Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on catalytic effects

Article abstract of DOI:10.1016/j.catcom.2014.12.014

Catalysis in aqueous systems under sonochemical conditions has become an irreplaceable method in green synthetic chemistry after more than two decades of studies in this domain. The present review has the aim of describing the state-of-the-art with a comprehensive view of advantages and limitations as well as new potential applications. Catalytic procedures in water assisted by ultrasound and/or hydrodynamic cavitation are environmentally friendly with milder conditions, shorter reaction times and higher yields. Sonochemical processes can reduce the formation of hazardous by-products, the generation of waste and also produce energy savings. Cavitational implosion generates mechanical and chemical effects such as cleaning of catalyst surface and formation of free radicals by sonolysis of water. The present overview of sonochemical reactions in water (oxidation, bromination, aza-Michael, C-C couplings, MCR and aldol reactions) should provide useful models for furthering the progress of organic synthesis using harmless and greener sound energy.

Full text of DOI:10.1016/j.catcom.2014.12.014

CATCOM-04168; No of Pages 8
Catalysis Communications xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Organic reactions in water or biphasic aqueous systems under
sonochemical conditions. A review on catalytic effects
a
c
c
d
Giancarlo Cravotto a,b, , Emily Borretto , Manuela Oliverio , Antonio Procopio , Andrea Penoni
⁎
a
Dipartimento di Scienza e Tecnologia del Farmaco, University of Turin, via P. Giuria 9, 10125 Torino, Italy
NIS-Centre for Nanostructured Interfaces and Surfaces, University of Turin, via P. Giuria 9, 10125 Torino, Italy
Dipartimento di Scienze della Salute, Università Magna Graecia, Viale Europa, 88100 Germaneto (CZ), Italy
Dipartimento di Scienza e Alta Tecnologia, University of Insubria, Via Valleggio 11, 22100 Como, Italy
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Catalysis in aqueous systems under sonochemical conditions has become an irreplaceable method in green syn-
thetic chemistry after more than two decades of studies in this domain. The present review has the aim of de-
scribing the state-of-the-art with a comprehensive view of advantages and limitations as well as new potential
applications. Catalytic procedures in water assisted by ultrasound and/or hydrodynamic cavitation are environ-
mentally friendly with milder conditions, shorter reaction times and higher yields. Sonochemical processes can
reduce the formation of hazardous by-products, the generation of waste and also produce energy savings.
Cavitational implosion generates mechanical and chemical effects such as cleaning of catalyst surface and forma-
tion of free radicals by sonolysis of water. The present overview of sonochemical reactions in water (oxidation,
bromination, aza-Michael, C–C couplings, MCR and aldol reactions) should provide useful models for furthering
the progress of organic synthesis using harmless and greener sound energy.
Received 21 September 2014
Received in revised form 6 December 2014
Accepted 16 December 2014
Available online xxxx
Keywords:
Reactions in water
Aqueous biphasic systems
Heterogeneous catalysis
Ultrasound
Cavitation
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
US promotes reagent diffusion from solution to the metal, electron
transfer from the active surface to the reducible point of the organic
Ultrasound (US) and hydrodynamic cavitation (HC) have proven
themselves to be an important stepping stone towards process intensifi-
cation in organic synthesis, placing sonochemistry among the elite of
green chemical methods [1,2]. An acoustic pressure wave consists of alter-
nate compressions and rarefactions in the transmitting medium along the
wave propagation direction. When a large negative pressure is applied to
a liquid, intermolecular van der Waals forces are not strong enough to
maintain cohesion and small cavities or gas-filled microbubbles are
formed. The rapid nucleation, growth and collapse of these micrometer-
scale bubbles constitute the phenomenon of cavitation. Sonochemical ef-
fects mainly arise from acoustic cavitation which generates enough kinet-
ic energy to drive reactions to completion and releases short-lived, high-
energy chemical species into solution after the implosive collapse of bub-
bles. It is now well-established that this process is capable of providing
very high temperatures (4500–5000°K as typical figure) and very high
pressures (≈1000 atm) in extremely short times (in the range of micro-
seconds), thus rendering cavitation a quasi-adiabatic phenomenon [3]. US
is especially efficient in activating hard metal surfaces as the well-known
cleaning effect of ultrasonic waves provides a de-passivated layer where
catalyst and reagent better interact with each other [4].
substrate and finally, the extraction of ions from the surface to generate
a soluble product [5]. Acoustic waves and cavitation strongly promote
all these steps as observed in the formation of common organometallics
under sonication [6,7]. Fig. 1 schematize the most common ultrasonic
devices to work in batch with high-intensity US.
It is possible to empirically distinguish true chemical effects from
mechanical ones, especially in heterogeneous reactions. In modern
synthesis, so-called false sonochemistry is closely related to mechano-
chemistry and illustrates the advantages of using pressure waves in
chemistry [8].
HC, a part of cavitational chemistry, also enables efficient catalysis
under mild conditions by generating cavitation at low energy con-
sumption. Easier scaling-up facilitates large-scale applications in several
chemical processes, mainly in aqueous media such as oil hydrolysis, po-
lymerization and depolymerization as well as oxidation reactions [9]
and pollutant degradation [10]. HC use in organic synthesis and catalysis
has not yet been explored as deeply as acoustic cavitation, but it is a
powerful tool which has captured both academic and industrial interest
[11].
Cavitation phenomena are able to dramatically enhance the reaction
rates of several chemical conversions by means of mechanical effects in
heterogeneous processes and chemical induction in homogeneous sys-
tems. Besides shortening reaction times and improving yields, cavitation
may also induce higher selectivities while simplifying experimental
⁎
Corresponding author at: Dipartimento di Scienza e Tecnologia del Farmaco,
University of Turin, via P. Giuria 9, 10125 Torino, Italy.
E-mail address: giancarlo.cravotto@unito.it (G. Cravotto).
http://dx.doi.org/10.1016/j.catcom.2014.12.014
1566-7367/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: G. Cravotto, et al., Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on
catalytic effects, Catal. Commun. (2014), http://dx.doi.org/10.1016/j.catcom.2014.12.014

2
G. Cravotto et al. / Catalysis Communications xxx (2014) xxx–xxx
were obtained via the condensation of 1,5-diaryl-1,4-pentadiene-3-
ones with aminoguanidine hydrochloride [15] (Scheme 2).
The nucleophilic attack of the amino group to the carbonyl is followed
by water elimination and DBSA catalysis is important in creating a good
leaving group. The condensation of the solid–liquid mixture is strongly
promoted by the emulsification generated by US in the presence of
BDSA that increase the interfacial contact area of the reagents. The com-
parison between US and simple stirring reported in Table 1 evidenced
the advantages of sonochemical catalysis, with shorter reaction times
and higher yields.
C
Li et al. [18] reported a simple, efficient procedure for the deoximation
of keto- and aldoximes to the corresponding carbonyl compounds using
silica sulfuric acid/paraformaldehyde in water in the presence of sodium
dodecylsulfonate (SDS) under US. The formation of ketones and alde-
hydes from oximes is useful because oxime serves as an efficient protec-
tive group for carbonyls, which are extensively used for the purification of
carbonyl compounds. A typical deoximation protocol requires harsh con-
ditions and reagents, sustained heating under reflux, a tedious work-up
and may generate side products. Silica sulfuric acid is an excellent candi-
date for sulfuric acid or chlorosulfonic acid replacement in organic reac-
tions and does not entail limitations such as the destruction of acid
sensitive functional groups, the use of rather toxic solvents and expensive
reagents (Scheme 3).
Sonochemical deoximation reactions were carried out on aldoximes
in good yields using silica sulfuric acid in the presence of SDS. Ex-
periments carried out under silent conditions gave comparable yields
but in a much longer reaction times. The various substituents on the ben-
zene ring affect product yield. When ketoximes that contain electron-
donating groups on the benzene ring were used as substrates, ketones
were obtained in good yields (92–97%), whereas ketoxime containing
electron-withdrawing group gave the ketones in about an 80% yield.
In addition, the catalyst can be reused three times without significant de-
crease in activity. It is worth noting that no Beckmann rearrangement
products were formed.
A
B
Fig. 1. US probe transducers, A) Cup horn bath, B) Cup horn cavitating tube, C) Immersion
horn.
procedure and workup. Synthetic protocols involving metal catalysis have
long been a favorite and most rewarding topic in sonochemistry. The
majority of such studies have focused on heterogeneous reactions per-
formed in water or aqueous media [12], considered the solvent of choice
in sonochemistry thanks to the excellent cavitation it facilitates from
room temperature up to 50–60 °C. Besides being inexpensive, abundant,
non-toxic and environmentally friendly, water can also be used as a dis-
persing medium under US. In addition to satisfying the above criteria,
water also causes special effects in reactions that arise from intra- and
inter-molecular non-covalent interactions and which lead to assembly
processes.
As stated by Sheldon (1996), in green procedures “The best solvent is
no solvent and if a solvent (diluent) is needed it should preferably be
water” [13]. Sonochemical reactions in water often bring to the fore pecu-
liar reactivities and selectivities that are not observed under anhydrous
conditions [14]. In this respect, the development of water-tolerant cata-
lysts and reagents has rapidly become an area of intense research.
One of the main limitations in the scale up of sonochemical
equipment is the energy consumption. The flow and loop US reactors
stand out above classic batch US reactors thanks to their greater effi-
ciency and flexibility as well as lower energy consumption. Fig. 2
shows a multi-horn flow reactor in which the reacting mixture is
pumped through the system.
3. Small catalyst molecules
Organic reactions catalyzed by small organic molecules have drawn a
great deal of attention. Urea derivatives may coordinate carbonyl groups
2. Use of surfactants
Organic reactions in water are often difficult because most organic
reactants, including catalysts, are insoluble in water. Surfactants, due
to their dual hydrophobic and hydrophilic nature, can ride out this prob-
lem by forming micelles and promoting reactions in water. An example
is p-dodecyl-benzenesulfonic acid (DBSA), a Brønsted acid-surfactant
that combines catalytic action and the ability to form stable colloidal
dispersions with water-insoluble substrates that facilitate reaction out-
come. Proton acid catalyzed organic reactions can be carried out in the
presence of water using DBSA [15]. It has been widely reported that
US, when compared with conventional protocols, accelerates reactions
via a more intimate mixing of reagents and enhances the activity of an
insoluble catalyst by enlarging its surface area [16]. Li et al. reported
two examples of improvements in organic syntheses in water via the
use of DBSA under US. Firstly [17], they reported a green, efficient pro-
cedure for the preparation of bis(indolyl)methanes from indole and ar-
omatic aldehyde in the present of DBSA in aqueous solution (Scheme 1).
The same group reported the DBSA catalyzed synthesis of amidino-
hydrazones under US in water. These versatile synthetic intermediates
Fig. 2. Multi-horn flow reactor (developed at the University of Turin in collaboration with
Danacamerini sa.).
Please cite this article as: G. Cravotto, et al., Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on
catalytic effects, Catal. Commun. (2014), http://dx.doi.org/10.1016/j.catcom.2014.12.014

G. Cravotto et al. / Catalysis Communications xxx (2014) xxx–xxx
3
DBSA
H2O
Table 1
R2
H
O
Reaction times and yields under US and under silent conditions.
+
R2
H
N
R1
US
Simple stirring
US 25 KHz,
23-25 °C,
10-150 min
N
R1
N
R2
R1
R2
Time (h) Isolated yield (%) Time (h) Isolated yield (%)
85-98%
R1= H or CH3
4-Cl
4-CH3
H
4-OCH3 4-OCH3
H
H
4-Cl
2
2
2
2
85
87
90
91
94
95
2 (4)
6
51 (58)
65
4-CH3
4-OCH3
2
45
Scheme 1. Sonochemical preparation of bis(indolyl)methanes.
5
80
4-Cl 2.5
4-CH3 2.5
2.5
8
67
72
and activate them via hydrogen bonding. Computational studies also indi-
cated that hydrogen bond donors are able to provide two or more hydro-
gen atoms to bind the oxygen atoms in carbonyl groups. Thus, various
carbonyl group urea catalyzed reactions have been developed. Li et al.
[19] used urea in water to catalyze the synthesis of 2,2′-arylmethylene
bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) derivatives from
aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione under US
(Scheme 4).
The main advantages of this procedure over some other reported
methods are shorter reaction time, simpler work-up and lower environ-
mental impact. Phase transfer catalysts have been used in previous re-
ports of this reaction, however, they are more expensive and dangerous
than urea as they are able to transfer chemicals from water into animal
tissues.
The availability, cost effectiveness and non-toxic properties of
glycine have prompted its use as a catalyst and organo-base in synthetic
chemistry. Datta and Pasha [12] have reported a one-pot multicomponent
synthesis of 2-amino-4H-chromenes from aryl-aldehydes, malononitrile
and resorcinol at 28–30 °C in water under US, using glycine as an organo-
catalyst (Scheme 5).
The use of a polar solvent was indispensable as the reaction yields
the Knoevenagel condensation adduct as the major product when car-
ried out in non-polar solvents, while only trace amounts of the desired
product were obtained in solvent-free conditions. This clearly indicates
that water is essential for shifting the reaction to the product side and
probably stabilizes the transition state. In the presence of water, the re-
action not only went efficiently to completion (9–45 min) but also gave
excellent yields. By comparing sonochemical with silent conditions in
similar reaction times, yield improved from a range of 25–47% up to
89–95%.
design of MCR in water is another attractive area as water is a cheap,
safe and environmentally benign solvent. Banitaba et al. [20] have de-
scribed a green and simple sonochemical protocol in water for assem-
bling 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile scaffolds
via a three-component reaction with kojic acid, malononitrile and aro-
matic aldehydes (Scheme 6).
This is a green sonochemical method that furnishes a shorter reac-
tion time, good yields, no need for a base, simple workup and excellent
functional group tolerance. The Authors compared reactions carried out
under sonochemical and silent conditions (high-speed stirring), at 30 °C
yields were 78 vs 50%, and at 60 °C 88 vs 74% respectively.
Ziarati et al. [21] have combined the advantages of US and nanotech-
nology to design a new MCR method for the preparation of pyrazolone
derivatives using CuI nanoparticles under US irradiation (Scheme 7).
A simple and green process for the preparation of nano-size copper
iodide via sonication was also reported. These nanoparticles were
used as an efficient catalyst for the synthesis of 2-aryl-5-methyl-2,3-
dihydro-1H-3-pyrazolones via the US-assisted four-component reac-
tion of hydrazine, ethyl acetoacetate, aldehyde and β-naphthol in
water. US can increase the surface area of the catalyst and supply addi-
tional activation through efficient mixing and enhanced mass transport.
Acoustic cavitation is indeed a very effective means for the dispersion of
solids and liquids emulsification by reducing the particle/droplet size,
the total surface area of the phase boundary increases at the same time.
This MCR in water gave excellent yields in short reaction times and
showed a wide range of applicability as it could be used with different
substrates, including aromatic aldehydes and hydrazines to provide
the corresponding pyrazolones in good yields.
4. Multi-component reactions
Another example of the synergy between a nanosized catalyst and US
was reported by Rostamizadeh et al. [22], which developed an efficient
procedure for the synthesis of 1,8-dioxo-octahydroxanthene derivatives.
In this method, several types of aromatic aldehyde, which contained
both electron-withdrawing and electron-donating groups, were rapidly
converted to the corresponding 1,8-dioxo-octahydro xanthenes in good
to excellent yields. The reaction was carried out in water under US irradi-
ation, using nanosized MCM-41-SO3H, which is an ordered mesoporous
material based nanocatalyst with covalently anchored sulphuric acid
groups inside the mesochannels. The combined use of MCM-41-SO3H
and US is best explained in terms of the intercalation of guest molecules
(reactant) into host nanoreactors. The intense localized pressure and
temperature regions generated by US help the insertion of reactants
into the nanocatalyst channels and the inherent Brönsted acidity of
the –SO3H groups, which are capable of bonding with the aldehyde car-
bonyl oxygens, assist in the generation of ionic intermediates via reactant
activation. In other words, ionic intermediates are generated inside the
Multi-component reactions (MCRs) have become a hot topic in
organic synthesis in recent years on account of their atom economy,
efficiency, rapidity and environmental friendliness. MCRs that lead to
various heterocyclic scaffolds are particularly useful for the creation of
chemical libraries of ‘drug-like’ molecules for biological screening,
since the combination of three or more small molecular weight building
blocks in a single operation leads to high combinatorial efficacy. The
Scheme 2. Sonochemical preparation of amidinohydrazone derivatives.
Scheme 3. Sonochemical reaction of deoximation.
Please cite this article as: G. Cravotto, et al., Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on
catalytic effects, Catal. Commun. (2014), http://dx.doi.org/10.1016/j.catcom.2014.12.014

4
G. Cravotto et al. / Catalysis Communications xxx (2014) xxx–xxx
Scheme 4. Urea-catalysed condensation of aromatic aldehydes and 1,3-cyclohexanedione.
Scheme 6. Sonochemical multi-component reaction with kojic acid, malononitrile and ar-
omatic aldehydes.
nanoreactor by the abundant energy released during bubble collapse and
the catalytic effect of the –SO3H groups (Scheme 8).
toluenesulfonic acid (p-TSA) catalyst in water under US irradiation
(Scheme 10).
This sonochemical procedure improved reaction rates and yields but
failed in the presence of Lewis acids, such as ZrOCl2, ZrOCl2/K10,
NaHSO4 and NaHSO4/SiO2. Cavitation activated the catalyst while
sonic waves favored the intercalation of guest molecules into the host
nanoreactor. When similar reactions were carried out under silent reac-
tions (simple stirring) much longer reaction times and higher tempera-
ture were required and poor yields were achieved (silent 60–90 °C
vs US → yields 0–50% vs 95%). The reaction worked well both when car-
ried out with electron-withdrawing (NO2, Cl, CN) and electron-
donating groups (Me, MeO), and afforded various xanthene derivatives
in 80–99% yields. This is a general method and can accommodate a
variety of functional groups.
The reaction was investigated with and without US irradiation at the
same temperature (60 °C) and in various solvents in order to better un-
derstand the role of US and the solvent effect. It was found that the use
of US leads to a higher yield in all reactions and that water was the solvent
of choice. The method is simple, starts from readily accessible commercial
starting materials and provides biologically interesting spirooxindole
derivatives in good yields. Moreover, it is worth noting that two C\C
and one C\O bonds are formed during the creation of a spirooxindole
fused pyrazolopyridine in this one-pot, three-component process.
Although not MCRs, it is worth mentioning that Dandia et al. [25]
have reported the novel aqueous mediated synthesis of other substitut-
ed spiro-compounds from the reaction of spiro [indole-3,20-oxiranes]
with thioacetamide in the presence of an LiBr catalyst under sonication
in water (Scheme 11).
They compared the use of a low-intensity ultrasonic (LIU) laboratory
cleaning bath (which gives economic benefits) and a high-intensity US
probe system (HIU). They also performed the reaction under micro-
wave radiation (MW) and under conventional stirring and used sol-
vents other than water, as reported in Table 2.
MW was not as efficient as US in the synthesis of spiro derivatives as
there was no appreciable increase in yield, but was still better than the
thermal method which gave a mixture of products. It appears that
sonochemical activation is principally due to the mechanical effects of
cavitation in this heterogeneous system.
Khorrami et al. [26] have developed a facile, one-pot and three
component procedure for the preparation of oxindole derivatives from
dimedone, 1H-pyrazol-5-amines and isatins in water under US and
in the presence of a non-toxic and readily available InCl3 catalyst
(Scheme 12). For the sake of comparison the reaction was also carried
out under silent conditions with high speed stirring. In all experiments
yields were lower than 30%.
The use of water as the reaction medium provides remarkable ben-
efits as it is highly polar and therefore immiscible with most organic
compounds. Moreover, the water soluble catalyst resides and operates
in the aqueous phase making the separation of the organic materials
easy. This procedure, which was developed for oxindole synthesis,
was applied to the reaction of 1,3-diphenyl-1H-pyrazol-5-amine and
isatins to obtain 3,3-bis(5-amino-1H-pyrazol-4-yl)indolin-2-ones in
good yields in 30–60 min (Scheme 13).
The synthesis of xanthenes and benzoxanthenes plays an important
role in pharmaceutical chemistry because of their relevance as building
blocks in drug design.
Mahdavinia et al. [23] have explored the use of US-assisted heteroge-
neous catalysis in the synthesis of various aryl-14H-dibenzo[a,j]xan-
thenes. They reported a general, efficient and eco-friendly method that
gave excellent yields via the use of a recyclable silica supported ammoni-
um dihydrogen phosphate (NH4H2PO4/SiO2) catalyst which provided
several advantages such as low toxicity, low cost, ease of handling and
high catalytic activity making it a potential new green catalyst. The exper-
imental procedure for the efficient one-pot preparation of aryl-14H-
dibenzo[a,j]xanthene is remarkably simple and requires no toxic organic
solvents or inert atmosphere. The reactions were carried out at 40 °C with
a 1:2 mol ratio aldehyde/β-naphthol mixture in H2O (US, 25 kHz)
(Scheme 9).
A number of different benzoxanthenes were obtained in high yields
while the mild reaction conditions respected sensitive functional groups,
such as the methoxy group, which often undergoes cleavage in strongly
acidic reaction media.
Indole and indoline fragments are important moieties found in a large
number natural products and medicinal agents and some spiro-
annulated indoline with heterocycles in the 3-position have shown high
biological activity. The spirooxindole system is the core structure of
many pharmacological agents and natural alkaloids. Therefore, a number
of methods have been reported for the preparation of spirooxindole fused
heterocycles. Bazgir et al. [24] have reported the synthesis of spiro
[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione via a three-
component condensation reaction between 4-hydroxycumarin, isatines
and 1H-pyrazol-5-amines in the presence of the inexpensive p-
H
R1
N
NH2
R2
Cu np
H2O
OH
OEt
Me
O
O
US, 20 kHz, 50 W
RT, 10 min
HN
R2
OH
O
N
OHC
R1
86-93%
Scheme 5. Glycine-assisted sonochemical multi-component reaction of malononitrile,
resorcinol and aromatic aldehydes.
Scheme 7. Sonochemical preparation of pyrazolones via MCR.
Please cite this article as: G. Cravotto, et al., Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on
catalytic effects, Catal. Commun. (2014), http://dx.doi.org/10.1016/j.catcom.2014.12.014

G. Cravotto et al. / Catalysis Communications xxx (2014) xxx–xxx
5
Scheme 8. Sonochemical 1,8-dioxo-octahydroxanthenes preparation catalysed by MCM-
41-SO3H.
5. Aza-Michael reactions
The conjugate addition of amines to conjugated alkenes (commonly
known as the aza-Michael reaction) is a key step in the synthesis of var-
ious complex natural products, antibiotics, α-amino alcohols and chiral
auxiliaries. Bandyopadhyay et al. [27] have developed a US-induced
eco-friendly procedure for the aza-Michael reaction. No metallic, enzy-
matic or corrosive catalysts or solid supports are used in this method.
The present procedure furnishes notable advantages that include a sim-
ple operational procedure, environmentally benign reaction conditions,
short reaction times and high product yields (Scheme 14).
The procedure was tested on several amines and unsaturated ke-
tones, a nitrile and an ester. The results can be considered nothing
short of spectacular as all the US-assisted reactions in water were very
rapid when compared to reactions in organic solvents under identical
conditions, while no catalyst was necessary to complete the reaction.
All reactions were completed within 10 min and gave the desired prod-
ucts in excellent yields (86–99%), high regio- and chemo-selectivity and
no side products were formed. The presence of water most probably
accelerated the reaction via the formation of hydrogen bonds with the
carbonyl group which increased the electrophilic character at the
β-carbon of the unsaturated compounds, resulting in significantly
increased nucleophilic attack by the amine. On the other hand, hy-
drogen bond formation between the water oxygen atom and the
amine hydrogen-atom increased the nucleophilic power of the amine
N-atom. In addition, water has a high dielectric constant and a permanent
dipole moment which allows the coupling between the oscillating electric
field and molecular tumbling to occur, giving highly efficient heating.
Under US, water therefore acts as a pseudo-organic solvent at the elevated
temperature inside the hot spots.
Scheme 10. Sonochemical preparation of spirooxindole derivatives.
and excess formaldehyde offered ready access to libraries of new polyols
(Scheme 16).
The above series of aldol reactions, when carried out in aqueous sus-
pension under US irradiation, afforded a number of aldols that cannot
usually be isolated in practical yields because they immediately undergo
elimination. This efficient approach offers ready access to polyols and
bis-benzylidene adducts.
7. Suzuki–Miyaura couplings
This reaction has gained considerable prominence as the biaryl motif
is present in a wide variety of common organic compounds. Cravotto
et al. [28] have reported the Pd-catalyzed Suzuki homocoupling of bo-
ronic acids which was successfully carried out in water under high-
intensity US using a Pd/C catalyst. Heterogeneous Pd/C catalysis facili-
tated work up and purification and was used without adding phosphine
ligands. Compared to other expensive and air-sensitive Pd catalysts, Pd/
C can be more easily handled, recovered from the reaction mixture via
simple filtration and reused (Scheme 17).
Reaction rates and yields were strongly influenced by the choice
of oxidant and excellent results were obtained using either molecu-
lar oxygen or 3-bromo-4-hydroxycoumarin. The 3-arylation of the
latter, carried out via the Suzuki procedure, failed and exclusively
afforded the homocoupling products which were symmetric biaryls.
Other oxidants (e.g., Cu(II) acetate and Cu(II) nitrate) were not
effective.
6. Aldol reactions
Cravotto et al. [16] have used US in water as a means to re-consider
the aldol reaction, one of the oldest organic reactions. It was found that
this reaction takes place under US, furnishing good yields in aqueous
heterogeneous systems, generally without requiring any catalyst. The
aldol reaction of acetophenone and a number of non-enolizable
aldehydes afforded the aldol in acceptable to good yields in aqueous
NaOH under sonication (18 kHz, 280 W), with only two exceptions
(Scheme 15).
Benzaldehyde reacted very quickly with acetone to afford the corre-
sponding aldol (4-hydroxy-4-phenylbutan-2-one) in a good yield (72%),
while the same reaction surprisingly only yielded cinnamaldehyde
(79%) when carried out with acetaldehyde. The reaction between benzal-
dehyde and a number of 1,3-dicarbonyl compounds afforded, in all cases,
the corresponding 2:1 adducts. This approach provides easy access to
bis(benzylidene) derivatives. The aldol reaction between acetophenones
The US-assisted reaction was much faster (reaction time reduced to
a minimum of 90 min), gave higher isolated yields and even afforded
homocoupling products that could not be obtained without resorting
to US. The dioxane–water medium was replaced with pure water and
Scheme 11. Sonochemical reaction of spiroindole-oxiranes with thioacetamide catalysed
Scheme 9. Sonochemical preparation of benzoxanthenes.
by LiBr.
Please cite this article as: G. Cravotto, et al., Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on
catalytic effects, Catal. Commun. (2014), http://dx.doi.org/10.1016/j.catcom.2014.12.014

6
G. Cravotto et al. / Catalysis Communications xxx (2014) xxx–xxx
Table 2
Reaction conditions and yield for the synthesis of spiro[indole-1,3-oxathiolane].
Entry
Solvent
Conditions
Time (min/h)
Yield (%)
1
2
3
4
5
6
H2O
H2O
H2O
DMF
THF
H2O
US bath (LIU)
US (HIU)
MW
MW
Stirring
Stirring
50 min
7 min
20 min
15 min
5 h
80
84
76
70
50
37
5 h
triphenylphosphine was omitted without any loss in efficiency. Further-
more, switching from KF to less expensive NaOAc did not affect the re-
action adversely. Therefore, the use of US meant that the Pd/C-catalyzed
Suzuki homocoupling of numerous arylboronic acids was carried out
under more advantageous conditions (in pure water, in the absence of
ligands and using oxygen as the oxidant) and afforded the correspond-
ing biaryls in good yields. These features are great advantages for the
large-scale preparation of these compounds.
Other groups have reported examples of the Suzuki reactions of
phenylboronic acid and a series of arylhalides in water under sonication.
Zhang et al. [29] investigated the use of cyclopalladated ferrocenylimine
as a kind of phosphine-free compound that demonstrates almost all the
properties of palladacycle catalysts. Their synthetic convenience and
facile modification make them attractive while their air moisture stabil-
ity makes these catalysts easy to handle. They reported examples of
Suzuki cross-coupling reactions that were catalyzed by ligand-free
cyclopalladated ferrocenylimines in water. It was possible to couple
arylhalides, including electron-withdrawing aryl chlorides, with phenyl-
boronic acid in moderate to good yields under both sonication and con-
ventional heating. Compared with conventional heating, the reaction
was strongly accelerated by US (Scheme 18).
Scheme 13. Sonochemical preparation of indolin-2-one derivatives via MCR.
in process development and non conventional techniques [30]. Al-
though many organic reactions with water soluble substrates/reagents
are carried out smoothly in aqueous media, some reactions with rigor-
ously heterogeneous substrate/reagent combinations proceed very
poorly in sealed tubes or in continuous flow systems leading to incom-
plete conversion. A great deal of effort has been made to overcome the
problem and the introduction of a co-solvent or the use of water soluble
substrates and catalysts are particularly noteworthy. Homogeneous cat-
alysts often create difficulties during product isolation. The application
of easily separable and recyclable heterogeneous catalysts allows for
cleaner work-up and avoids time-consuming and tedious catalyst puri-
fication. US irradiation, however, can offer an additional advantage in
aqueous phase organic synthesis as it causes a greater number of molec-
ular collisions under mild conditions. P. Shil et al. [31] have developed a
fast, efficient and cost effective process for the synthesis of a solid sup-
ported palladium(0) nano/microparticle catalyst (SSPd) and investigat-
ed its applications. They reported a methanol/water mediated flow
reaction technique for the Suzuki cross-coupling of aryl halides (Cl, Br
and I) with phenyl boronic acid under sonication. The use of a mild
base, the recyclability of the SS–Pd catalyst and the ambient tempera-
ture meet the essential precepts of a green chemical approach for a
Suzuki reaction based biaryl synthesis (Scheme 19).
8. Suzuki reaction in flow reactors
Flow reaction strategies have attracted huge amounts of interest
from organic chemists in recent years, particularly from those interested
The SS–Pd catalyst was found to be very stable in aqueous media,
easily separable and recyclable for up to five runs without significant
loss in activity. The main disadvantage of large scale Suzuki reactions
under thermal conditions is often the volatility of the haloarenes
Scheme 12. Sonochemical preparation of oxindole derivatives by MCR.
Scheme 14. Sonochemical Aza-Michael reaction.
Please cite this article as: G. Cravotto, et al., Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on
catalytic effects, Catal. Commun. (2014), http://dx.doi.org/10.1016/j.catcom.2014.12.014

G. Cravotto et al. / Catalysis Communications xxx (2014) xxx–xxx
7
OH
Br
Ar-B(OH)2
O
O
KF, 50%-water-wet 10% Pd/C H2O, O2
US (18.1 kHz, 80 W/cm2, 105 min
OH
OH
Ar
O
O
O
O
Ar-Ar
Scheme 17. US-assisted Suzuki homocoupling in the presence of O2 or 3-bromo-4-
hydroxycoumarin.
Scheme 15. Sonochemical aldol reaction of non-enolizable aldehydes with acetophenone.
between water and benzoyl chloride and to enhance the overall re-
action rate effectively. A novel dual-site phase-transfer catalyst, 1,4-
bis(tributylammoniomethyl) benzene dibromide, was prepared
from the reaction of p-xylylene dibromide and tributylamine and
used to conduct the benzoylation of sodium 4-acetylphenoxide via
US-assisted third-liquid phase-transfer catalysis. The overall reaction
rate was greatly enhanced by up to 6 times when using US irradiation
(28 kHz at 300 W) as compared to silent conditions. A US-assisted
solid–liquid phase-transfer catalysis (U-SLPTC) was used for the esterifi-
cation of sodium 4-hydroxybenzoate with benzyl bromide [33]. The
quasi-aqueous phase was generated by adding water and the prepared
catalyst. US can effectively enhance the overall reaction rate and the
liquid-jets generated by the US waves were able to remove the surface de-
posited side-product. The reaction mechanism of U-SLPTC was identified
by analyzing the variation and distribution of the catalytic intermediate
between phases and resulted in a greener esterification procedure.
which separate from the reaction mixture resulting in the incomplete
conversion of the substrates, whereas by-product formation decreased
in a flow system under temperature control, thus facilitating the large
scale process. The up-scaling of biaryl synthesis to 5 g scale was success-
fully achieved and may be of industrial interest in the future. US enables
to carry out the reaction in methanol–water by increasing the solubility
of the solid base (K2CO3), which drove the reaction to the products with
satisfactory yields.
9. Phase-transfer catalysis
A further method with which to perform reactions between mutual-
ly insoluble reactants is the use of phase-transfer catalysts under mild
conditions which can provide high conversion and product selectivity.
Phase-transfer catalysis reaction systems can be divided into several
categories according to the phases present. The third-liquid phase trans-
fer catalysis (TLPTC) is a reaction system where the catalyst is highly
concentrated within a separate phase which is located between the
aqueous phase and a low-polar or non-polar solvent phase meaning
that the intrinsic reaction can be greatly promoted. TLPTC can be con-
sidered a green technology because of its high reaction rates, mild reac-
tion conditions, easy product and catalyst separation, lack of halide-
containing solvent and easier catalyst recovery. The combined use of
US and liquid–liquid phase-transfer catalysis has provided significant
improvements in reaction rate. Yang and Chiu [32] investigated the
green synthesis of 4-acetylphenyl benzoate via the reaction of sodium
4-acetylphenoxide in the aqueous phase and benzoyl chloride in the
organic phase by combining US with a novel dual-site phase-transfer
catalyst in TLPTC conditions and a batch reactor. Generally, benzoyl
chloride can easily react with water in the liquid–liquid system interface
to give benzoic acid. The hydrolysis side reaction of benzoyl chloride in
synthesizing esters not only reduces product yield but also causes diffi-
culty in the subsequent separations. This drawback can be solved by the
TLPTC system. In the present US irradiation facilitated tri-liquid system,
the formed third-liquid phase was employed to reduce the contact
10. Sonochemical reactions in aqueous biphasic systems
Reactions following a ionic mechanism in heterogeneous liquid–liquid
biphasic systems, are strongly affected (rates and yields) by mechanical
effects associated with sound waves to an extent depending on surface
tension, density and temperature. Even bigger sonochemical activation
occurs in electron-transfer mechanism paths [3]. These biphasic systems
will also be sensitive to the mechanical component of shock waves in ad-
dition to chemical activation. Water is one of the most common solvent in
sonochemistry, however, a little organic solvent can be beneficial in some
cases or even crucial [34].
10.1. Oxidation of secondary alcohols
Mills and Holland [35] have studied the effect of US on the kinetics of
the oxidation of octan-2-ol and other secondary alcohols using sodium
bromate and mediated by ruthenium tetraoxide (RuO4) which is gener-
ated in situ from RuO2 in a biphasic system. RuO4 is a common oxidant
Scheme 16. US-assisted polyols synthesis by aldol reaction of acetophenones and
formaldehyde.
Scheme 18. Sonochemical Suzuki reaction with palladacycle catalysts.
Please cite this article as: G. Cravotto, et al., Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on
catalytic effects, Catal. Commun. (2014), http://dx.doi.org/10.1016/j.catcom.2014.12.014

8
G. Cravotto et al. / Catalysis Communications xxx (2014) xxx–xxx
SS-Pd (3 mol % Pd)
K2CO3
X
systems well suited for application in practical protocols for catalysis
in water.
R
MeOH/H2O 2:3
B(OH)2
R
+
Acknowledgment
US 20 kHz, RT, 2.5-4 h
This work was supported by the University of Turin (Progetti Ricerca
Locale 2013).
Scheme 19. Sonochemical Suzuki reaction with SSPd catalysts.
References
[1] M. Sillanpää, T.-D. Pham, R.A. Shrestha, Ultrasound Technology in Green Chemistry,
Springer Science + Business Media, 2011, ISBN 978-94-007-2409-9.
[2] S. Puri, B. Kaur, A. Parmar, H. Kumar, Curr. Org. Chem. 17 (2013) 1790–1828.
[3] G. Cravotto, P. Cintas, Chem. Soc. Rev. 35 (2006) 180–196.
[4] P. Cintas, G. Palmisano, G. Cravotto, Ultrason. Sonochem. 18 (2011) 836–841.
[5] P. Cintas, J.-L. Luche, Organometallic sonochemistry, in: J.-L. Luche (Ed.), Synthetic
Organic Sonochemistry, Plenum Press, New York, 1998, pp. 165–234.
[6] A. Tuulmets, K. Kaubi, K. Heinoja, Ultrason. Sonochem. 2 (1995) 75–78.
[7] G. Cravotto, P. Cintas, Chem. Sci. 3 (2012) 295–307.
in organic synthesis that has proven itself to be selective in the oxidation
of primary alcohols to aldehydes, ethers to esters, amides to imides, al-
kenes to aldehydes and aldehydes to acids. Besides the excellent mixing
that sonication provides, US generates a steady-state level with the for-
mation of an emulsion of aqueous microdroplets with high interfacial
surface area.
[8] G. Cravotto, A. Procopio, E. Oliverio, L. Orio, D. Carnaroglio, Green Chem. 13 (2011)
2806–2809.
[9] G.V. Ambulgekar, S.D. Samant, A.B. Pandit, Ultrason. Sonochem. 11 (2004) 191–196.
[10] D.H. Bremner, S. Di Carlo, A.G. Chakinala, G. Cravotto, Ultrason. Sonochem. 15
(2008) 416–419.
[11] P.R. Gogate, Adv. Chem. Res. 9 (2011) 139–163.
[12] B. Datta, M.A. Pasha, Ultrason. Sonochem. 19 (2012) 725–728.
[13] R.A. Sheldon, J. Mol. Catal. A Chem. 107 (1996) 75–83.
[14] U.M. Lindström, Organic Reactions in Water: Principles, Strategies and Applications,
Blackwell Publishing Ltd., 2007, ISBN 9780470988817. (online).
[15] J.-T. Li, C. Du, X.-Y. Xu, G.-F. Chen, Ultrason. Sonochem. 19 (2012) 1033–1038.
[16] G. Cravotto, A. Demetri, G.M. Nano, G. Palmisano, A. Penoni, S. Tagliapietra, Eur. J.
Org. Chem. 22 (2003) 4438–4444.
[17] J.-T. Li, M.-X. Sun, G.-Y. He, X.-Y. Xu, Ultrason. Sonochem. 18 (2011) 412–414.
[18] J.-T. Li, X.-T. Meng, B. Bai, M.-X. Sun, Ultrason. Sonochem. 17 (2010) 14–16.
[19] J.-T. Li, Y.-W. Li, Y.-L. Song, G.-F. Chen, Ultrason. Sonochem. 19 (2012) 1–4.
[20] S.H. Banitaba, J.S. Shiva, D. Khalili, Ultrason. Sonochem. 20 (2013) 401–407.
[21] A. Ziarati, J. Safaei-Ghomi, S. Rohani, Ultrason. Sonochem. 20 (2013) 1069–1075.
[22] S. Rostamizadeh, A.M. Amani, G.H. Mahdavinia, G. Amiri, H. Sepehrian, Ultrason.
Sonochem. 17 (2010) 306–309.
[23] G.H. Mahdavinia, S. Rostamizadeh, A.M. Amani, Z. Emdadi, Ultrason. Sonochem. 16
(2009) 7–10.
[24] A. Bazgir, S. Ahadi, R. Ghahremanzadeh, H.R. Khavasi, P. Mirzaei, Ultrason.
Sonochem. 17 (2010) 447–452.
[25] A. Dandia, R. Singh, S. Bhaskaran, Ultrason. Sonochem. 17 (2010) 399–402.
[26] A.R. Khorrami, F. Faraji, A. Bazgir, Ultrason. Sonochem. 17 (2010) 587–591.
[27] D. Bandyopadhyay, S. Mukherjee, L.C. Turrubiartes, B.K. Banik, Ultrason. Sonochem.
19 (2012) 969–973.
[28] G. Cravotto, G. Palmisano, S. Tollari, G.M. Nano, A. Penoni, Ultrason. Sonochem. 12
(2005) 91–94.
10.2. Bromination of aromatic compounds
Lévêque et al. [34] have reported the molybdate-catalyzed bromina-
tion of various aromatic compounds in the presence of KBr/H2O2 in an
aqueous/chloroform biphasic system. This reaction occurred rapidly
under US irradiation, whereas it did not take place at all under conven-
tional mechanical stirring (1400 rpm) (see Table 2).
The bromination of phenol did not occur after 2 h of stirring, where-
as bromophenol was obtained in good yields under US irradiation (71%
and 81% at 36.6 and 480 kHz, respectively). Anisole and acetanilide were
also efficiently brominated in 4 h under sonication. US was decisive in
initiating the reaction over a large range of frequencies. Yields strongly
decreased in the absence of H2O2, although the sono-production of
H2O2 was expected under prolonged sonication. US may accelerate the
decomposition of the peroxomolybdate–hypobromite intermediate
and thus accelerate the catalytic cycle. As the reaction takes place
smoothly at pH values of below two, the activation mechanism of the
Mo-catalyzed bromination by US can be attributed to the secondary in-
direct sonochemical effect, i.e., the lowering of pH via the sonolysis of
CHCl3–H2O solvents. The strategic use of the secondary sonochemical
effect, such as the in situ lowering of pH by sonolysis should be taken
into account when applying US (Table 3).
[29] J. Zhang, F. Yang, G. Ren, T.C.W. Mak, M. Song, Y. Wu, Ultrason. Sonochem. 15 (2008)
115–118.
[30] G. Cravotto, W. Bonrath, S. Tagliapietra, C. Speranza, E. Calcio Gaudino, A. Barge,
Chem. Eng. Process. 49 (2010) 930–935.
11. Conclusions
[31] A.K. Shil, N.R. Guha, D. Sharma, P. Das, RSC Adv. 3 (2013) 13671–13676.
[32] H.-M. Yang, C.-C. Chiu, Ultrason. Sonochem. 18 (2011) 363–369.
[33] K. Kulkarni, J. Friend, L. Yeo, P. Perlmutter, Ultrason. Sonochem. 21 (2014) 395–400.
[34] J.-M. Lévêque, M. Fujita, A. Bosson, H. Sohmiya, C. Pétrier, N. Komatsu, T. Kimura,
Ultrason. Sonochem. 18 (2011) 753–756.
Catalysis in aqueous systems under sonochemical conditions is well
documented however, further diffusion and scaling up, should entail
the development of more specific catalysts and a cost analysis. Besides
the low environmental impact, chemists can take advantage from
recent progress in US reactor engineering with new reliable flow-
[35] A. Mills, C. Holland, Ultrason. Sonochem. 2 (1995) 33–38.
Table 3
Reaction conditions and yields for the molybdate-catalyzed bromination of aromatic
compounds.
Substratea
Time (h)
Yield %b (o:p ratio)
Stirring (1400 rpm)
US (36.6 kHz)
US (480 kHz)
2
2
4
0
–
0
71 (26:74)
17 (32:68)c
96 (4:96)
81 (27:73)
15 (33:67)c
75 (4:96)
4
0
92 (0:100)
100 (0:100)
a
Substrate 0.1 mmol, H2O2 0.1 mmol, KBr 0.126 mmol, (NH4)6Mo7O24 0.005 mmol,
solvent CHCl3 1 mL + H2 O5 mL, temp. 20 °C.
b
Determined by GC–MS (internal standard: dodecane).
Without H2O2.
c
Please cite this article as: G. Cravotto, et al., Organic reactions in water or biphasic aqueous systems under sonochemical conditions. A review on
catalytic effects, Catal. Commun. (2014), http://dx.doi.org/10.1016/j.catcom.2014.12.014