic ring-opening of epoxides with carboxylic acids. (Scheme 21).53 However, we must note that, for this particular
transformation, the use of polyethylene glycol (PEG-400)
formation of ethers, derived from the ring-opening of the resulted more advantageous since higher yields at lower
epoxides with glycerol, as by-products was observed. Apparently, temperatures (60 vs. 90 1C) were in general reached. Formation
the aminopolysaccharide 27 favours a better diffusion of the of Z-isomers was preferential in both media and the solvent/
organic reactants in glycerol, limiting also the reactivity of this catalyst systems could be reused up to three times with
polyol. In addition, the emulsions formed in glycerol were comparable activities and Z-selectivities.
found to be unstable. Thus, after centrifugation, the reaction PEG-400 and glycerol were similarly employed as recyclable
media rapidly became biphasic, which allowed easy separation solvents for hydrochalcogenation reactions of phenylacetylene
of the reaction products without assistance of any organic (Scheme 22).54 The nucleophilic species of selenium and tellurium
solvent. This particular property of glycerol also enabled the were in this case generated in situ from the corresponding
homogeneous catalyst 27 to be recycled up to ten times without diphenyl dichalcogenide and NaBH4 at 60 1C. Interestingly,
any change in activity or selectivity. The versatility of the while the reactions conducted in PEG-400 afforded selectively
aminopolysaccharide 27 as catalyst was further demonstrated the corresponding (Z)-b-phenylchalcostyrenes 31, the formation
by conducting successfully other classical base-catalyzed reactions of a mixture of the E and Z isomers of the dichalcogenated
in glycerol, such as the Knoevenagel condensation of benzal-
dehyde with malononitrile, the Henry condensation of
benzaldehyde with nitroethane or the Michael addition of
nitroethane to 2-cyclohexen-1-one.51
Selective ring-opening reactions of epoxides with carboxylic
acids were also performed in glycerol using poly(propylene)-
imine (PPI) dendrimers, decorated on the surface with glyceryl
moieties, as basic catalysts (as a representative example the 2nd
generation of these functionalized PPI dendrimers 29 is given in
Fig. 3).52 Owing to the presence of glyceryl units surrounding the
PPI core, the dendritic catalysts were successfully immobilized in
glycerol, which also facilitated the separation of the products 28
and a convenient dendrimer-recycling. Scheme 22 Hydrochalcogenation reactions of phenylacetylene.
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Scheme 23 Synthesis of loperamide and pimozide in glycerol formal.

Scheme 24 Epoxidation of cyclooctene in glycerol-derived solvents.
alkenes 32 was observed when glycerol was used as solvent. It is also important to note that recycling of the catalytically
The lower solubility of the starting materials in glycerol vs. active phase, i.e. fluorinated solvent + selenium catalyst, was
PEG-400 was evoked to explain the different reactivities possible through distillation of the cyclohexene oxide from the
observed. reaction mixture.
Recent years have also seen the use of different glycerol Ionic liquids (ILs) are widely used in carbohydrate
derivatives as green solvents in synthetic organic chemistry. In chemistry owing to their unique ability to dissolve a large
this context, improved processes for the preparation of the number of mono-, oligo- and polysaccharides.58 In this
antidiarrhetic and antipsychotic drugs loperamide 33 and context, their use as solvents for the acid-catalyzed dehydration
pimozide 34, respectively, have been patented using glycerol of fructose 36 to 5-hydroxymethylfurfural 37 (HMF), a useful
formal (Scheme 23).55 This inert solvent conveniently replaces synthetic intermediate in the preparation of a wide range of
the methyl isobutyl ketone employed in the most classical fine chemicals, has been extensively investigated in recent
preparations. In addition, glycerol formal exhibits a superior years.59 However, the high prices and toxicity of ILs are major
technical performance than methyl isobutyl ketone as obstacles to the practical application of these methodologies at
evidenced by the lower equivalents of base required (1.1 vs. the productive scale. As a possible solution, Jérôme and
1.6–2.6 equiv. of Na2CO3), the reduced temperature regime co-workers have demonstrated that ILs can be partially
(60–90 vs. 120 1C), the shorter reaction times (2–7 vs. 15–65 h), substituted by inexpensive and safe glycerol carbonate.60
and the possibility of carrying out an aqueous work-up, thus Thus, as shown in Table 2, using the acidic ion-exchange resin
simplifying the isolation and purification of the products. Amberlyst 70 as a catalyst, up to 80 wt% of 1-butyl-3-methyl
Within a broad comparative study, a family of 13 common imidazolium chloride ([BMIM]Cl) could be replaced by
solvents and 18 glycerol-based ethers (1,3-dialkoxy-2-propanols glycerol carbonate without a dramatic effect on the HMF
and 1,2,3-trialkoxypropanes) were evaluated as suitable reaction yield (entries 1–4). The glycerol carbonate content could be
media for cyclooctene epoxidation with H2O2 using bis[3,5- further increased from 80 to 90 wt% working under biphasic
bis(trifluoromethyl)phenyl]diselenide 35 (1 mol%) as a cata- (entry 6 vs. 5) or more diluted conditions (entry 7 vs. 5), the use
lyst (Scheme 24).56 Although the best results were achieved in of a biphasic media ([BMIM]Cl/glycerol acetate–methyl
2,2,2-trifluoroethanol (TOF = 491 h1), the use of some isobutyl ketone) allowing also the effective separation of 37
glycerol-based ethers bearing fluorinated alkyl chains also since it selectively dissolves in the methyl isobutyl ketone
allowed fast conversions (TOF = 130–214 h1). Indeed, phase. Similar studies were also performed with pure and
some of them performed better than dichloromethane crude glycerol instead of glycerol carbonate.60 However, in
(TOF = 153 h1), which is one of the most commonly used these cases only 35 wt% of [BMIM]Cl could be effectively
solvents in these epoxidation reactions. As in the case of 2,2,2- replaced since side reactions between glycerol and 37 occur at
trifluoroethanol, the activating properties towards H2O2 via higher glycerol contents.
hydrogen bonding have been evoked to explain the beneficial Using Amberlyst 70 as catalyst, direct production of HMF
effect of these new reaction media. The range of applicability 37 in a [BMIM]Cl/glycerol carbonate mixture (10 : 90 wt%)
of this catalytic transformation was successfully extended to could be achieved starting from inulin 38, a natural poly-
the epoxidation of the more challenging olefin cyclohexene.57 saccharide extracted from chicory or dahlia tubers (Scheme 25).60
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Table 2 Acid-catalyzed dehydration of fructose in [BMIM]Cl/glycerol this transesterification process with MW heating (a 100-fold
carbonate mixturesa increase in the reaction rate was observed).
Transition-metal catalyzed reactions

Early attempts to use glycerol as solvent for metal-catalyzed
reactions were reported in 1968 by Tarama and Funabiki,
Entry [BMIM]Cl/glycerol carbonate (wt% ratio) t/min Yield (%) who studied the partial reduction of butadiene into butene
in a glycerol/methanol solvent mixture (1 : 1 v/v).62
1 100 : 0 15 95
2 65 : 35 35 98 Unfortunately, the hydrogenation process, performed at
3 50 : 50 30 91 20 1C and promoted by pentacyanocobaltate(II) generated
4 20 : 80 25 75 in situ from CoCl2 and an excess of KCN, proceeded with
5 10 : 90 20 60
lower rates and selectivities than in H2O. Thus, while 1-butene
6b 10 : 90 30 70
7c 10 : 90 40 72 was almost the only isomer generated in water, an approxi-
8 0 : 100 20 10 mately 50/40/10 ratio of 1-butene/cis-2-butene/trans-2-butene
a
Reactions performed at 110 1C using 1 g of fructose, 2.5 g of the was obtained in glycerol/MeOH.
[BMIM]Cl/glycerol carbonate mixture and Amberlyst 70 (0.1 equiv. Despite this early interest, glycerol has only been recognized
H+). b Reaction performed in the presence of methyl isobutyl ketone. as a useful solvent for catalysis in very recent years. In this
c
Reaction performed starting from 0.5 g of fructose dissolved in 2.5 g sense, works by Wolfson and co-workers in 2007 demon-
of the [BMIM]Cl/glycerol carbonate mixture. strated that glycerol is a suitable medium for Heck-type C–C
couplings.38,63 In particular, using the cross-coupling between
iodobenzene and n-butyl acrylate as model reaction, they
evaluated the catalytic activities of several palladium species
in pure glycerol (Scheme 27). Best results were obtained
using PdCl2, Pd(OAc)2 and [Pd(OAc)2(TPPTS)2] (TPPTS =
tris(3-sulfophenyl)phosphine trisodium salt), associated with
Na2CO3, which led to the selective formation of n-butyl
cinnamate 41a in 32–100% yield after 4 h at 80 1C. Worthy
of note, this chemical transformation could be considerably
accelerated under microwave irradiation. Thus, using a
domestic MW oven with a temperature rise from 26 to
117 1C, [Pd(OAc)2(TPPTS)2] as a catalyst and Na2CO3 as a
base, 41a could be generated in 93% yield after only 10 min of
irradiation.
Scheme 25 Acid-catalyzed production of HMF from inulin. The Heck coupling of iodobenzene was also operative with
i-butyl acrylate and styrene, furnishing i-butyl cinnamate 41b
As proposed by the authors, the residual water contained in the and stilbene 41c, respectively, in high yields. Alternatively,
acidic resin (54–59 wt%) is able to promote the initial hydrolysis bromobenzene could also be employed as starting material,
of 38 to fructose 36, which subsequently undergoes the acid- although in this case, as usually observed in Heck reactions,
catalyzed dehydration reaction. the efficiency of the process was significantly reduced.63
Finally, an efficient and green synthesis of isoamyl acetate Interestingly, these catalytic reactions were compatible with
40, an industrially relevant food additive because of its the use of crude glycerol as solvent, albeit slightly lower
characteristic banana flavor, has been described by trans- conversions than in pure glycerol were in general reached.42
esterification of isoamyl alcohol 39 employing Amberlyst 36 This decrease in activity has been attributed to the presence of
as a catalyst, and triacetin (glycerol triacetate) as both an acyl fatty acid salts in the solvent, impurities presumably able to
donor and a solvent (Scheme 26).61 The use of triacetin deactivate the catalytically active species. However, it is
enabled easy isolation of the product by simple extraction important to note that, when crude glycerol was used as
with petroleum ether, as well as separation and recycling of the solvent, addition of a base was not required since basic
heterogeneous catalyst by filtration. Experiments conducted in residues present in the solvent are sufficient to generate the
a domestic microwave oven also revealed the compatibility of catalytically active Pd(0) species.
Scheme 26 Transesterification of isoamyl alcohol in triacetin. Scheme 27 Heck-type reactions performed in glycerol.
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Related cross-coupling reactions between ethyl acrylate and

iodobenzene have also been investigated by Bellina and
co-workers employing the glycerol-based ionic liquids C as
solvents (Fig. 2).30 Reactions performed at 100 1C in the
presence of 5 mol% of PdCl2 and NaOAc (1.1 equiv.)
delivered the desired ethyl cinnamate in variable yields after
1 h (3–87%). In general, better results were obtained on
increasing the length of the alkyl chain in the cation, that is,
on increasing the lipophilicity of the solvent. Unfortunately,
reuse of these IL systems was not very encouraging due to the
considerable loss of activity after the first recycling. Scheme 29 Unsymmetrical b,b-diarylations of acrylates in glycerol.
In contrast to classical monoarylation processes, which have
found widespread applications in organic synthesis, efficient
b,b-diarylations of alkenes remain scarce.64 Such a double

C–C couplings are generally favoured at high temperatures,
hence glycerol can be particularly adequate for such trans-
formations. Accordingly, Jérôme and co-workers have

recently reported the high yield synthesis of a variety of
diaryl alkenes 43 through the diarylation of acrylates with
iodoarenes in this medium (Scheme 28).65 Reactions promoted
by palladium nanoparticles stabilized over the aminopoly- Scheme 30 Biphenyl synthesis through Suzuki coupling in glycerol.
saccharide 27 (see Scheme 20) and triethylamine were carried
out in the presence of 3 equivalents of the corresponding aryl (up to three consecutive runs without loss of activity) was
iodides at 120 1C for 30 h. Interestingly, under these experi- provided by [PdCl2(dppf)] (dppf = 1,1 0 -bis(diphenyl-
mental conditions no monoarylated derivatives were detected phosphino)ferrocene).
in the crude reaction mixtures, although small amounts Olefin metathesis is one of the most powerful tools presently
(o10%) of biphenyls, typical homo-coupling side-products available to generate new C–C bonds,67 with recent efforts in
in Heck-type reactions, were produced. It is also noteworthy this area being focused on the development of environmentally
that diaryl alkenes 43 showed a good stability in glycerol, friendly procedures to perform this type of transformations.
which contrasts favorably with their behavior in aqueous In this context, a wide variety of elaborated water-soluble
media, where the ester moieties are prone to undergo partial metal-catalysts have been designed to realize these processes in
hydrolysis making difficult their isolation in good yields.66 aqueous media.68 The higher capacity offered by glycerol to
The catalytic system Pd/27 is also suitable for performing dissolve transition-metal complexes has been recently
the selective monoarylation of acrylates, just by decreasing the exploited by Colacino and co-workers to develop ring closing
quantity of aryl iodide (1 vs. 3 equiv.) and the temperature metathesis (RCM) reactions in this green medium using
(90 vs. 120 1C) employed. Taking advantage of this behavior, a classical ruthenium-carbenes.69 In particular, they explored
convenient synthetic route to unsymmetrical diarylated the efficiency of the first and second generations of Grubbs
alkenes 44 could be developed through the sequential Heck (45a–b), Hoveyda–Grubbs (46a–b) and Zhan (47a–b) catalysts
couplings of acrylates, first with iodobenzene at 90 1C, and in the RCM of N,N-diallyltosylamine 48 (Scheme 31).
then with 2-iodonaphthalene at 120 1C (Scheme 29).65 By performing the reactions at 40 1C under MW-irradiation
Concerning the isolation of the products, the best results were with a ruthenium loading of 5 mol%, all the catalysts
achieved by extracting 43–44 from the glycerolic medium with checked proved to be active, with the most soluble one 47b
scCO2, since the use of classical organic solvents led to showing the best performance (complete conversion after
concomitant extraction of the Pd/AP catalyst.
The feasibility of Suzuki-type processes in glycerol has also
been demonstrated using the coupling between iodobenzene
and phenyl boronic acid as model reaction (Scheme 30).63 The
behavior of different palladium catalysts was evaluated in this
transformation, finding that Pd(OAc)2 and [Pd(OAc)2(TPPTS)2]
presented the highest activities, whereas the best recyclability
Scheme 28 b,b-diarylation of acrylate derivatives in glycerol. Scheme 31 Catalytic RCM of N,N-diallyltosylamine in glycerol.
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Scheme 32 Pd-catalyzed telomerization of butadiene with CO2.
30 min of irradiation). The low solubility of N-tosyl-2,5-

dihydro-1H-pyrrole 49 in glycerol allowed its isolation by Scheme 33 Co(II)-catalyzed enantioselective CQC reduction by
simple extraction with diethyl ether. In addition, after lyophi- NaBH4.
lization to remove traces of water and Et2O, the glycerolic
phase containing the Ru catalyst could be reused in two reduction of (E)-ethyl-3-phenylbut-2-enoate into (R)-ethyl-3-
further catalytic cycles without a significant loss of activity. phenylbutanoate 52 by NaBH4, using chiral azabis(oxazoline)
The potential of glycerol carbonate esters 50 to act as ligands 53–54 and a mixture of the glycerol-based
solvents for catalytic C–C bond forming reactions was ether BTFEP (1,3-bis(2,2,2-trifluoroethoxy)propan-2-ol) and
evaluated in the Pd-catalyzed telomerization of butadiene with ethanol as solvent (Scheme 33).72 When compared with its
carbon dioxide to form the d-lactone 51 (Scheme 32).26 homologue 53, ligand 54 conferred a higher stability to the
Control on the selectivity of this reaction towards 51, a resulting catalytic system, thus leading to a better conversion,
valuable intermediate in organic synthesis,70 is a challenging selectivity and recyclability. Interestingly, the catalytic
task since several side reactions can occur, i.e. dimerization performances of these cobalt(II)/azabis(oxazoline) systems in
and oligomerization of butadiene, formation of acyclic BTFEP/EtOH surpassed by far those achieved using the ionic
acids and esters, etc. In this sense, although somewhat worse liquid [BMIM][PF6] as solvent.
yields and selectivities were observed using carbonate esters 50 In the last few decades, metal-catalyzed transfer hydrogenation
when compared with results obtained in lighter carbonates (TH) reactions from 2-propanol to unsaturated compounds
(ethylene-, propylene- and butylene-carbonate), only the use have emerged as an efficient reduction method of organic
of these high-boiling point solvents allowed total separation of substrates such as ketones, aldehydes, imines and olefins.73
the product by distillation in a semi-technical scale, and the Like 2-propanol, glycerol can also act as a solvent and
reuse of the catalytic system. hydrogen donor in TH reactions. Interest in TH processes
In addition to the early attempts made by Tarama and from glycerol relates also with the concomitant formation of
Funabiki to perform hydrogenations in a glycerolic medium,62 dihydroxyacetone (DHA), the expected oxidized form of
Wolfson and co-workers also investigated the hydrogenation glycerol,74 due to the industrial relevance of this chemical.75
of styrene into ethylbenzene in neat glycerol using The first report on TH in glycerol, published by Crotti and
[RhCl(TPPTS)3] or Pd/C as the catalyst (10 bar of H2, co-workers in 2009, examined the reduction of acetophenone
80 1C).38 Addition of Pluronic, a non-ionic surfactant, was by the iridium(I) derivatives [Ir(1,5-hexadiene)(N–N)][Cl]
necessary to compensate for the poor solubility of styrene in (N–N = 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4phen),
the medium, but even so the catalytic activities remained 4,7-dimethyl-1,10-phenanthroline (Me2phen), 4,4 0 -dimethyl-
moderate. The same authors equally explored the hydrogenation 2,2 0 -bipyridine (Me2bipy), 2,2 0 -bipyridine (bipy)).76
of carbonyl compounds in glycerol (10 bar of H2, 60 1C).39 The highest rate was achieved by employing [Ir(1,5-
Moderate yields on the reduced alcohols were reached with hexadiene)(Me2phen)][Cl] associated with K2CO3 at 100 1C,
Pd/C (52–60%), while molecular rhodium or ruthenium but conversion in 1-phenylethanol was quite modest (39%)
precursors appeared to be almost inactive. The poor catalytic (Scheme 34). In addition, authors observed the gradual
performances, inferior than those observed in methanol or decomposition of DHA, probably favoured by the presence
toluene, were ascribed to the low solubility of hydrogen gas in of a base and the high temperature employed. In order to
glycerol. Note that, the use of the chiral ruthenium catalyst minimize the DHA decomposition, Crotti and co-workers also
[RuCl(Z6-p-cymene){(S)-BINAP}][Cl] (BINAP = 2,2 0 - explored the ability of the iridium(I) complex 55 (Fig. 4),
bis(diphenylphosphino)-1,1 0 -binaphthyl) in the hydrogenation
of ethyl acetoacetate induced a high enantioselectivity (99%
ee, with (S)-ethyl-3-hydroxybutyrate as the major enantio-
mer), albeit with a very disappointing yield (7%).39 Despite
its limited potential, this reaction merits to be highlighted since
it stands as the first example of an asymmetric metal-catalyzed
process carried out in glycerolic media.71
More recently, high enantioselectivities, combined with
excellent yields, have been described for the Co(II)-catalyzed Scheme 34 Transfer hydrogenation of acetophenone in glycerol.
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and reagent. This coupling between an aldehyde (or a ketone)

and glycerol, promoted by Pd/C and camphorsulfonic acid
under H2 atmosphere, offers an easy entry to glycerol mono-
ethers 56–57.81 Interestingly, despite the similar pKa values of
the different hydroxyl groups in glycerol, 1-O-alkylation
Fig. 4 Structure of the iridium(I) complex 55. occurred preferentially, thus generating ethers 56 as the major
reaction products. This high selectivity is specific to glycerol
since related etherification reactions of 1,2-propanediol, a diol
previously described as an efficient catalyst for TH reactions with both primary and secondary hydroxyl functions, gave rise
under base-free conditions in isopropanolic media,77 to promote to 1 : 1 mixtures of the two possible regioisomers, i.e.
the reduction of acetophenone in glycerol.78 Unfortunately, 55 1-O-alkyl and 2-O-alkyl ethers. Concerning the mechanism
turned out to be almost inactive (yields o8%). In contrast, of these catalytic reactions, the authors demonstrated that
when benzaldehyde, a more reactive substrate, was used as 5- and 6-membered cyclic acetals are first formed from the
starting material it could be reduced to benzyl alcohol under starting aldehyde and glycerol, and then they are reduced with
these base-free conditions, albeit with moderate conversion hydrogen to generate the final acyclic ethers.
(up to 46%). Once again, despite the absence of a base, DHA Glycerol-based acetals and ketals are valuable chemical
still underwent degradation, with its final proportion being intermediates,82 and the development of efficient and selective
well below than that of benzyl alcohol (12–24% vs. 18–46%).78 routes of access is of particular interest. Glycerol acetalization
The hydrogen transfer from glycerol to benzaldehyde can be promoted by conventional acid catalysts, however such
was also explored using a catalytic system composed of the procedures are environmentally unfriendly due to extensive
ruthenium dimer [{RuCl(m-Cl)(Z6-p-cymene)}2] and KOH salt formation, and they suffer from a lack of selectivity
(1 mol% of Ru, 12 mol% of base).79 Both conventional towards the two possible regioisomers, i.e. the five-membered
heating (70 1C) and MW irradiation (domestic oven, 900 W) cyclic acetal (1,3-dioxolane 58) and the six-membered one
led to moderate yields in benzyl alcohol (33–45%), and (1,3-dioxane 59). In contrast, it has been recently demonstrated
complete transformation of benzaldehyde could only be that the iridium dimer [{Ir(m-Cl)Cl(Z5-C5Me5)}2] catalyzes the
achieved by increasing the ruthenium loading to 25 mol%.79a glycerol acetalization with acetone in good yield (75%) and
Reduction of olefins through TH processes in glycerol excellent selectivity (98%) towards the corresponding 1,3-
proved to be more satisfactory than reduction of carbonyl dioxolane 58 (Scheme 37).83 Comparable results were also
compounds. Thus, palladium supported on carbon (0.2–0.3 obtained with cyclohexanone, but the involvement of more
mol% Pd) was found to hydrogenate quantitatively cyclo- sterically hindered ketones resulted in a drop of the conversion
hexene or styrene after 5–9 hours of heating at 70 1C in pure (only 14% for R1 = R2 = iPr). The acetalization with
glycerol (Scheme 35).79a However, we must note that bulky acetophenone, an unsymmetrical ketone, exhibited once again
olefins (i.e. stilbene and 1,1-diphenyl ethylene) and linear a good regioselectivity (96% of 58), but a total lack of
aliphatic alkenes (i.e. 1-hexene and 1-octene) were only diastereoselectivity (cis/trans ratio = 1 : 1). As expected,
partially reduced through this methodology (7–35% yields).80 aldehydes showed higher reactivity than ketones (yields up
The reductive etherification of glycerol with carbonyl to 87%), albeit with a slightly lower regioselectivity (78–82%).
compounds depicted in Scheme 36 is another example of a Cycloisomerization of (Z)-enynols represents an appealing
catalytic process in which the glycerol acts both as a solvent route for the construction of furan rings due to its atom-
economical nature.84 However, despite its synthetic interest,
efforts devoted to develop this process in a green media have
been scarce.85 Recently, the heteroannulation of (Z)-2-en-4-
yn-1-ol derivatives 60 into furans 61 has been conveniently
performed in glycerol using the hydrophilic palladium(II)
catalyst cis-[PdCl2(DAPTA)2] (Scheme 38).86 Although
slightly higher activities were observed in aqueous medium,
catalyst recycling after extraction of the product with diethyl
Scheme 35 Pd-catalyzed transfer hydrogenation of olefins in glycerol. ether was much more effective in glycerol. Thus, while the
Scheme 37 Ir-catalyzed glycerol acetalization with carbonyl

Scheme 36 Reductive etherification of glycerol. compounds.
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Scheme 38 Palladium-catalyzed cycloisomerization of (Z)-enynols.

Scheme 41 Hantzsch synthesis of pyridines in glycerol.
presence of 5 mol% of CuI and zinc dust, and were operative

with several diaryl diselenides and a variety of substituted
aromatic vinyl bromides, with cis- or trans-disposition on the

CQC bond. Interestingly, the stereochemistry of the starting
products was mainly retained in the final vinyl selenides 66.
Following a similar methodology, phenyl styryl telluride has

been synthesized from diphenyl ditelluride. We note also that
the catalytic system could be recovered, after extraction of the
products with ethyl acetate, and reused 4 times with only a
Scheme 39 Ru-catalyzed isomerization of estragole into anethole. slight decrease in the activity.
In recent years, considerable attention has been paid to the
synthesis of 1,4-dihydropyridines owing to their significant
performances of the aqueous solution decreased rapidly, biological activities.89 One of the most reliable methodologies
allowing only five consecutive runs, the catalytic behavior of is the Hantzsch reaction, a one-pot three-component process,
the glycerolic phase was maintained during 17 runs, leading to which involves the coupling between an aldehyde, two
cumulative TON values up to 8190, which are the highest equivalents of a b-ketoester and an ammonium salt. In this
reported up to date for this catalytic transformation. context, Narsaiah and Nagaiah have recently developed a
trans-Anethole 63 is a relevant compound with important procedure to prepare Hantzsch pyridines in glycerol.90 Thus,
applications in the cosmetic industries and as a food and as shown in Scheme 41, using 10 mol% of CeCl3 as a catalyst,
beverage additive. According to current food regulatory a variety of electron-rich or electron deficient aromatic-,
instructions, the cis-anethole content is limited to 1% for heteroaromatic- or aliphatic-aldehydes were efficiently
human uses due to its toxicity and organoleptic properties. transformed into 1,4-dihydropyridines 67 by coupling with
Hence, the search for highly trans-selective formation of ethyl acetoacetate and ammonium acetate.
anethole represents a challenge for synthetic chemists. In this
context, a green protocol based on the isomerization of
Biocatalysis
estragole 62 into anethole has been designed in glycerolic
media employing different ruthenium(IV) catalysts Biocatalysis plays an important role within the Green
(Scheme 39).87 Best results were accomplished with the dimeric Chemistry context, since it usually provides highly chemo- regio-
precursor 64 and the mononuclear derivative 65 in glycerol/ and stereoselective synthetic routes under mild conditions.91
EtOH or glycerol/MeOH mixtures which allowed full Although the natural solvent for enzymes is water, the hydro-
conversions in short times and, most importantly, with high phobic character of most of the organic compounds has made
trans-selectivities (99%). Similar results were also obtained using almost mandatory the use of partly or fully nonaqueous
water/MeOH or water/EtOH solvent systems, but catalyst environments. However, it is well-documented that enzymes
recycling was again more effective from the glycerolic mixtures. are denatured in the presence of organic solvents, and that the
Coupling reactions of vinyl bromides with diaryl diselenides specific catalytic activities of enzymes that are stable in organic
have also been studied using glycerol as the reaction medium media are generally lower than those in aqueous systems.92 In
(Scheme 40).88 Seleniations proceeded efficiently in the this sense, the ability of glycerol to mimic the effect of
water preserving enzyme structure,92 makes this solvent an
appropriate candidate for biocatalysis.
In 2006, Wolfson and co-workers reported the first
biocatalytic transformation in pure glycerol, accomplishing
successfully the asymmetric reduction of methyl acetoacetate
with both free (FBY) and immobilized (IBY; alginate beads)
baker’s yeast.93 As illustrated in Table 3, IBY showed a higher
catalytic activity than FBY, while the enantioselectivity of the
product, (S)-methyl 3-hydroxybutyrate, was very high
Scheme 40 Copper(I)-catalyzed seleniation of vinyl bromides in (>95% ee) with both catalysts (entry 1). The higher performance
glycerol. of IBY was attributed to the presence of residual water, which
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Table 3 Enantioselective reduction of methyl acetoacetate with Studies by Andrade and co-workers have also demonstrated
baker’s yeast in glycerola the utility of glycerol as co-solvent for biocatalytic trans-
formations in aqueous solution. Thus, in the enantioselective
bioreduction of 2 0 -chloroacetophenone by cells of Aspergillus
terreus in phosphate buffer solution (pH 7), they observed
remarkable yield and enantioselectivity improvements by
Entry Additive FBY (%) ee (%) IBY (%) ee (%)
adding variable amounts of glycerol (entries 2 and 3 vs. 1 in
1 None 61 >99 (S) 87 >99 (S) Table 4).95 As shown in Table 4, such improvements were in
2 Waterb 73 97 (S) 94 97 (S)
3 Glucose 71 >99 (S) 96 >99 (S) general not observed using other water–organic solvent
4 Sucrose 75 >99 (S) 99 >99 (S) mixtures (entries 4–13). Three factors have been evoked to
5 Ethanol 67 95 (S) 90 >99 (S) explain the beneficial effect of glycerol in this reaction: (i) it
a
Reactions performed at 37 1C for 96 h using 1 g of substrate, 50 mL improves the solubility of the substrate, (ii) unlike the other
of glycerol, 10 g of FBY or 50 g of IBY (generated from 10 g of FBY) organic solvents, it generates a homogeneous medium in
and 5 g of additive. b 5 wt%. combination with water that avoids mass transfer limitations
facilitating the enzyme–substrate interactions, and (iii) it
stabilizes the protein native structure and prevents its
remained inside the IBY beads during their preparation. In denaturation, thus preserving the enzymatic activity. We note
accord with this, the addition of 5 wt% of water to glycerol that similar positive results were obtained in the bioreduction
increased the activity without changing significantly the of other ortho-, meta- and para-substituted halo-acetophenones
enantioselectivity (entry 2 vs. 1). Addition of various hydrogen (F, Cl, Br).95 In addition, the synthetic utility of the process
sources, such as glucose (entry 3), sucrose (entry 4) or ethanol was confirmed by performing the catalytic reactions at a
(entry 5), equally increased the activity (up to 99% conversion), preparative scale, which delivered the desired optically active
while keeping the high enantioselectivity. Using IBY as the alcohols in high isolated yields (up to 80% with 95–99% ee).
catalyst and sucrose as the additive, good results were also The higher ability of glycerol vs. water to dissolve organic
obtained in the asymmetric reduction of ethyl acetoacetate, i.e. compounds has also been exploited to facilitate the hydrolytic
99% conversion after 48 h with >99% ee. However, we must kinetic resolution of racemic styrene oxide at high substrate
note that, under the same reaction conditions, the activity of concentrations.96 Thus, using the recombinant Pichia pastoris
IBY towards the aliphatic prochiral ketones 2-octanone and yeast which expresses the epoxide hydrolase gene of Rhodotorula
2-butanone was much lower (up to 22% conversion after 96 h glutinis as the biocatalyst, enantiopure (S)-styrene oxide (98% ee)
with >97% ee).93 could be obtained in 41% yield (maximum yield = 50%) from
Remarkably, although higher activities were observed when 1.8 M racemic styrene oxide, after 24 h at 4 1C, by adding 40%
these reduction reactions were performed in aqueous medium, (v/v) of the surfactant Tween 20 and 5% (v/v) of glycerol to the
the use of glycerol as solvent enabled a more efficient product KH2PO4 buffer (pH 8.0). Note that, in the absence of glycerol,
extraction, since glycerol does not form emulsions with the the recombinant cells only catalyzed the kinetic resolution
extracting solvent (ethyl acetate, diethyl ether, n-hexane and efficiently at concentrations below 1.3 M (0.526 M in the absence
dichloromethane were evaluated).93,94 of both Tween 20 and glycerol).
The utility of triacetin as green solvent and acyl donor for
Table 4 Influence of organic co-solvents in the asymmetric bioreduc- lipase-catalyzed kinetic resolution of racemates has also been
tion of 2 0 -chloroacetophenonea recently demonstrated by Dlugy and Wolfson.97 Thus, as
shown in Scheme 42, they successfully performed the kinetic
resolution of representative secondary alcohols and amines 68
in triacetin using Candida antarctica lipase B immobilized on
acrylic resin (iCAL-B). Full conversions (50%) and excellent
enantioselectivities (97–99% ee) were in all cases reached at
Entry Solvent Yield (%) ee (%) 80 1C employing an enzyme to substrate (E/S) ratio of
1 PBS 24 65 (S) 16.5 g mol1. In the course of the alcoholysis process, glycerol
2 PBS–glycerol (9 : 1) 49 92 (S)
3 PBS–glycerol (4 : 1) 44 >99 (S)
4 PBS–DMSO (9 : 1) 51 >99 (S)
5 PBS–DMSO (4 : 1) 10 >99 (S)
6 PBS–acetonitrile (9 : 1) 9 >99 (S)
7 PBS–acetonitrile (4 : 1) — —
8 PBS–toluene (9 : 1) 4 —
9 PBS–toluene (4 : 1) o1 —
10 PBS–diethyl ether (9 : 1) 4 —
11 PBS–diethyl ether (4 : 1) 3 —
12 PBS–THF (9 : 1) 2 —
13 PBS–THF (4 : 1) 2 —
a
Reactions performed at 32 1C for 48 h using 3.0 g of fungal cells,
20 mL of substrate and 50 mL of solvent. PBS = phosphate buffer
solution (Na2HPO4/KH2PO4; pH 7).
Scheme 42 Kinetic resolutions using triacetin and glycerol.
View Online
diacetate, glycerol monoacetate and glycerol are formed as

by-products. However, their high solubility in triacetin
allowed the easy separation of the desired alcohol (or amine)
and ester (or amide) enantiomers from the crude reaction
mixture by simple extraction with diethyl ether. In the same Scheme 43 StEH1-catalyzed hydrolysis of (1R,2R)-2-methylstyrene
work, efficient kinetic resolution of 2-heptyl acetate and oxide.
2-octyl acetate racemates 69 could also be achieved using
glycerol as the solvent and acyl-acceptor (Scheme 42).97 The (iCAL-B and CAL-B showed also a remarkable activity in
effective resolution of a racemic mixture of 2-pentyl acetate EAC:Gly; entry 8). Remarkably, contrary to the case of
with iCAL-B in glycerol was similarly achieved.38 ethylene glycol (entries 2 and 7), competence of glycerol with
Triacetin was also employed as solvent and acyl donor in 1-butanol in the transesterification process was not observed.
the transesterification of isoamyl alcohol 39 into isoamyl In addition, after incubation of iCAL-B in either toluene or
acetate 40 (see Scheme 26).98 Both free (CAL-B) and ChCl:Gly for 18 h at 60 1C, its activity dropped by 12% in
immobilized Candida antarctica lipase B (iCAL-B) were able toluene, compared to that observed before incubation, and
to promote efficiently the transesterification process, with the only by 5% in ChCl:Gly, thus demonstrating the higher
latter showing a higher efficiency (73% of conversion after 5 h long-term stability of the enzyme in this alternative reaction
at 80 1C). At the end of the reaction, 40 could be easily medium.100c iCAL-B-catalyzed aminolysis of ethyl valerate
separated from the reaction mixture by extraction with with 1-butylamine could also be conveniently performed in
petroleum ether, and the immobilized lipase was recovered ChCl:Gly with a rate and conversion similar again to that
by simple filtration and re-used three additional times without reached in toluene.100a,b
significant loss of its efficiency. The deep eutectic mixture ChCl:Gly can also be used as a
Deep eutectic solvents (DESs) have recently emerged as suitable co-solvent for biocatalytic transformations in aqueous
promising reaction media for biocatalysis.99 In this context, solution. In this sense, the rate of esterase-catalyzed hydrolysis
using the transesterification of ethyl valerate with 1-butanol as of p-nitrophenol acetate in BES buffer (N,N-bis(2-hydroxy-
model reaction, the activities of selected lipases in different ethyl)-2-aminoethanesulfonic acid and its sodium salt)
DESs based on choline chloride (ChCl) or ethylammonium increased moderately upon addition of 10 vol% of ChCl:Gly
chloride (EAC) mixtures with the organic hydrogen-bond (three-fold increase for pig liver esterase and Rhizopus oryzae
donors acetamide (Acet), urea (U), malonic acid (MA), esterase and a 25% increase for Pseudomonas fluorescens
ethylene glycol (EG) or glycerol (Gly) were evaluated by esterase), while an impressive 20-fold increase in conversion
Kazlauskas and co-workers.100 As shown in Table 5, all the was observed in the EHAD1-catalyzed hydrolysis of styrene
enzymes tested showed similar or higher activities to that oxide (EHAD1 = epoxide hydrolase AD1 from Agrobacterium
shown in toluene (entry 9) when the glycerol-based deep radiobacter).100 The effect of ChCl:Gly in the catalytic hydrolysis
eutectic mixture ChCl:Gly (entry 3) was used as solvent of (1S,2S)- and (1R,2R)-2-methylstyrene oxide was also
evaluated using the Solanum tuberosum epoxide hydrolase
1 (StEH1).101 In this case, enzyme function was not significantly
Table 5 Lipase-catalyzed transesterification of ethyl valerate with affected by the presence of the glycerol-based DES. However, it is
1-butanol in DESs and toluenea of note that it was able to enhance the regioselectivity of the
hydrolysis of the (1R,2R) enantiomer, favouring the epoxide ring
opening at the benzylic carbon, as compared to the phosphate
buffer-only system (70/71 ratio = 2.33 vs. 1.35; Scheme 43).
Unfortunately, no explanation was given for this solvent-effect
on the regioselectivity.
Entry Solvent iCAL-Bb CAL-Bb CAL-Ab,c PCLb,d
1 ChCl:Acet 23 96 0.5 0.0
2 ChCl:EG 11 (99) 32 (93) 3.0 0.2
Conclusions
3 ChCl:Gly 96 96 70 22
This Feature Article has outlined the utilization of glycerol and
4 ChCl:MA 30 58 0.7 0.0
5 ChCl:U 93 99 1.6 0.8 some of its derivatives as green reaction solvents for synthetic
6 EAC:Acet 63 92 2.7 0.0 organic chemistry, an emerging research field that has as main
7 EAC:EG 23 (54) 33 (79) 20 0.0 objective the valorization of a waste generated by the biodiesel
8 EAC:Gly 93 91 2.1 0.5
9 Toluene 92 92 76 5.0 industry. The current availability of glycerol on a large scale
a and at a low cost, combined with its intrinsic properties, i.e. no
Reactions performed at 60 1C for 24 h using 40 mM ethyl valerate,
400 mM 1-butanol and 10 mg cm3 of the corresponding enzyme.
toxicity, no flammability, obtaining from renewable sources
b
Percentage conversions of ethyl valerate to butyl valerate are given and biodegradability, makes it an ideal candidate to develop
(%). Number in parentheses is the percentage conversion including the greener synthetic processes. However, despite all these
side reaction with the ethylene glycol component of the deep eutectic considerations, problems associated with its high viscosity,
solvent. No side reactions were observed in the rest of the cases. which could provoke poor substrate diffusion in the medium,
c
CAL-A = lyophilized Candida antarctica lipase A. d PCL = and the presence of three reactive and metal-coordinating
lyophilized Pseudomonas cepacia lipase (recently reclassified as
hydroxyl groups should be taken into account prior to its
Burkholderia cepacia).
utilization as solvent for a particular reaction. Extraction of
View Online
highly polar reaction products from glycerol is also a problem G. C. Fontes and M. A. Z. Coelho, Food Bioprod. Process., 2009,
that needs to be solved prior to practical uses. 87, 179.
8 For recent reviews on this topic, see: (a) P. D. Vaidya and
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adjusted according to the requirements of each reaction by (b) S. Adhikari, S. D. Fernando and A. Haryanto, Energy
chemical modification of its structure, thus allowing to Convers. Manage., 2009, 50, 2600.
overcome some of the above-mentioned drawbacks. However, 9 For a recent review on this topic, see: N. Rahmat, A. Z. Abdullah
and A. R. Mohamed, Renewable Sustainable Energy Rev., 2010,
synthetic routes must be improved since most of the glycerol- 14, 987.
based solvents presently available are synthesized through 10 (a) P. T. Anastas, J. C. Warner, Green Chemistry Theory and
very costly processes. Practice, Oxford University Press, Oxford, 1998;
(b) A. S. Matlack, Introduction to Green Chemistry, Marcel
In summary, although much effort has to be made in the Dekker, New York, 2001; (c) Handbook of Green Chemistry and
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the numerous publications appeared in the last five years Publishing, Abingdon, 2002; (d) M. Lancaster, Green Chemistry:
reveal that this field is of major interest to the chemical An Introductory Text, RSC Editions, Cambridge, 2002;
(e) M. Poliakoff, J. M. Fitzpatrick, T. R. Farren and

community, and the authors hope that this comprehensive P. T. Anastas, Science, 2002, 297, 807.
account will stimulate further work. 11 Studies performed by GlaxoSmithKline workers suggest that
close attention to the effective use and reuse of solvents is likely
to result in the greatest improvements to making chemical

Acknowledgements processes ‘‘greener’’: A. D. Curzons, D. J. C. Constable,
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ChemComm Dynamic Article Links

Cite this: Chem. Commun., 2011, 47, 6208–6227

www.rsc.org/chemcomm FEATURE ARTICLE

Received 31st January 2011, Accepted 4th March 2011

Introduction of triglycerides with a short-chain aliphatic alcohol, typically

Alba E. Dı´az-Álvarez studied Javier Francos received his

prices, which has been accompanied by a growing imbalance

in the supply/demand of this chemical. The current inability of

This scenario could have negative implications on the

Pascale Crochet studied Victorio Cadierno studied

LC50 (rat-1 h) 570 mg m3

Glycerol Glycerol-based ethers, esters and carbonates

Scheme 4 Preparation and derivatization of glycerol carbonate.

The hydrogen bond ability (a = 0.81) of solketal is typical for

gradability and low toxicity.22 In this context, glycerol

results in signiﬁcant variations of polarity, viscosity, hydrogen

Scheme 5 Nucleophilic substitution and reduction reactions in

this ‘‘green’’ medium (Scheme 5).38 Reactions performed at 80 1C

Organic synthesis without transition metals

Scheme 9 Base-catalyzed aldol condensation of n-valeraldehyde.

Scheme 10 Addition of thiophenol to citral in glycerol.

Scheme 8 Catalyst-free Friedel–Crafts alkylations of indoles in

Scheme 12 Acid-catalyzed dehydrative dimerization of alcohol 10.

Scheme 14 Catalyst-free condensations of aldehydes with 1,3-cyclo-

Scheme 16 Multicomponent reactions of 1,3-cyclohexanediones and formaldehyde in glycerol.

these MCRs, glycerol not only showed a signiﬁcant beneﬁcial

Fig. 3 PPI dendrimer used in the catalytic ring-opening of epoxides.

Scheme 21 Hydrothiolation of 1,3-butadiynes in PEG-400 and

A green and general protocol for the synthesis of thio-

Scheme 23 Synthesis of loperamide and pimozide in glycerol formal.

Transition-metal catalyzed reactions

Related cross-coupling reactions between ethyl acrylate and

b,b-diarylations of alkenes remain scarce.64 Such a double

formations. Accordingly, Jérôme and co-workers have

Scheme 32 Pd-catalyzed telomerization of butadiene with CO2.

30 min of irradiation). The low solubility of N-tosyl-2,5-

and reagent. This coupling between an aldehyde (or a ketone)

Scheme 37 Ir-catalyzed glycerol acetalization with carbonyl

Scheme 38 Palladium-catalyzed cycloisomerization of (Z)-enynols.

presence of 5 mol% of CuI and zinc dust, and were operative

aromatic vinyl bromides, with cis- or trans-disposition on the

Following a similar methodology, phenyl styryl telluride has

diacetate, glycerol monoacetate and glycerol are formed as

(e) M. Poliakoﬀ, J. M. Fitzpatrick, T. R. Farren and

to result in the greatest improvements to making chemical

Springer, Dordrecht, 2005. 2011, 52, 133.

2010, 3, 70. 94 The baker’s yeast catalyzed asymmetric reduction of methyl

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