Acs Joc 1c00805

pubs.acs.
org/joc Perspective
Organic Sonochemistry: A Chemist’s Timely Perspective on

Mechanisms and Reactivity
R. Fernando Martínez,* Giancarlo Cravotto, and Pedro Cintas*
Cite This: J. Org. Chem. 2021, 86, 13833−13856 Read Online
ACCESS Metrics & More Article Recommendations

See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
ABSTRACT: Sonochemistry, the use of sound waves, usually

within the ultrasonic range (>20 kHz), to boost or alter chemical
properties and reactivity constitutes a long-standing and
sustainable technique that has, however, received less attention
Downloaded via 186.84.187.85 on November 6, 2021 at 22:59:35 (UTC).
than other activation protocols despite affordable setups. Even if

unnecessary to underline the impact of ultrasound-based strategies
in a broad range of chemical and biological applications, there is
considerable misunderstanding and pitfalls regarding the inter-
pretation of cavitational effects and the actual role played by the
acoustic field. In this Perspective, with an eye on mechanisms in
particular, we discuss the potentiality of sonochemistry in synthetic
organic chemistry through selected examples of past and recent developments. Such examples illustrate specific controlling effects
and working rules. Looking back at the past while looking forward to advancing the field, some essentials of sonochemical activation
will be distilled.
“Alfred L. Loomis, Wall Street banker and scientist, with a solution. This is reminiscent of the renaissance of sonochem-
beautif ully equipped research laboratory at his Tuxedo istry in organic synthesis in the early 1980s as narrated by one
Park residence where he cooperates in pure science pioneer, Jean-Louis Luche, who attempted a difficult Grignard
necromancy with his f riend, Professor R. W. Woods, of reaction in a cleaning bath when all else failed. The
Johns Hopkins University, made public yesterday details of a transformation succeeded and led to new avenues and
new form of sorcery, super-audible sounds.” strategies in metal activation and improved one-pot Barbier-
■ The New York American (1927)1 type reactions that bypassed tedious and hazardous organo-
INTRODUCTION AND MOTIVATION metallic reactions.2 Readers are referred to recent books and
reviews that address the multiple applications of ultrasonics
Nearly one century after the seminal discovery by Loomis and and sonochemistry and provide sufficient knowledge for
associates of chemical, physical, and physiological effects further research.3−7 Previous textbook-like monographs,
induced by ultrasonic frequencies, sonochemistry has become suitable for beginners and practitioners alike, deal with key
a promising and cost-effective technique to reconsider concepts and useful tips while illustrating the broad
sustainable chemical syntheses in line with the ever-increasing applicability of ultrasonic waves.8 In fact, sonochemistry
impact of environmental concerns. Sonochemistry has moved owes credit to some pioneers who paved the way to the
from a specialized field to inter- and multidisciplinary domains current state of the art, both demystifying the technique and
ranging from nanotechnology to drug delivery, among others. showing the fundamentals embedded in acoustics along with
Although the use of ultrasonic activation has long been working rules. To name a few who influenced our approach to
brought into the mainstream of organic synthesis, modern
organic sonochemistry, but by no means excluding others:
synthetic challenges such as selective functionalization, stereo-
Jean-Louis Luche, Ken Suslick, Tim Mason, Arnim Henglein,
chemical control, or mechanistic interpretations still represent
Peter Riesz, Takashi Ando, Oleg Abramov, and Jacques Reisse.
unsolved and/or open questions.
Compared to other enabling techniques, namely photo-
chemistry, electrochemistry, and microwave chemistry, for Special Issue: Enabling Techniques for Organic Syn-
which some variables are known and should be adjusted; thesis
sonochemistry is often viewed as a black art, where it is less Received: April 7, 2021
easy to predict what you are going to get. Ways of thinking Published: June 22, 2021
with this technique lie invariably in cavitation (vide infra),
which is complex enough to model or interpret all effects in
© 2021 American Chemical Society https://doi.org/10.1021/acs.joc.1c00805

13833 J. Org. Chem. 2021, 86, 13833−13856
The Journal of Organic Chemistry pubs.acs.org/joc Perspective
Herein, we concentrate on sono-organic methods and

general trends, which reflect well-established points and open
up prospects for future explorations, especially in organic and
medicinal chemistry. We begin with some introductory aspects
of cavitational effects, followed by practical remarks on
common ultrasonic reactors and how a series of external
parameters, often overlooked or misunderstood, matter. The
Perspective continues with some empirical rules, which show
the opportunities and challenges for achieving creativity and
selectivity under eco-friendly conditions. We finally address
future orientations and innovations, such as piezo-redox
catalysts, flow designs, and in-line automation.
■ WHAT IS CAVITATIONAL CHEMISTRY?

Ultrasound refers to inaudible acoustic waves, which are
Figure 1. Representation of chemical and mechanical effects induced
by acoustic cavitation.
generally considered as being about 20 kHz, even though the
audible upper limit of frequency in humans depend on age and heterogeneous reactions involving solid−liquid and liquid−
other physiological conditions. Power ultrasound is devoted to liquid interfaces, such forces result in high-velocity flows,
high-intensity applications that produce permanent changes in acoustic streaming, which enhance both mass and energy
the physical and chemical properties of materials. Most transfers. Bubble implosion on surfaces generates microjets,
sonochemical reactions are conducted at ultrasonic frequencies hammering, and interparticle collisions,17 all accounting for the
between 20 and 100 kHz with intensities high enough to cause well-established mechanical action and cleaning of acoustic
cavitation in the liquid medium. This unique phenomenon cavitation.8,18 In aqueous media and in the presence of oxygen,
provides the kinetic energy that fuels a transformation to formation of reactive oxygen species (ROS) will take place,
completion and involves a juxtaposition of purely chemical with the OH radical being the most significant and nonspecific
(i.e., bond-breaking and bond-forming reactions) and oxidizing agent. Accordingly, a large variety of organic
mechanical (cleaning, dispersion, friction, interface instability, molecules, especially pollutants, can be degraded by sonication
degassing, defoaming, and others) effects. Within this context, alone or combined with other protocols.19 Good correlations
ultrasound-induced chemistry can be appropriately defined as between octanol−water partition coefficients and reaction rates
cavitational chemistry.9,10 Cavitation refers to the generation of have been observed, as hydrophobic pollutants tend to
voids or microsized cavities when a liquid suffers a sufficient accumulate near cavitation bubbles.20 The cytotoxicity
pressure drop that disrupts its cohesive forces. The subsequent associated with some ROS can also be harnessed in
and violent collapse to restore the intermolecular interactions sonodynamic therapies, involving the action of sonosensitizers
releases a huge energy input accounting for the aforemen- under ultrasonic stimulation.21
tioned effects. Although cavitation can be produced by various Remarkably, cavitation is a geochemical phenomenon that
methods, there is little doubt that acoustic cavitation is the best occurs naturally under intense hydrodynamic conditions,
known. The extreme conditions inside the microbubble with turbulent streams, earthquakes, or waterfalls and wherever a
temperatures of several thousand Kelvin and more than 1000 shear force rapidly disrupts the continuity of aqueous surfaces.
atm were notably advanced by Lord Raleigh in the first Collapsing waves in primeval oceans would have generated
hydrodynamic model as early as 1917.11 Given the small size sufficient cavitation to induce chemical reactions and hence,
(∼1 μm) and transient lifetime (∼1 ns) of bubbles, the formation of organic compounds.22 The putative role of
physical nature of cavitation has been ascertained through light cavitation in prebiotic synthesis of life-based building blocks
emission spectra (sonoluminescence) that occur during bubble was suggested long time ago,23,24 but its potentiality has
collapse, which have even unveiled formation of plasma-like scarcely been explored. A recent and detailed study from
conditions in recent studies.12−14 Grieser’s team reported that cavitation may be effective in
Surprisingly, the first chemical effects observed by Loomis producing amino acid mixtures from carbon and nitrogen
and his co-workers were ascribed vaguely to “frequency effects” sources available in the early biosphere.25 Ultrasonic irradiation
(they employed high-frequency transducers, unusual by that (355 kHz, 70 W) of a mixture of nitrogen, methane, water, and
time). By 1929, however, the first description of ultrasonic acetic acid led to formation of a few amino acids (glycine,
oxidations suggested the putative role of hydroxyl radicals.15 ethylglycine, and alanine) at rates in the range 1−100 nM/min
Richards reported the first comprehensive review of supersonic (Scheme 1).
transformations, including sonochemical ones, in 1939 with It is believed that pyrolytic decomposition of substrates
348 references.16 would occur within the imploding bubbles, affording H•, HO•,
•
A catching picture of cavitation and its effects is shown in NH•, and NH2• radicals, among others, with acetic acid being
Figure 1. Volatile reagents and solvents will be trapped in the sufficiently volatile to enter an expanding bubble and
microbubbles, then undergoing homolytic cleavage and/or fragmented into carbonaceous radicals as well. Both radical−
conversion into excited states. This represents a primary radical and radical−molecule reactions should be equally
sonochemistry that can be followed by secondary effects, as probable given the high radical concentration within the
such reactive species delivered into the liquid will react with bubbles and yielding the end products in solution. This sort of
molecules at the vicinity of the collapsing bubble or recombine cavitational syntheses provides new vistas in origin-of-life
to form stable products. Bubble collapse is accompanied by studies, as evidenced recently by Zeiri et al. from a
shock waves and shear forces that may cause further rupture of computational simulation of cavitational impacts (via shock
nonvolatile molecules accumulated at the bubble interface. In wave modeling) on variable gaseous mixtures (CO, CO2, CH4
13834 https://doi.org/10.1021/acs.joc.1c00805
J. Org. Chem. 2021, 86, 13833−13856
Scheme 1. Prebiotic-like Cavitational Synthesis of Amino + N2, NH3, or HCN) showing the generation of prebiotic
Acids monomers like glycolaldehyde, glyceraldehyde, urea, cyana-
mide, formamide, isocyanic acids, and others.26
■ OPTIMIZATION AND MODES OF OPERATION.

APFEL’S RULES
Although this Perspective is not intended to be a tutorial on
ultrasonics, like in the case of raising techniques, electro-
chemistry, for instance,27 some background and guidelines are
pertinent showing the simplicity of the technique through
three common devices. The toolbox relies on the proper use of
operational modes to ensure reproducibility, as gathered in
Figure 2. Some basic precepts and tips for proper use of ultrasonic devices. The image (from left to right) shows the usual setups (bath, probe, and
cup horn) to conduct sonochemical reactions.
J. Org. Chem. 2021, 86, 13833−13856
Figure 2.6,28 Such setups usually work at a given frequency with Although global effects vary with the acoustic frequency,32 it
wave amplitudes controlled by external voltage. Multifrequency makes no sense to worry about using specific frequencies.
reactors, even reaching the MHz zone, are more expensive and Moreover, in some common devices, such as baths, the
require a bit of expertise. Dosimetry methods to determine the resonance frequency is modified by other parameters like
actual acoustic power are strongly encouraged,8 especially with temperature, the level of liquid in the tank, and the transducer
ultrasonic baths. Numerous practitioners report essentially the load owing to the reaction mixture.8,28
nominal frequency (generally between 25 and 40 kHz) and Since sound is caused by pressure waves, the acoustic
output power indicated by the supplier, which are largely intensity can be defined as the power per surface unit and
meaningless. Nor do reviewers, unfamiliarized with sonochem- denoted as
istry, recognize the importance of determining a few working
parameters. Since sound radiation is devoid of quantum I = PA 2/2ρc (1)
character, similar chemical effects can be attained within a
broad range of frequencies. Certainly, there are frequency where PA is the acoustic pressure amplitude of the wave, ρ the
effects, but they should be assessed separately as a function of density of the liquid, and c the speed of sound in that medium.
the acoustic intensity. The solvent is more than the reaction This expression is valid only for planar or spherical waves
medium. While conventional chemistry pays attention to generated within low-pressure variations. Cavitation at low-
solvent’s properties like acidity or polarity, physical character- frequency ultrasound induces significant changes in acoustic
pressures and complex, nonlineal behaviors are observed.33 A
istics (volatility, viscosity, or surface tension) play key roles in
relative measurement (and usually invoked in chemical
sonochemical activation as they will affect both sound
studies) can be obtained from the amplitude of the emitter.
propagation and cavitational implosion.
However, a common mistake is to associate the ultrasonic power
The design of devices enables various adjustments like
ef fect with the vibrational amplitude because the acoustic power
pulsed on/off irradiation, pressurized vessels, or bubbling gas.
transmitted depends on the emitting surface. Even worse, if the
Even if the hot-spot temperature inside the microbubbles will
amplitude is maintained at the same level during a chemical
determine the outcome of a sonochemical reaction (amount
reaction, any modification of the system (such as temperature,
and nature of excited species), the macroscopic temperature
viscosity, concentration, etc.) will also modify the power. In
has the same relevance as in silent reactions. Pulsed mode or
other words, the amplitude must change if the power is to
thermostated vessels provide accurate thermal control. A
remain constant. That said, running a reaction at different
“quick and dirty” solution, yet practical with cleaning baths,
vibration amplitudes enables comparisons of synthetic
involves the deliberate addition of ice or cold water as the
efficiency, provided that other parameters, including the
temperature rises after prolonged sonication.
shape and dimensions of the probe assembly, are specified.
In the late 1980s and early 1990s, some sonophysicists, long
Probably the best way to characterize the energy delivered
engaged in cavitation, became rather perplexed when chemists
into the reactor is the notion of ultrasonic power, i.e., the
reported sonochemical experiments, often using baths, without
transmitted acoustic power (in watts or milliwatts) or the
knowing the acoustic field to some detail.29 As mentioned
power density (W/cm2). This value can be inferred from
above, this criticism is also pertinent in 21st century
physical or chemical measurements.8,28,34 The easiest physical
sonochemistry, although a full physical modeling of that field
method implies the assimilation of the reaction vessel to a
is not required and it is obviously beyond the scope of calorimeter, where the temperature is measured and plotted
synthetic purposes. In context, however, one should recall a against time. Above the cavitation threshold, the acoustic
few precepts, postulated by Apfel some decades ago,30 which energy is partially dissipated into heat. The calorimetric power
are known as Apfel’s golden rules and expressed in a Socratic (in watts) can be deduced from the following relationship with
style: “know thy liquid”, “know thy sound field”, and “know slope ΔT/Δt
when something happens”. Apfel reasoned that the first
determines the cavitational threshold, the second the accuracy P(w) = m ·Cp·ΔT /Δt (2)
of measurements, and the third tells us that the effects of
cavitation indirectly inform about the magnitude of cavitation where m is the mass of liquid irradiated with ultrasound and Cp
itself. In short, the rules warn about the measurement and the isobaric thermal capacity. It is obvious, by virtue of the
significance of the acoustical parameters and, as a consequence, nonlinear behavior of cavitation bubbles, that the bulk
on the right use and calibration of ultrasonic devices. temperature may not be spatially homogeneous and variations
The definition and use of physical parameters in the field of occur within the reaction vessel.35 Accordingly, irradiation
ultrasonics are rarely obvious to the chemist and can be the focused on small volumes is desirable in the search for
source of misinterpretations and overestimations. They are, reproducibility. Chemical dosimetry involves the estimation of
however, of paramount importance for reproducibility and radical species by sonolysis, which can be quantified by UV−
should remain constant for comparative analyses. Ultrasonic vis or fluorescence measurements.36 In aqueous media, OH
frequencies are divided into two broad groups: low-frequency/ radicals are created and monitored by different methods, the
high-power (from ca. 18 kHz to 100 kHz) and high-frequency/ most popular being the Weissler reaction, based on the
low-power (from 100 kHz to 10 MHz). The former is the oxidation of an aqueous KI solution to I2; addition of some
usual area of sonochemistry where mechanical effects are halogenated solvents greatly enhances the oxidation rate.8 In
prevalent, while enhanced radical production and therefore organic solvents, radicals other than OH• can be generated,
chemical effects, are associated with the high-frequency and the decomposition of reagents like DPPH (2,2-diphenyl-1-
range.28,31 The reactive species generated within the collapsing picryl-hydrazyl) has become a very sensitive probe of organic
bubble and diffusing into the surrounding liquid, follow sonolysis. Spin-trapping of the radicals with monitoring by ESR
different evolution as a function of the bubble lifetime and is an accurate method, not always available in every
radius, which depend among others on the frequency. laboratory.37 More sophisticated and accurate protocols take
J. Org. Chem. 2021, 86, 13833−13856
advantage of sonoluminescence spectra or chemiluminescence from an electrophilic aromatic substitution under stirring to a
mapping obtained by oxidative degradation of luminol.38,39 bimolecular nucleophilic substitution by sonication, as the
These methods provide a topology of the ultrasonic field, i.e., more vigorous ultrasonic agitation alters the surface sites of the
the spatial distribution of acoustic energy and location of catalyst, thereby hampering the former reaction. This
maxima in cavitation. interpretation, now widely accepted, might not exclude the
■ SONOCHEMICAL REACTIVITY: CONVERGENT AND

DIVERGENT PATHWAYS
generation of radical species on a solid surface, provided the
organic precursor is prone to undergo a SET pathway.
A paradigmatic illustration of sonochemical convergence is a
When we were introduced to the field of ultrasonics, our Wittig−Horner olefination catalyzed by Ba(OH)2, for which
motivation as organic chemists was to understand an there is compelling evidence of a radical pathway with
apparently new model of chemical reactivity, other than sonication playing a 2-fold role.41 The hydroxy groups on
photochemistry and electrochemistry. Luche proved to be an the catalyst surface serve as single-electron releasing sites which
efficient mentor and wondered about the central point:2,10 under ultrasound produce the radical anion of the
When and where does sonochemistry take place? phosphonate ester. The other ultrasonic effect is to cleave
A general misconception dealing with ultrasonic activation is the trace amounts of water affording OH• radicals in sufficient
the often unproven assumption that a radical pathway is concentration to sustain the catalytic cycle (Scheme 3).
triggered and single-electron transfer (SET) occurs, as
cavitational implosion causes solvent’s pyrolysis and homolytic Scheme 3. Convergent Sonochemical Wittig−Horner
ruptures. The reaction partners can be unaffected and the Reaction Catalyzed by Barium Hydroxide
whole reaction remains insensitive to sonication or exhibits a
weak effect. This consideration is behind the so-called Luche’s
rules in an attempt to determine whether or not the rate-
limiting step is actually the sonication-sensitive step and,
whether cavitation or new chemical intermediates dictate the
reaction outcome. Luche himself cautioned about the general
use of a classification based largely on empirical observations.
There is a consensus on the Second Class reactions involving
heterogeneous ionic reactions, both solid−liquid and liquid−
liquid, where mechanical effects derived from violent bubble
collapse at the interfaces (vide supra) account for rate and yield
enhancements. Moreover, polar and nonvolatile molecules can
accumulate at the bubble-liquid interface, yet experiencing Homogeneous reactions in solution, illustrated by numerous
breakage by shock waves. As we shall see shortly, the addition and substitution reactions, appear to be the most
categorization is unclear in numerous cases and borderline problematic cases to understand. The hydrolysis of saccharose
situation emerge. When seeking a mechanistic rationale, a is a valuable example where the increase of reaction rate
convenient approach is the elucidation of convergent and observed with irradiation is related to the cavitational event, as
divergent processes (Scheme 2).10,40 This view on reactivity some formic acid, most likely generated by oxidation of the
sugar with OH radicals, catalyzes this pH-dependent reaction.
Scheme 2. General Classification of Sonochemical Reactions The conjecture could be confirmed by performing a
Relative to Silent Conditions Depending on Product mechanically stirred reaction in the presence of HCOOH
Distribution with quasi-identical results as for the sonolyzed reaction.42
Acid-catalyzed hydrolysis of esters or acetalization reactions
exhibit, however, weak sonication effects with only marginal
increases in the rate. The fact that irradiation at higher
frequencies does not modify the rate with respect to the
nonsonicated reactions points to the negligible effect of radical
production on such purely ionic mechanisms.10 Conversely,
heterogeneous acetalization of unprotected sugars, which
remain insoluble in the reaction mixture, are significantly
accelerated by the sonication treatment.43 Clearly, the polar
mechanism is not affected, but the enhanced mass transfer
relative to conventional stirring leads to a greater yield.
Notably, products are usually cleaner as acceleration avoids
envisages the plausibility of competitive, simultaneous polar side reactions occurring in solution, and due to acid catalysis in
and radical pathways. When silent and ultrasonic reactions a simultaneous way as the heterogeneous transformation
converge to the same product(s), only an overall acceleration proceeds. Such side reactions, being homogeneous polar
usually results from sonication along with a different product processes, are not affected by sonication either.
distribution. If the two reaction pathways are divergent and Substrates with ambident reactivity or those leading to
afford different products, sonication carries a true chemical stabilized carbon- or heteroatom-centered radicals represent
component that leads to switching. It is worth pointing out the realm of the third class of sonochemical reactions, which
that both convergence and divergence under sonication do not can follow either SET reactions or conventional ionic/
necessarily imply a competitive radical route. This reminds us that concerted routes. The direct coupling of metals and organic
the first sonochemical switching reported involved the change partners usually requires harsh conditions or are virtually
J. Org. Chem. 2021, 86, 13833−13856
negligible at room temperature, most likely owing to the carbon chemistry, and account for the positive effect in
heterogeneous nature of the system. Sonication in the presence activating volatile metal carbonyls.
of electron carriers (like benzophenone or 4,4′-ditert- It is somewhat counterintuitive that violent cavitation
butylphenyl affording almost instantaneous production of leading to turbulent hydrodynamic regimes achieves selective
their colored radical anions) leads to dramatic reaction rates transformations, which would not occur under other conven-
in the so-called supersonic preparation of versatile metal tional conditions. In the synthesis of (+)-milbemycin-β1,
reagents.44 This result would not be expected on a mechanical structurally related to avermectins and isolated from
effect alone and lends instead support to a SET pathway Streptomyces bacteria, and employed for veterinary use, a key
triggered by ultrasound. Two noticeable examples are lithium alkylation step was only successful with ultrasound and
diisopropylamide (LDA) and samarium(II) iodide, widely compatible with a sensitive array of functional groups (Scheme
employed in contemporary organic synthesis.45,46 Scheme 4 6). Likewise, the synthesis of naturally occurring bioactive
compounds benefitted from the pluses of sonication, as
Scheme 4. Preparation of LDA by Activation of Lithium exemplified in the synthesis of a key intermediate en route
with Ultrasound and Isoprene as Electron-Transfer Reagent to tetronasin, an ionophore antibiotic (Scheme 7).44 The use
of NaSePh in the second step, sonochemically generated by
cleavage of PheSeSePh with sodium in THF, proved to be
instrumental. In the presence of benzophenone as ET reagent,
sonication speeds up the reaction from 72 h (without the
ketone) to 0.1 h.
These transformations take place under heterogeneous
conditions and can reasonably be categorized within the
Type-III class of sonochemical reactions capable of following
either polar or radical mechanisms. Selectivity could then be
ascribed to reactions occurring prevalently at the solid−liquid
interface, rather than in solution, with adsorption−desorption
depicts the expeditious sonochemical preparation of LDA that
can be conducted in less than 30 min at room temperature and promoted by cavitation. The argument is reinforced by other
bypass the inert and dry conditions used conventionally.47 cases where both regio- and stereoselectivity are enhanced
Sonication of diisopropylamine, lithium powder, and an using low acoustic powers. Conversely, poor selection takes
electron carrier (ideally isoprene as the only byproduct is place as the ultrasonic intensity increases, thereby removing
volatile methylbutene), in THF or a THF−heptane mixture, faster adsorbed species or transient intermediates that would
affords the desired LDA reagent. Electron transfer from the evolve in the bulk liquid.49 The point is further witnessed by a
metal surface to the dialkylamine occurs almost immediately recent and salient Pd-catalyzed meta-selective C−H function-
under sonication. alization of arenes tethered with a controlling distal group.50
The ease with which some metal reagents are obtained by Using a cleaning bath at room temperature without special
sonication can further be coupled with elegant elaborations of power control, alkylation, olefination, acetylation or cyanation
natural product skeleta, like the families of avermectins and proceeded selectively at meta-position and without a trace of
milbemycins, especially aided by transition-metal carbonyls. disubstituted meta-isomers observed under thermal reactions at
Thus, π-allyl tricarbonyliron lactones (ferrilactones), which can higher temperature and longer reaction times (Scheme 8).
be isolated as stable crystalline solids from a variety of Some reactions did not occur in the absence of sonication. The
carbonyl, epoxide, or aryl sulfone reagents, lead to four-, five-, rationale should be involving a conventional metal-catalyzed
and six-membered lactones and lactams. Ultrasound enables arene substitution, although the assistance of acoustical force
their transformation into more sensitive substances such as cuts the energy barrier and enhances a direct meta-
glycosides, glycals, and medium-ring cyclic ethers that are functionalization.
unavoidable under thermal conditions.44,48 As portrayed in In retrospect, the main application of ultrasonically activated
Scheme 5, malyngolide (isolated from a 1:1 diastereomeric zerovalent metals is linked to one-step Barbier-type reactions,
mixture by chromatography), a natural product present in blue usually affording convergent results relative to silent reactions
algae and active against mycobacteria and micrococcus, could be and employing more sustainable conditions such as aqueous
easily prepared from a vinyl epoxide through a sonochemical media.51 SET mechanisms are plausible for electropositive
reaction with Fe2(CO)9 in benzene. Sonication releases metals and those having low ionization potential energy as
Fe(CO)5 or Fe(CO)4 that can be trapped by alkenes and surfaces become rapidly depassivated from hard and unreactive
other double bonds. Such coordinatively unsaturated metal coatings. Cheap and less hazardous metals, rather than ionic
species play the equivalent role of radicals or carbenes in all- compounds, have also been harnessed for orthogonal
Scheme 5. Short Synthesis of Malyngolide Involving the Sonochemical Formation of a Stable Ferrilactone
J. Org. Chem. 2021, 86, 13833−13856
Scheme 6. Semisynthetic Route to Enantiopure Milbemycin-β1a
a
The first step fails without sonication.
Scheme 7. Key Intermediate’s Synthesis toward Tetronasin reactive species.57,58 As discussed above, the heterogeneous
sonochemistry of small molecules will always be influenced by
mechanical energy transfer as the turbulent implosion leads to
friction and deformation at boundary surfaces.59 This
tribochemical consideration mirrors the mechanical interpre-
tation of ultrasonic agitation in liquids as an elongational flow
field, where the strain rate depends on the time passed since
the onset of cavitational collapse, the radius of the imploding
bubble, and on the distance to the bubble.60 In homogeneous
and/or dilute systems, however, the tensile forces lack
directionality and molecular control is much more difficult to
achieve than in standard mechanochemistry involving solid−
solid and solid−liquid contacts.61 A way to convey mechanical
activation to small molecules relies on the use of covalently
linked polymer chains that, playing the role of large tweezers,
concentrate and propagate the mechanical input on labile
functional groups. Such entities now called mechanophores are
embedded in or near the middle of polymer chains, thereby
undergoing specific cleavage, whereas that mechanical
protocols, like the azide−alkyne cycloaddition. Thus, we were activation fails if chains are not attached to both ends of the
able to develop an improved click reaction using metallic mechanophore. A salient result that challenges the validity of
copper that overcomes other limitations such as the in situ Woodward−Hoffmann rules for pericyclic reactions was
generation of Cu(I) species and the removal of copper salt described by Moore and associates on the sonication of a
byproducts.52 The Cu(0)-based protocol can be applied to benzocyclobutene mechanophore in the middle of poly-
simple and elaborated substrates (like cyclodextrins) and gives ethylene glycol side chains (PEG) (Scheme 10).62 Both cis-
rise to products in higher yields and shorter times than the and trans-derivatives experience ring opening affording an
nonirradiated reactions. This also avoids the use of additional (E,E)-configured diene, whose presence could be corroborated
ligands to stabilize Cu(I). Polar solvents are required, which by spectroscopic identification using a chromophore-contain-
allow for higher cavitational energy coupled with heating ing molecule. Under thermal activation only the trans-isomer is
(Scheme 9). expected to give the (E,Z)-diene.
Divergent sonochemistry, by which irradiation switches the It is obvious that mechanical scission caused by strain after
reaction outcome to products unavailable under silent bubble collapse is most likely responsible for polymer cleavage.
conditions, is widely documented, although surely the most Ultrasound does seemingly induce conrotatory opening in
prominent results have been reported in recent years in the trans-benzocyclobutene and disrotatory motion in the cis-
context of ultrasound as mechanical force.53−56 Most examples isomer. In principle, the conversion between (E,Z) and (E,E)
involve polymer chains in solution irradiated by low-frequency products could involve a biradical transition structure;
probes in high-intensity fields for which mechanical effects and however, radical production appears to have a negligible effect
acoustic streaming are prevalent over chemical production of in the present case. Accordingly, the intuitive conclusion is that
Scheme 8. Direct and Selective Meta-C−H Substitution of Arenes Mediated by Ultrasound
J. Org. Chem. 2021, 86, 13833−13856
Scheme 9. Alkyne−Azide 1,3-Dipolar Cycloadditions Activated by Sonication Using Metallic Copper
Scheme 10. Forbidden Ring-Opening Reaction of poly(ethylene glycol) chains.68 The divergent results under
Benzocyclobutene Mechanophores Induced by Ultrasonic thermal and ultrasonic rupture are shown in Scheme 11.
Activation
Scheme 11. Divergent Sonochemical and Thermal Scission
of Azobisnitriles within Long Polymer Chains
thermally forbidden mechanisms may become mechanochemi-

cally allowed pathways within a certain range of forces. Mechanical activation conducted with a high-intensity 20
Theoretical simulations indicate that mechanical force can kHz probe at mild temperature (6−9 °C) led in less than 60
bias a given reaction toward a nonconventional fragmentation min to selective formation of a cyano alcohol derivative, arising
easier to achieve.63,64 Sonicated polymer solutions can mimic likely from oxidation of radical intermediates, which should
the response of macromolecules to mechanical loads in also be generated by thermal fragmentation of the starting
compressed solid polymers, although thermodynamically polymer. Thermal activation, however, required a higher
controlled mechanochemical reactions are difficult to assess temperature (82 °C) for 24 h and gave rise to products
in solution, as the equilibrium is re-established once the resulting from hydrogen abstraction and dimerization. The
polymer escapes the elongational flow.61 Thermodynamically distinctive hydroxyalkylation under sonication evidence the
forbidden reactions, such as cis-to-trans isomerization of rigid role played by species produced after cavitational implosion,
bonds, can reach a lower transition barrier under mechanical which are inaccessible by thermal degradation. This had
strain that can be rationalized in terms of force distribution already been observed by Nakamura et al. in a series of studies
along a flexible polymer backbone.65,66 on sonochemical initiation of radical chain reactions where
Although mechanisms and conditions for both polymer hydroxy groups are added to C−C double bonds.69
fragmentation and polymer formation in acoustic fields are well Numerous mechanophores and metallo-mechanophores
established and receive increasing attention,67 it is fair to say undergo expeditious scission or transformation in the middle
that the mechanophore concept grew up from the scission of a of polymer chains subjected to pulling forces caused by
diazo bond stabilized by adjacent cyano groups and within two cavitation.70 An interesting and recent addition is the
J. Org. Chem. 2021, 86, 13833−13856
mechanochemical unzipping of polyladderenes, for which force Scheme 13. Mechanochemical Stabilization and Hydrolytic
causes an extensive rearrangement of the structure converting Acceleration of Maleimide−Thiol Adducts during
the nonconjugated and, hence, insulating, polyladderene Sonication
structure into a conjugated polyacetylene with semiconducting
properties.71,72 Due to the strained arrangement of fused four-
membered rings, ladderenes undergo facile ring fragmentation.
A terminal cyclobutene ring of the chloro-substituted [5]-
ladderane monomer breaks through ring-opening metathesis
polymerization (ROMP) with a Grubbs ruthenium carbene
catalyst. Further dehydrohalogenation affords homopolymers
loaded with ladderene mechanophores along the skeleton.
Sonication of the soluble mixture under argon causes extensive
formation of a polyacetylene, which self-aggregates after
prolonged irradiation resulting in an insoluble blue-colored
polymer (Scheme 12).
Scheme 12. Formation of Polyladderene-Polyacetylene

Copolymers under the Mechanical Action of Ultrasound
centered mechanophore. Similar strategies have been tailored
to drugs linked to polymers by covalent or noncovalent
interactions. Thus, the aminoglycoside antibiotics neomycin B
and paromomycin are released from RNA aptamers, as the
carrier, by ultrasound-induced cleavage of both noncovalent
interactions and labile covalent bonds with the phosphodiester
RNA moiety. H-bonding interactions between a peptide and
the antibiotic vancomycin (yet bound to a polymer or gold
nanoparticle) can easily be disrupted by sonication. 75
Complementary methods against infectious diseases combine
both antibiotics, not necessarily linked to carriers, and the
sonobactericide effect of bubble cavitation that fragments the
cell wall and degrades other biomolecules required for bacterial
function.76 Furthermore, cell membrane permeabilization, a
process described as sonoporation, can be induced by stable
cavitation at higher frequencies and enhances intracellular
delivery of some drugs in tumor cells.77
Application to bio-/physiological processes along with drug At this stage, most convergent sonochemical reactions have
release represent extensions of sonolytically activated mecha- traditionally been gathered within the classification of false
nophores. It is noteworthy a paradoxical example where mild sonochemistry, benefiting from mechanical action and enhanced
sonication stabilizes through stretching, compounds that would be mass transfer. However, they can be divergent in nature, as the
unstable in the absence of force, as reported recently for nonirradiated reaction does not occur at all or requires
maleimide−thiol adducts.73 Such derivatives are employed in conditions that can be circumvented by sonication. An
bioconjugation, although they are susceptible to retro-Michael interesting example is the ultrasonic treatment of silanes
reaction and, as a result, thiol exchange in vivo that diminishes opening the path to new silicon structures. Due to the inverse
the therapeutic effect of bioconjugates. Pulsed sonication in polarization of the Si−H bond, small silicon hydrides are more
aqueous buffer at pH 7.4 of a polyethylene glycol (PEG)− reactive and energetic than the corresponding alkanes, and
maleimide reagent modified with trastuzumab, a clinically used ignite in air spontaneously. Heating of silanes leads to pyrolytic
antibody, accelerates adduct hydrolysis, thereby stabilizing the disproportionation and oligomerization reactions producing
resulting conjugates and cutting significantly the competing long-chain silanes, but elevated temperatures (∼400 °C) and
retro-Michael reaction (Scheme 13). In addition, sonication inert atmospheres are necessary. An alternative ultrasonic ring-
does not change the binding of the antibody to its target opening polymerization of cyclopentasilane (Si5H10) for
ligand. In fact, antibody−PEG conjugates prepared under instance, causes ultrafast decomposition leading to silicon
ultrasonic irradiation showed ligand-binding activity similar to nanoparticles that can further be polymerized with ultrasound
those of silent conditions in an enzyme-based assay. or UV light to Si-based materials for electronic or solar
Likewise, mechanical scission of disulfides bearing cargo applications.78 The initiation of polymerization, assumed to be
molecules within the center of a water-soluble polymer enables homolytic pyrolysis, is sonocatalytic in nature and not thermic,
the liberation of anticancer molecules, such as camptothecin owing to the low macroscopic temperature of the solution
and gemcitabine, accompanied by fluorescent reporters.74 (between 20 and 75 °C).
Sonication (20 kHz probe, 15.84 W/cm2) causes the reductive Heterogeneous and aqueous biphasic reactions, for which
cleavage of the disulfide bond, and the resulting thiols are then ultrasound often gives rise to remarkable improvements
involved in a subsequent 5-exo-trig cyclization that liberates the without altering the conventional mechanism, have become
drug molecules (Scheme 14). As expected, terminally appealing in the context of a green chemistry agenda.5,6,79
functionalized polymers failed to release the small molecules, Enabling technologies make it possible reactions hitherto
thus confirming the stretching force of long chains on the unknown having pluses in terms of higher yields and
J. Org. Chem. 2021, 86, 13833−13856
Scheme 14. Mechanical and Reductive Cleavage of Disulfide-Centered Polymers Aimed at Drug Release by Ultrasonication
selectivities in shorter times. A critical appraisal based on green rapid micromixing of the reaction partners. 84 As a
metrics should be advocated nevertheless.80,81 Enabling consequence, sonication may replace the assistance of phase-
techniques, namely ultrasound, microwaves, electrochemistry transfer catalysis and facilitate the coupling of insoluble
or mechanochemistry, are not green on their own. It is ironic to substrates in aqueous media. Representative developments
claim benign syntheses under such “green conditions” while that illustrate the efficient sonomixing of biphasic solutions are
ignoring the amount of volatile solvents needed for product portrayed by olefin metathesis in aqueous emulsions or on-
isolation and purification, as well as the fate of waste generated. water reactions. A sonochemical ring-closing metathesis
That said, ultrasound exerts a beneficial homogenizing effect (RCM) at room temperature, without surfactants or organic
that enables water and water−organic cosolvent mixtures to be cosolvents, takes place inside the water-insoluble droplets of
used, along with “in-water” and “on-water” reactions that the diene, leading to carbocycles in almost quantitative yields
depend strongly on interfacial contact.82 Early work by Ando (Scheme 15).85 The ring-forming process occurs under neat
and co-workers showed that ultrasound alone may replace the conditions as well, although accompanied by side products
role of water and heterogeneous solid−solid and solid−liquid resulting from diene oligomerization. The latter was prevented
reactions are more favored than those run in homogeneous under the micellar conditions attained with sonication.
solution. As example, a strong oxidant like KMnO4 oxidizes A one-pot synthesis of the antitumoral indole alkaloid
alkenes smoothly in aqueous solution depending on the pH of cephalandole A involves the catalyst-free condensation of 2-
the solution, but attacks double bonds very slowly in apolar aminophenol with an indolyl carboxylic acid derivative in water
solvents. The latter is much more efficient under sonication, under ultrasonic agitation. This application discloses a
presumably by destroying or altering the crystal lattice of the convenient atom-economical protocol for the construction of
solid salt.83 Kinetic studies conducted under ultrasonic 2-oxo-benzo[1,4]oxazines in aqueous media that combines
irradiation provided further evidence on hydrophobic inter- ultrasound and heating.86 A related transformation, using a
actions, which are responsible for the acceleration of some chiral diamino ligand as catalyst, (S,S)-diphenylethylenedi-
reactions in aqueous media. Sonication caused retardation of amine, affords the anticoagulant drug warfarin in optically pure
polar reactions in water, whereas rates were restored and form87 and could be accomplished in sonicated aqueous
enhanced in water−ethanol mixtures, likely associated with solution (Scheme 16).
J. Org. Chem. 2021, 86, 13833−13856
Scheme 15. Ring-Closing Alkene Metathesis Using Acoustic tration (50% w/v) that allows the maximum solubilization of
Emulsification acetophenones, aniline, and aryl aldehydes facilitates the three-
component coupling when sonication is applied (Scheme
17).90
Scheme 17. Synthesis of β-Amino Carbonyl Compounds by

Three-Component Reaction in Hydrotropic Solution
Irradiated with Ultrasound
Scheme 16. Sonochemical Syntheses of Heterocyclic Drugs

in Aqueous Media ■ CAVITATIONAL EFFECTS CAN BE USED TO
RESOLVE MECHANISTIC PATHWAYS
The late Nobelist George Olah once said that “mechanisms
cannot be proven, only disproven”. By determining the
influence of acoustical parameters on rates and reaction
products, a sonochemical study can inform on the actual effects
of cavitation. As witnessed in the preceding results, ultrasonic
activation is of enormous value in chemical processing, but
investigation in sonochemical mechanisms is rather unusual.
Seeing as a reaction does not occur under silent conditions,
cavitation points to effects other than thermal activation. In a
high atom-economy construction of fused heterocycles,
pyrano[3,4-e][1,3]oxazines, extruding 2 equiv of methanol
only (Scheme 18), reagents were mixed on KF/alumina as
Scheme 18. Mismatched Cavitational and Thermal Effects

on the Kinetic Activation of a Solid Catalyst
The use of surfactants can increase the solubility of organic

substrates and have a positive effect on inertial cavitation, in
part due to the enhanced growth rate of the bubbles.88 A
cationic surfactant, cetyltrimethylammonium hydroxide, has
been used to increase the solubility of isatin and aryl/ catalyst and sonicated (37 kHz), giving rise to the product after
heteroaryl ketones, whose condensation gives rise to quinolines 45 min at 70−80 °C.91 No reaction occurred using the same
in 75−95% yield at room temperature under sonication (22 catalyst at the same temperature in the absence of irradiation,
kHz, 40% amplitude). Irradiation increases the reaction rate even after 12 h. Given the low volatility of substrates, they will
(by ca. 3-fold) and avoids strong bases like NaOH or KOH not undergo pyrolytic cleavage in the bubble and cavitation
employed in the silent reaction. It is pertinent to note, in terms just provides sufficient kinetic energy to surmount the reaction
of energy savings (energy supplied in kJ per mass of product), barrier. At such a frequency and low power, the kinetic effect
that sonication saved more than 78% energy with respect to might stem primarily from acoustic streaming. However, the
the nonirradiated procedure.89 A similar effect to that of thermal effect alone has little effect on the catalyst’s activation.
surfactants on solvent’s surface tension can be obtained by The key role of cavitation should instead be related to
hydrotropes in aqueous solution. The term hydrotrope denotes shockwaves and microjets that cause local deformation at the
a nonmicelle forming substance, i.e., compounds that do not solid surface and increase the possible reaction sites.
have a critical concentration above which self-aggregation takes Nearly two decades ago, we coped with the interpretation of
place, while increasing the solubility of hydrophobic a sonochemical cycloaddition, which are still among the most
compounds. Aqueous hydrotropic solutions merge both low challenging cases to disentangle. Both moderate accelerations
vapor pressure and increased viscosity, relative to pure water, and greater yields have been reported for a few [4 + 2] and [3
thus causing stronger cavitational collapse during compres- + 2] cycloadditions, the most successful involving quinones as
sional cycles and therefore faster reactions. A hydrotropic dienophiles as well as the use of azadienes.92 The redox
solution containing sodium p-toluensulfonate at a concen- properties of such partners might then lead to an electron
J. Org. Chem. 2021, 86, 13833−13856
transfer instigated by ultrasound giving a radical cation such results are inconsistent with a concerted process while
generated by the diene or its dienophile. This situation supporting a stepwise double Michael addition as shown in
resembles the mechanism of radical cycloadditions and related Scheme 19. The formal cycloaddition could also be accelerated
pericyclic reactions developed by Bauld and associates, though under Lewis acid catalysis and sonication at −10 °C. Given the
initiated by aminium radical cations.93 homogeneous working conditions, the question is whether
The addition of furan (as 2π component) to masked o- there is any sonochemical effect not related to a mechanistic
benzoquinones, generated in situ by oxidation of the switching. UV−vis monitoring in the presence and absence of
corresponding phenol with (diacetoxyiodo)benzene (DAIB), furan revealed that sonication greatly increases the dispersion
was accelerated by sonication, though neither the regiochem- of the parent quinone, thus inducing an efficient mixing in the
istry nor diastereoselection were affected (Scheme 19).94 system without mechanical stirring. The sonochemical batch
reactor behaves, at least for small volumes, like a flowlike
Scheme 19. Addition of Furan to Masked o-Quinones reactor where convective currents avoid local supersaturation
Proceeding through a Probable Stepwise Mechanism and accounts for the observed improvements.
Epoxidation and oxidations not involving radical pathways
appear to be candidates to elucidate the effect of sonication as
changes in frequency and intensity will produce different
amounts of oxidizing free radicals. The use of aqueous
hydrogen peroxide for epoxidation of hydrophobic alkenes
needs the assistance of cosolvents and phase-transfer
surfactants.95 A fine example of mechanistic switching, yet
giving the same product, takes place by combining ultrasound
and a hydrophobic ionic liquid, instead of acetonitrile under
silent conditions, as reported for the epoxidation of alkenes
with H2O2/NaHCO3 and a manganese−porphyrin catalyst.96
The bleaching of the catalyst in CH3CN favored an
epoxidation route where peroxycarbonate (NaHCO4) was
the actual oxidant. In contrast, the ionic liquid (methyl-
Yields were dependent on acoustic energy, temperature, and octylpyrrolidinium-NTf2) protected the catalyst from degrada-
solvent composition. A radical initiator (aminium salt) had no tion and ultrasonic irradiation (20-kHz probe, Pelect = 11.5 W,
appreciable effect on the yield relative to the silent process, nor 0.79 W/mL) kinetically induced the formation of high-valent
did oxygen/argon atmospheres alter the extent of cycloadduct oxo-Mn-porphyrin as oxidant. The ultrasonic effect could be
formation. The combined effect of acoustic power and unambiguously demonstrated by using a chiral bis-binaphthyl
temperature is noticeable (Figure 3). Working with a 30 kHz Mn-porphyrin as catalyst. Enantioenriched epoxides were
obtained in the ionic liquid as solvent, while a racemate
formed in CH3CN without sonication owing to decomposition
of the metalloporphyrin.
The same team conducted epoxidation of cis-cyclooctene at
much higher frequency (800 kHz) using H2O2 and H2WO4 as
catalyst.97 Tungstate salts are in fact appropriate and
sustainable catalysts in the sonochemical processing of biomass
derivatives.98 At high frequency, the increasing production of
OH radicals coming from either water or H2O2 sonolysis
would favor a more efficient and faster path not accessible
without irradiation. Under conventional conditions and due to
the strong exothermicity of epoxidation, there is a sharp
increase of temperature (from 25 to 95 °C in 5 min) that
Figure 3. Cycloadduct yield as function of temperature at three renders the process uncontrolled. To check the influence of
acoustic powers for the reaction of methyl vanillate and furan. sonochemical parameters, high-frequency irradiation was
Reproduced with permission from ref 94a. Copyright 2003 Elsevier applied at low acoustic power to ensure a steady 60 °C
B.V.
temperature, giving rise to a retarded reaction with respect to
silent conditions. Surprisingly, little H2O2 (less than 2%) is
probe between −20 and +20 °C at three different energy levels decomposed by ultrasound as inferred from measurements
(3.6, 10.8, and 17.4 W/cm2), all above the cavitational with a chemical dosimeter, and higher loadings of tungstic acid
threshold, the yields were the lowest at the highest power and do not catalyze hydrogen peroxide decomposition either.
remained practically constant as temperature varied. At 10.8 These results suggest that OH• radicals formed by sonolysis
W/cm2, the yields improved slightly, whereas higher yields do not undergo side reactions that decompose progressively
were attained at the lowest acoustic power (3.6 W/cm2) with a H2O2. Rather, the sonochemical conditions favor the milder
significant variation with temperature (up to 70% at −10 °C). formation of stable peroxotungstate species. The use of
The paradoxical anti-Arrhenius effect of sonochemical reaction biphasic conditions with an onium salt as PT catalyst was
was evident as cavitational collapse enhanced by lowering the explored, but no effect from radical production could be
temperature and hence the solvent’s volatility. The increase in determined. The pluses of sonication are related to an efficient
viscosity as temperature decreased halted the cavitational mixing, in line with the above-discussed cycloaddition, and
activation and the cycloaddition slowed down at −20 °C. All enhanced phase transfer to bring active peroxotungstate
J. Org. Chem. 2021, 86, 13833−13856
The Journal of Organic Chemistry
■
pubs.acs.org/joc Perspective
species from aqueous to organic phase to epoxidize cis- PIEZOELECTRICITY AND PIEZO-REDOX
cyclooctene (Scheme 20). While the silent reaction produces CHEMISTRY
Ultrasonic energy is transmitted by power transducers, which
Scheme 20. Catalytic Cycle Induced by High-Frequency have the ability to convert high-frequency electrical fields into
Ultrasound in the H2O2-Mediated Biphasic Epoxidation of mechanical vibration. This takes advantage of the piezoelectric
Cyclooctene ef fect in certain crystals, by which a mechanical force applied to
an ionic crystal produces an electric polarization, and therefore
a measurable voltage. This is the direct piezoelectric effect. The
inverse piezoelectric effect occurs when a voltage applied to the
material leads to mechanical strain (Figure 4). Piezoelectricity
Figure 4. Schematic representation of direct (left) and inverse (right)

piezoelectric effects.
has the origin in the lack of a center of symmetry in the crystal

structure and the anisotropic effect can only be observed in
some directions of natural and artificial crystals.100 Along with
piezoelectric transducers, magnetostrictive materials have been
employed as well, where a magnetic field converts into
mechanical motion. However, the development of piezoelectric
higher conversion and yield after 15 min, almost complete ceramics with improved mechanical properties make these
selectivity toward epoxide formation is provided by sonication materials suitable for most power ultrasonic systems.
between 15 and 45 min. This result is linked to the accurate Furthermore, piezoelectric crystals can also be ferroelectric
control of temperature (between 60 and 80 °C), which also with a hysteresis loop, a nonlinear relationship between
allows a low loading of H2WO4 as catalyst compared with the polarization and the applied electric field.101 Common
nonirradiated reaction.97 piezoelectric materials include oxides like BaTiO3, PbTiO3
A more direct participation of water sonolysis at high and LiNbO3 together with more complex compositions, albeit
frequency that alters product selectivity is evidenced by glucose in all cases they show perovskite-type structures. It is
oxidation catalyzed by cupric oxide at 550 kHz.99 While noteworthy that piezoelectricity can be substantially improved
ultrasound alone and Cu(II) catalysts can independently by metal doping, which may find further applicability in sonar
oxidize glucose to gluconic acid, water sonolysis at high and ultrasonic imaging.102
frequency under argon leads to H• and OH• radicals, the Piezoelectric materials, in the form of massive solids or
former being trapped by the oxygenated lattice of the catalyst. particles, have shown to catalyze redox reactions under
This leaves concomitantly a broader coverage of OH• radicals mechanical force, like those produced by shear conditions of
on the CuO surface that selectively oxidizes glucose to low-frequency ultrasound as well as strong mechano-vibration.
glucuronic acid (Scheme 21). Moreover, cavitation bubbles are It is believed that charges occur in the catalyst, thereby
generating a strain-induced voltage that can be coupled with
Scheme 21. Selective Sonocatalytic Oxidation of D-Glucose electron transfer with substrates. Such mechanoredox catalysts
to D-Glucuronic Acid under High-Frequency Ultrasound can be viewed as analogous to photoredox catalysts, which
hold significant promises for synthetic explorations. In order to
understand how piezoelectricity can mediate a redox trans-
formation, some physical considerations are needed, the basis
being that aligned dipoles exist within the solid. A compressive
force will decrease the dipole separation, thus leading to a net
charge on the faces of the material and hence a voltage.
Conversely, a tensile force will produce an opposite voltage. As
a result, a piezoelectric material combines both mechanical and
electric properties.103 For an elastic solid, the relation between
stress (σ) and strain (ε) is given by Hooke’s law in the form
much smaller at high frequency than at the usual 20 kHz, thus
σ = Eε (3)
preventing the mechanical damage of shock waves on the
catalyst after implosion. Gluconic acid is formed as byproduct where E is Young’s modulus. For the remaining discussion,
in low yield (<10%), probably due to diffusion of radicals into however, and given the potential confusion between E for
the bulk liquid. The use of a radical scavenger inhibited the Young’s modulus and the standard nomenclature for electric
formation of glucuronic acid, thus illustrating the synergistic field strength (with identical symbol), Hooke’s law should now
effect of OH• radicals and the solid catalyst. be expressed as
J. Org. Chem. 2021, 86, 13833−13856
Figure 5. (Top) Micrometer-sized BaTiO3 or ZnO experience acoustic vibrations that cause water splitting via piezoelectric effect. (Bottom) (a)
SEM and (b) TEM images of BaTiO3 dendrites grown on a glass substrate; (c) SEM and (d) TEM images of ZnO fibers grown on a Si(100) wafer.
(e) Morphologies of a single ZnO fiber (upper image) and BaTiO3 dendrite (lower image). Reproduced from ref 104. Copyright 2010 American
Chemical Society.
σ = c Eε (4) causing the liberation of H2 and O2 from water (Figure 5).

E This phenomenon is conceptually different from other
where c is the elastic Young’s modulus and the superscript (E) sonochemical and mechanocatalytic processes where the
denotes the electrical conditions under which the modulus is
reagent undergoes a redox reaction to split water.105,106 The
measured, in this case, a constant electric field. On the other
piezoelectric catalyst is involved in donating strain-induced
hand, the behavior of a capacitor can simply be described by
electrons and holes without decomposition or redox change.
E = βD (5) Irradiation with an ultrasonic transducer (which actually
harnesses the inverse piezoelectric effect) leads to the rapid
with E being the electric field, D the electric displacement and
production of H2 and O2, with gas generation ceasing when
β the dielectric coefficient. In a piezoelectric material σ and E
ultrasound is turned off. This kind of miniature devices for low-
are coupled in the way that application of force not only
induces mechanical stress, but also produces electric charge. In cost water splitting can be advantageous over other electro-
mathematical form, the following equations dictate the chemical and photochemical procedures, although optimum
behavior through a piezoelectric constant (h) that links the performance depends on both lengths and resonance
mechanical and electrical responses: frequency of the piezoelectric material. Longer fibers may
undergo a greater bending and hence an increase in strain-
σ = c Dε + hD (6) induced voltage.
Piezoelectric (nano)particles can be literally employed as
E = −hε + βD (7) chemical transducers for reduction of organic molecules or
D
the only variation being that the c modulus replaces the above metallic precatalysts required for coupling reactions or radical
cE to indicate measurement under constant charge conditions. polymerizations.107 Scheme 22 depicts the radical polymer-
Ultrasonic agitation of a piezoelectric material can be ization of n-butyl acrylate using a suspension of BaTiO3 NPs
sufficient to generate the electrochemical potential required for sonicated in the presence of n-butyl acrylate, ethyl α-
water splitting.104 Thus, hydrothermally synthesized ZnO bromoisobutyrate as initiator, and equimolar amounts of
microfibers (also exhibiting piezoelectric properties) and Cu(OTf)2, Me6TREN, i.e., N,N,N′,N′,N″,N″-hexamethyl[tris-
BaTiO3 microdendrites were vibrated with ultrasound, thereby (aminomethyl)amine], and Bu4NBr as the catalyst precur-
developing a strain-induced charge on their surfaces and sor.108 The piezoelectric material reduces the Cu(II)
J. Org. Chem. 2021, 86, 13833−13856
Scheme 22. Sonication-Induced Mechano-Radical electrons to small molecules, followed by oxidative quenching
Polymerization with Piezoelectric BaTiO3. Bottom: of a donor molecule, thus leading to bond formation. This has
Mechanistic Simplification of the Sonochemical Activation been shown by Kubota and co-workers using ball milling to
agitate BaTiO3 that reduces aryl diazonium salts, which are
then applied to arylation and borylation reactions (Scheme
24).110 It is worth pointing out that ball milling generally
Scheme 24. Mechanoredox Arylation Mediated by a SET

Pathway with Piezoelectric Material
precatalyst to its active Cu(I) form that activates the alkyl

halide. Ultrasound not only produces alkyl radicals by
homolytic cleavage but also sufficient mechanical input to provides sufficient stress to activate the piezoelectric material,
control polymer growth. while grinding or other mechanical methods afford poor or no
Combination of BaTiO3-mediated step-growth polymer- results, as revealed by solvent-free C−H trifluoromethylation
ization and Cu-catalyzed azide−alkyne click cycloaddition of N-heterocycles and short peptides developed by the same
using the above-mentioned Cu(II)-precatalyst gave rise to a group. Moreover, the optimum performance hinges on the
linear polytriazole.109 Further application of this protocol to a number and size of the balls and longer reaction times.111
polyurethane−trialkyne mixture afforded a polymer, which Piezoactivation of biomolecules, like enzymes, can inspire
could be cross-linked mechanochemically. The resulting gel major developments, although it is well-known that ultrasound
solidified after prolonged ultrasonic irradiation (Scheme 23). affects enzyme activity and may cause extensive degradation
Mechanical activation other than ultrasound in the presence after long irradiation times.112 In a recent study, Yoon et al.
of piezoelectric crystals can trigger a similar mechano-redox were able to implement a peroxygenase catalyzed oxy-
reaction. Above a critical agitation threshold, highly polarized functionalization that exploits the piezocatalytic generation of
particles will be formed serving as strong reductants to transfer H2O2 via oxygen reduction on bismuth oxychloride (BiOCl)
under ultrasound (40 kHz, 70 W).113 Bismuth-based ceramics
Scheme 23. Click Azide−Alkyne Polymerization Using have gained popularity for transducer applications as improved
Cu(I) Species Generated by Ultrasonic Reduction of Cu(II) lead-free ferroelectrics,114 even though bismuth salts remain
Precatalyst with BaTiO3 Particlesa underestimated as piezoelectric reagents115 compared to
titanate compounds.116 An illustration of the oxyfunctionaliza-
tion reaction is shown in Figure 6, where ultrasonic activation
of BiOCl in aqueous buffer solution containing a recombinant
unspecific peroxygenase from Agrocybe aegerite (300 nM)
accelerated the selective hydroxylation of ethylbenzene to
enantiopure (>99% ee) (R)-1-phenylethanol. The mechanism
Figure 6. Sonication-induced catalytic C−H oxyfunctionalization

using piezoelectric BiOCl microsheets plus an unspecific peroxyge-
a
Photo (bottom) reproduced with permission from ref 109. nase. Reproduced from ref 113. Copyright 2020 American Chemical
Copyright 2018 Wiley-VCH Verlag GmbH & Co. Society.
J. Org. Chem. 2021, 86, 13833−13856
should involve the reaction of electrons from the piezoelectric

material with O2 and H2O leading to superoxide (O2•−) and
OH• radical intermediates. The authors hypothesized that such
radical species may inactivate peroxygenase, thus hampering its
catalytic activity. To minimize the oxidative stress of short-
lived OH• radicals, the enzyme was spatially separated from
BiOCl and placed in a dialysis membrane bag, which allowed
the diffusion of H2O2 and products without altering the
catalytic effect.
■ FLOW AND AUTOMATION: THE PRESENT AND

FUTURE
Figure 9. Sonochemical Barton decarboxylation of carboxylic acids
Chemistry from this century on should be dominated by the under continuous flow. The protocol was optimized for hexanoic acid
juxtaposition of automation and machine-learning algorithms, and N-phenylmaleimide using dicyclohexylcarbodiimide (DCC).
Reproduced with permission from ref 128. Copyright 2016 the
Royal Society of Chemistry.
Perspective, we are concerned with acoustoflow synthesis at

the meso- and microscale levels. Unlike batch conditions, flow
and microflow devices exhibit enhanced heat and mass
transfers along with improved reaction kinetics, due to the
small path occupied by reagents in channels of microscopic
diameters, and enable the preparation of organic compounds,
especially active pharmaceutical ingredients.123 In addition, the
reduced dimensions allow the facile penetration of external
energy souces, namely ultrasound, microwaves, or light.124 The
Figure 7. Continuous flow nitration of phloroglucinol assisted by
rapid formation and consumption of intermediates and
sonication. Reproduced from ref 125. Copyright 2014 American
Chemical Society. products, generated in small amounts, entail the safe handling
of hazardous substances. Overall, such benefits are not only
linked to greater efficiency, but also to lower environmental
which will lead to (almost) complete robotization of synthetic impact. The point is well illustrated by a continuous nitration
and operational steps.117,118 The increasing adoption of of phloroglucinol leading to a potentially explosive poly-
continuous flow systems over batch reactors, still with timid nitrophenol as shown in Figure 7.125 The nitration reaction
implementation by the industry, has much to do with more requires an oxidizing and toxic mixture of sulfuric acid and
efficient processes in terms of costs and risks, and in agreement ammonium nitrate, whose manipulation jeopardizes the
with a more sustainable chemistry. protocol, even in dilute conditions. Mixtures of mono- and
While industrial applications of acoustic and hydrodynamic trinitrophloroglucinols are usually obtained, although the latter
cavitation require scale-up considerations (reactor design for could be generated in 98% yield (determined by HPLC) at 40
instance),119,120 which are not covered here, ultrasound and °C using a thermostated ultrasonic bath, which homogenized
flow systems are ideal partners as one moves downward, i.e., the reaction mixture as well.
miniaturization, because acoustic microfluidics constitutes an The most serious drawback of a microfluidic reactor is
emerging technology enabling cell and particle manipula- associated with clogging of small channels caused by
tion.121 Moreover, bubble-based robotics and on-a-chip heterogeneous mixtures and/or concomitant precipitation of
systems should help to develop novel acoustic micro/ products, which can be avoided by cavitational agitation.126
nanomotors and sensors. 122 For the purpose of this The best way to overcome that limitation is to immerse the
Figure 8. Capillary sonoreactor for phase-transfer catalysis. Reproduced with permission from ref 127. Copyright 2009 Elsevier B.V.
J. Org. Chem. 2021, 86, 13833−13856
Figure 10. Telescoped eight-step continuous flow synthesis affording a polycyclic intermediate of biological importance. Reproduced from ref
129b. Copyright 2016 American Chemical Society.
microchannel device in an ultrasonic bath as depicted in Figure production (H• and OH•) and removing oxygen from the
8. The system in question was employed for the phase-transfer solution. The transformation proceeds with formation of CO2
reaction of benzyl chloride and sodium sulfide catalyzed by an and dicyclohexyl urea as byproducts.
ammonium salt.127 Multistep continuous synthesis will require external input to
An optimized Barton decarboxylation has been achieved quicken the flow of heterogeneous mixtures through a narrow
under ultrasonic continuous flow, which enabled large-scale tubing. An impressive example is shown in Figure 10 detailing
synthesis.128 The reductive decarboxylation of hexanoic acid the synthesis of a biologically active intermediate from a
was selected as a case study, using CH2Cl2−MeOH as solvent tricyclic ketone. The complete operational protocol could be
system pumped by HPLC. The mixture was entered into a executed by a single researcher, who also controlled the
tubular reactor (Teflon coil, 0.8 mm internal diameter and 40- machined setup with a low-cost computed-assisted webcam.129
m length) heated in an ultrasonic bath below 35 °C (Figure 9). The telescoped eight-step route comprises in addition three
Both power (10 to 100%, 300 W) and frequency (37 to 80 transformations involving five intermediate downstream
kHz) were regulated, while in order to ensure a liquid mixture processing steps. Sonication was applied to enhance mass
the pressure was set to 0.1 MPa by a back-pressure valve transfer in two critical points (steps 1 and 2), thereby
(BPR). Being a radical mechanism, the Barton decarboxylation increasing overall efficiency.
took advantage of both mechanical and chemical effects A different design for handling solid-forming reactions
provided by cavitation, by bringing energy for radical involves a multilayered piezoelectric actuator (50 kHz, 300 W)
J. Org. Chem. 2021, 86, 13833−13856
Figure 11. Multilayered Teflon-made microsonoreactor that enables rapid dissolution of solid particles by ultrasonic irradiation as shown by
microscopic images. Reproduced with permission from ref 130. Copyright 2011 the Royal Society of Chemistry.
by collapse contribute to break and dissolve solid particles

(Figure 11).
Chemical syntheses on a drop scale have been performed
using a piezoelectric chip irradiated by surface acoustic waves
(SAWs). The miniaturized device consists of a piezoelectric
substrate (LiNbO3) with two interdigital transducers at each
end in the form of 250 nm thick Ti−Al electrodes and then
connected to a power source (Figure 12).131 By applying an
electric field to the piezoelectric material, SAWs are generated
as periodic distortions with an amplitude of a few nm and
wavelengths of several μm propagating across the surface with
the velocity of sound in the solid.132 The distance between the
electrodes determines the SAW frequency, which may vary
from less than 1 MHz to a few GHz. Results collected in Figure
12 were obtained at 20 MHz, usually under net conditions or
using a nonvolatile solvent like diethylene glycol, and
proceeded at far shorter reaction times than reported
conventionally with other energy sources.
Clearly, the working frequencies and acoustic conditions
deviate from those of standard power ultrasonics. Cavitation
effects should be discarded, as greater intensities would
otherwise be required to induce cavitation beyond the MHz
threshold. The observed enhancements are largely thermal,
and in fact, irradiation with such standing acoustic waves, even
for short periods, causes a significant increase in temperature of
the drop (tens of degrees). While SAWs have become a
promising tool in chemical sensing and nanoparticle
Figure 12. Piezoelectric device employed for some drop reactions
(∼40 μL) shown below, irradiated by surface acoustic waves (SAWs) manipulation,133 from a mechanistic standpoint such soft
generated by an external oscillating electric field on the piezoelectric waves can be an alternative to other droplet generation and
material (LiNbO3). Reproduced with permission from ref 131. aerosol-based methods employing heat or ionization activa-
Copyright 2009 the Royal Society of Chemistry. tions. Furthermore, SAWs can inform on catalytic reactions on
surfaces. Thus, up to 6-fold rate enhancement has been
integrated with a Teflon microreactor. The equipment was reported for the catalytic oxidation of CO over platinum films
employed in expeditious and high-yielding (typically >95%) using SAWs under high vacuum.134 Although various
Pd-catalyzed C−N cross-couplings between aryl chlorides and hypotheses have been suggested, both photoelectron micros-
anilines.130 Gas bubbles induced by stable cavitation followed copy and dynamic simulations support the thermal activation
J. Org. Chem. 2021, 86, 13833−13856
The Journal of Organic Chemistry
■
pubs.acs.org/joc Perspective
resulting from energy dissipation along with reversible surface AUTHOR INFORMATION
deformation.135 The latter can enhance catalytic rates via
Corresponding Authors
sorption−desorption process induced by the acoustic oscil-
R. Fernando Martínez − Department of Organic and
lations.
Inorganic Chemistry, Faculty of Sciences, and IACYS-Green
■ CONCLUSIONS AND OUTLOOK

“Oye hijo mio,́ oye el silencio, Es un silencio onduloso”
Chemistry and Sustainable Development Unit, University of
Extremadura, 06006 Badajoz, Spain; orcid.org/0000-
0002-3278-6074; Email: [email protected]
[“Hear my son, hear the silence, It is a wavy silence”] Pedro Cintas − Department of Organic and Inorganic
Chemistry, Faculty of Sciences, and IACYS-Green Chemistry
Federico Garciá Lorca (1931)136 and Sustainable Development Unit, University of
One could conclude that sonochemistry, dealing with the Extremadura, 06006 Badajoz, Spain; orcid.org/0000-
chemical use of sound in a broad range of frequency and 0002-2608-3604; Email: [email protected]
power, has gained a pole position among enabling techniques
with an eye on more sustainable protocols. In some ways, Author
however, the discipline cannot be regarded as mature. We Giancarlo Cravotto − Dipartimento di Scienza e Tecnologia
should ask questions like, why one or the other product are del Farmaco, Universita degli Studi di Torino, Torino 10125,
obtained, whether we can understand how activation happens, Italy; orcid.org/0000-0001-7574-7350
and if the use of ultrasound is really justified, rather than Complete contact information is available at:
claiming another synthetic variation. While ultrasonic https://pubs.acs.org/10.1021/acs.joc.1c00805
activation is rooted in well-established principles of cavitational
phenomena, the first action to be taken, which agrees with the Notes
rules suggested by Apfel, is know the equipment you need and The authors declare no competing financial interest.
how it works. Reproducible experiments can be run paying Biographies
attention to a few parameters without worrying about others.
In our Perspective, we have given a glimpse on known facts.
One can anticipate that some reactions and substrates will be
sensitive to sonication in either physical or chemical terms.
Whether or not ultrasound switches the conventionally
assumed mechanism often needs further evidence, where the
sonochemical experiment itself can be as informative as other
elucidation methods. Attempts to classify sonochemical
reactions can result in ill-conceived conclusions if structural
and solvent effects that usually accompany cavitation are not
investigated in detail. A reductionist approach that merely
considers either convergent or divergent results with respect to
conventional chemistry may be the key to identifying the tools
that are required to understand how the reaction takes place.
Whatever the mechanism can be, a different result under
R. Fernando Martı ́nez studied Chemistry at the University of
sonication is not synonymous with a radical/electron transfer Extremadura, where he received his B.Sc. in 2006. In 2010, he
pathway as often and erroneously invoked; two polar received his Ph.D. at the University of Extremadura under the
mechanisms can compete each other. Perhaps the most supervision of Prof. Juan C. Palacios. In 2011, he moved to Oxford,
divergent results arise from the conceptual framework of where he worked as a postdoctoral researcher in the groups of Prof.
sono-mechanochemistry as another manifestation of mechanical George W. J. Fleet and Prof. Angela J. Russell (University of Oxford).
effects, especially in polymer chains, induced by turbulent In 2015, he joined the group led by Prof. Marı ́a Luz López Rodrı ́guez
solvent flows at the microscale. The issue is complex, although at the Complutense University of Madrid. Since 2017, he has been
inertial motion in an acoustic field may affect both bonding working as Associate Professor at the University of Extremadura.
and energy barriers. As far as we know, cavitation does not
involve an electric field component (as once postulated) and
our present-day interpretation relies largely upon the hot spot
theory. Piezoelectric materials, the source of ultrasonic
transducers, are susceptible to electric polarization under
strain. This peripheral effect can advantageously be exploited in
new mechano-redox processes that provide salient and
unexpected results. A translation of cavitational flow into a
continuous operation has enabled further innovation in
microfluidics and acoustophoretic devices, which should be
part of the future of chemistry. Despite bottlenecks and
insufficient knowledge of cavitational effects, the impact of
ultrasound-based chemistry is steadily increasing in multiple
synthetic and nonsynthetic applications.
J. Org. Chem. 2021, 86, 13833−13856
Pedro Cintas received his Ph.D. in organic chemistry from the (4) Power Ultrasonics. Applications of High-Intensity Ultrasound;
University of Extremadura and carried out postdoctoral studies with Gallego-Juárez, J. A., Graff, K. F., Eds.; Elsevier: Amsterdam, 2015.
Wolfgang Oppolzer in Geneva (Switzerland). He has been fortunate (5) (a) Chatel, G. Sonochemistry. New Opportunities for Green
enough to teach organic chemistry since the early 1990s, learning Chemistry; World Scientific Publishing: Singapore, 2017. (b) Chatel,
regularly more chemistry from both students and coworkers. He is a G., Colmenares, J. C. Sonochemistry: from Basic Principles to Innovative
Applications. Topics in Current Chemistry; Springer: Berlin, 2017.
member of the European Society of Sonochemistry, the American
(6) Lévêque, J.-M.; Cravotto, G.; Delattre, F.; Cintas, P. Organic
Chemical Society, and the Board of Ultrasonics Sonochemistry. Sonochemistry. Challenges and Perspectives for the 21st-Century;
Springer Nature: Cham, Switzerland, 2018.
(7) (a) For selected reviews and chapters, mostly oriented to organic
chemistry/synthesis: Shingare, M. S.; Shingate, B. B. Ultrasound in
synthetic applications and organic chemistry. In Handbook on
Applications of Ultrasound. Sonochemistry for Sustainability; Chen, D.,
Sharma, S. K., Mudhoo, A., Eds.; CRC Press, Inc.: Boca Raton, FL,
2011; pp 213−261. (b) Banerjee, B. Recent developments on
ultrasound assisted catalyst-free organic synthesis. Ultrason. Sonochem.
2017, 35, 1−14. (c) Banerjee, B. Recent developments on ultrasound-
assisted one-pot multicomponent synthesis of biologically relevant
heterocycles. Ultrason. Sonochem. 2017, 35, 15−35. (d) Lupacchini,
M.; Mascitti, A.; Giachi, G.; Tonucci, L.; d’Alessandro, N.; Martinez,
J.; Colacino, E. Sonochemistry in non-conventional, green solvents or
solvent-free reactions. Tetrahedron 2017, 73, 609−653. (e) Penteado,
F.; Monti, B.; Sancineto, L.; Perin, G.; Jacob, R. G.; Santi, C.;
Lenardão, E. J. Ultrasound-assisted multicomponent reactions,
Giancarlo Cravotto became a researcher at the University of Turin organometallic and organochalcogen chemistry. Asian J. Org. Chem.
after spending four years in the chemical and pharmaceutical industry 2018, 7, 2368−2385. (f) Draye, M.; Chatel, G.; Duwald, R.
and one year at the Technische Universität in Berlin (Prof. P. Ultrasound for drug synthesis: A green approach. Pharmaceuticals
Weyerstahl). He is currently Full Professor of Organic Chemistry with 2020, 13, 23.
research activity in the domain of green organic synthesis and (8) (a) Mason, T. J.; Lorimer, J. P. Applied Sonochemistry. Uses of
processing documented by about 450 scientific, peer-reviewed papers Power Ultrasound in Chemistry and Processing; Wiley-VCH: New York,
and 20 patents. He was Director of the Department of Drug Science 2002. (b) Mason, T. J.; Peter, D. Practical Sonochemistry. Power
and Technology (University of Turin) from 2007 to 2018, serving Ultrasound Uses and Applications, 2nd Ed.; Woodhead Publishing Ltd.:
currently as vice-Director. He collaborates with a variety of industrial Cambridge, UK, 2002.
partners. He was awarded the Organic Chemistry for the Environment, (9) Cravotto, G.; Cintas, P. Power ultrasound in organic synthesis:
Energy and Nanosciences prize (2018) and Gold medal “E. Paternò” moving cavitational chemistry from academia to innovative and large-
(2020) auspiced by the Italian Chemical Society. scale applications. Chem. Soc. Rev. 2006, 35, 180−196.
■
(10) (a) Luche, J.-L. Sonochemistry. From experiment to theoretical
considerations. In Advances in Sonochemistry; Mason, T. J., Ed.; JAI
ACKNOWLEDGMENTS Press, Ltd.: London, 1993; Vol. 3, pp 85−124. (b) Luche’s distinction
We express our heartfelt thanks to the many collaborators who between true and false sonochemistry, the former denoting reaction
have helped develop all our past and current projects on outcomes that arise from cavitation-generated species and the latter
applied sonochemistry and related hybrid techniques. Con- stemming largely from enhanced mass transfer in heterogeneous
tinued support from the Junta de Extremadura and Fondo processes, has proven to be useful for classification, although there are
numerous borderline situations that hamper generalization.
Europeo de Desarrollo Regional (as witnessed by recent grants (11) (a) For historical perspectives on sonochemistry and cavitation:
IB16167, IB16022, and GR18015) is warmly appreciated. Bremner, D. Historical introduction to sonochemistry. In Advances in
Additional funding from the European Union through the EU Sonochemistry; Mason, T. J., Ed.; JAI Press, Ltd.: London, 1990; Vol.
H2020 MSCA-ETN COSMIC framework for research and 1, pp 1−37. (b) Cravotto, G.; Cintas, P. Introduction to
training is highly acknowledged as well.
■
sonochemistry: A historical and conceptual overview. In Handbook
on Applications of Ultrasound. Sonochemistry for Sustainability; Chen,
DEDICATION D., Sharma, S. K., Mudhoo, A., Eds.; CRC Press, Inc.: Boca Raton, FL,
This article is dedicated to Jean-Louis Luche (1941−2014) 2011; pp 23−40.
(12) (a) McNamara, W. B., III; Didenko, Y. T.; Suslick, K. S.
and his family (wife and daughters). Jean-Louis contributed
Sonoluminescence temperatures during multi-bubble cavitation.
significantly to the current status of synthetic sonochemistry Nature 1999, 401, 772−775. (b) Didenko, Y. T.; Suslick, K. S. The
and guided the field with generosity and humility, supporting energy efficiency of formation of photons, radicals and ions during
and inspiring students and friends.
■
single-bubble cavitation. Nature 2002, 418, 394−397. (c) Suslick, K.
S.; Flannigan, D. J. Inside a collapsing bubble: sonoluminescence and
REFERENCES the conditions during cavitation. Annu. Rev. Phys. Chem. 2008, 59,
(1) Conant, J. Tuxedo Park. A Wall Street Tycoon and the Secret 659−683.
Palace of Science that Changed the Course of World War II; Simon & (13) Flannigan, D. J.; Suslick, K. S. Inertially confined plasma in an
Schuster: New York, 2002; pp 50−51. imploding bubble. Nat. Phys. 2010, 6, 598−601.
(2) Luche edited in the late 1990s a multiauthor monograph with a (14) For brief remarks on acoustic cavitation, see: Suslick, K. S.;
focus on organic sonochemistry and sonosynthesis: Synthetic Organic Eddingsaas, N. C.; Flannigan, D. J.; Hopkins, S. D.; Xu, H. The
Sonochemistry; Plenum Press: New York, 1998. chemical history of a bubble. Acc. Chem. Res. 2018, 51, 2169−2178.
(3) Handbook on Applications of Ultrasound. Sonochemistry for (15) Schmitt, F. O.; Johnson, C. H.; Olson, A. R. Oxidations
Sustainability; Chen, D., Sharma, S. K., Mudhoo, A., Eds.; CRC Press, promoted by ultrasonic radiation. J. Am. Chem. Soc. 1929, 51, 370−
Inc.: Boca Raton, FL, 2011. 375.
J. Org. Chem. 2021, 86, 13833−13856
(16) Richards, W. T. Supersonic phenomena. Rev. Mod. Phys. 1939, (32) Pétrier, C.; Jeunet, A.; Luche, J.-L.; Reverdy, G. Unexpected
11, 36−64. frequency effects on the rate of oxidative processes induced by
(17) (a) Xu, H.; Zeiger, B. W.; Suslick, K. S. Sonochemical synthesis ultrasound. J. Am. Chem. Soc. 1992, 114, 3148−3152.
of nanomaterials. Chem. Soc. Rev. 2013, 42, 2555−2567. (b) Pokhrel, (33) (a) Leighton, T. G. The Acoustic Bubble; Academic Press:
N.; Vabbina, P. K.; Pala, N. Sonochemistry: science and engineering. London, 1994. (b) Lauterborn, W.; Kurz, T.; Geisler, R.; Schanz, D.;
Ultrason. Sonochem. 2016, 29, 104−128. Lindau, O. Acoustic cavitation, bubble dynamics and sonolumines-
(18) Verhaagen, B.; Fernandez Rivas, D. Measuring cavitation and cence. Ultrason. Sonochem. 2007, 14, 484−491. (c) Kauer, M.; Belova-
its cleaning effect. Ultrason. Sonochem. 2016, 29, 619−628. Magri, V.; Cairós, C.; Linka, G.; Mettin, R. High-speed imaging of
(19) (a) Cao, H.; Zhang, W.; Wang, C.; Liang, Y. Sonochemical ultrasound driven cavitation bubbles in blind and through holes.
degradation of poly- and perfluoroalkyl substances-A review. Ultrason. Ultrason. Sonochem. 2018, 48, 39−50.
Sonochem. 2020, 69, 105245. (b) Wu, Z.; Abramova, A.; Nikonov, R.; (34) For a good overview on the importance of controlling acoustic
Cravotto, G. Sonozonation (sonication/ozonation) for the degrada- power in particular: Wood, R. J.; Lee, J.; Bussemaker, M. J. A
tion of organic contaminants-A review. Ultrason. Sonochem. 2020, 68, parametric review of sonochemistry: control and augmentation of
105195. sonochemical activity in aqueous solutions. Ultrason. Sonochem. 2017,
(20) Serna-Galvis, E. A.; Montoya-Rodríguez, D.; Isaza-Pineda, L.; 38, 351−370.
Ibañez, M.; Hernández, F.; Moncayo-Lasso, A.; Torres-Palma, R. A. (35) Al-Juboori, R. A.; Yusaf, T.; Bowtell, L.; Aravinthan, V. Energy
Sonochemical degradation of antibiotics from representative classes. characterisation of ultrasonic systems for industrial processes.
Considerations on structural effects, initial transformation products, Ultrasonics 2015, 57, 18−30.
antimicrobial activity and matrix. Ultrason. Sonochem. 2019, 50, 157− (36) Mason, T. J.; Lorimer, J. P.; Bates, D. M.; Zhao, Y. Dosimetry
165. in sonochemistry: the use of aqueous terephthalate ion as a
(21) (a) Son, S.; Kim, J. H.; Wang, X.; Zhang, C.; Yoon, S. A.; Shin, fluorescence monitor. Ultrason. Sonochem. 1994, 1, 591−595.
J.; Sharma, A.; Lee, M. H.; Cheng, L.; Wu, J.; Kim, J. S. (37) Riesz, P. Free radical generation by ultrasound in aqueous
Multifunctional sonosensitizers in sonodynamic cancer therapy. solutions of volatile and non-volatile solutes. In Advances in
Chem. Soc. Rev. 2020, 49, 3244−3261. (b) Lin, X.; Song, J.; Chen, Sonochemistry; Mason, T. J., Ed.; JAI Press Ltd.: London, 1991;
X.; Yang, H. Ultrasound-activated sensitizers and applications. Angew. Vol. 2, pp 23−64.
Chem., Int. Ed. 2020, 59, 14212−14233. (38) Fernandez Rivas, D.; Prosperetti, A.; Zijlstra, A. G.; Lohse, D.;
(22) Ben-Amots, N.; Anbar, M. Sonochemistry on primordial earth- Gardeniers, H. J. G. E. Efficient sonochemistry through microbubbles
its potential role in prebiotic molecular evolution. Ultrason. Sonochem. generated with micromachined surfaces. Angew. Chem., Int. Ed. 2010,
2007, 14, 672−675. 49, 9699−9701.
(23) (a) Sokol’skaya, A.; El’piner, I. Chemical synthesis under the (39) Lee, J.; Yasui, K.; Ashokkumar, M.; Kentish, S. E.
action of supersonic waves in a water saturated with gases of a Quantification of cavitation activity by sonoluminescence to study
the sonocrystallization process under different ultrasound parameters.
reducing atmosphere. Dokl. Akad. Nauk SSSR 1958, 119, 1180−1182.
Cryst. Growth Des. 2018, 18, 5108−5115.
(b) Sokolskaya, A. Glycine and alanine synthesis from formaldehyde
(40) In a sonochemical context, the terms convergent and divergent
and hydroxylamine in the field of ultrasound waves. Origins Life 1976,
suggested by Luche too, are intended to mean “the same” and “not
7, 183−185.
the same”, respectively, when silent and irradiated processes are
(24) (a) Anbar, M. Cavitation during impact of liquid water on
compared each other. In organic synthesis, the usual connotation
water. Geochemical implications. Science 1968, 161, 1343−1344.
given to a convergent approach involves coupling of fragments with
(b) Negrón-Mendoza, A.; Albarrán, G. Chemical effect of ionizing
similar complexity and/or functionality, thereby assembling the target
radiation and sonic energy in the context of chemical evolution. In
molecule in a convergent plan (as opposed to a stepwise linear
Chemical Evolution: Origin of Life; Ponnamperuma, C., Chela-Flores, strategy); for a recent overview, see: Gao, Y.; Ma, D. In Pursuit of
J., Eds.; A. Deepak Publishing: Hampton, VA, 1993; pp 235−247. Synthetic Efficiency: Convergent Approaches. Acc. Chem. Res. 2021,
(25) Dharmarathne, L.; Grieser, F. Formation of amino acids on the
54, 569−582.
sonolysis of aqueous solutions containing acetic acid, methane, or (41) Sinisterra, J. V.; Fuentes, A.; Marinas, J. M. Barium hydroxide as
carbon dioxide, in the presence of nitrogen gas. J. Phys. Chem. A 2016, catalyst in organic reactions. 17. Interfacial solid-liquid Wittig-Horner
120, 191−199. reaction under sonochemical conditions. J. Org. Chem. 1987, 52,
(26) Kalson, N.-H.; Furman, D.; Zeiri, Y. Cavitation-induced 3875−3879.
synthesis of biogenic molecules on primordial earth. ACS Cent. Sci. (42) Makino, K.; Mossoba, M. M.; Riesz, P. Chemical effects of
2017, 3, 1041−1049. ultrasound on aqueous solutions. Evidence for hydroxyl and hydrogen
(27) For useful and recent background on another enabling free radicals (.cntdot.OH and. cntdot.H) by spin trapping. J. Am.
technique, electrochemistry: (a) Kingston, C.; Palkowitz, M. D.; Chem. Soc. 1982, 104, 3537−3539.
Takahira, Y.; Vantourout, J. C.; Peters, B. K.; Kawamata, Y.; Baran, P. (43) Einhorn, C.; Luche, J.-L. Ready preparation of sugar acetals
S. A survival guide for the “electro-curious”. Acc. Chem. Res. 2020, 53, under ultrasonic irradiation. Carbohydr. Res. 1986, 155, 258−261.
72−83. (b) Little, R. D. A perspective on organic electrochemistry. J. (44) Low, C. M. R. Ultrasound in synthesis: natural products and
Org. Chem. 2020, 85, 13375−13390. supersonic reactions? Ultrason. Sonochem. 1995, 2, S153−S163.
(28) Mason, T. J.; Cordemans de Meulenaer, E. Practical (45) Collum, D. B.; McNeil, A. J.; Ramirez, A. Lithium
considerations for process optimization. In Synthetic Organic diisopropylamide: solution kinetics and implications for organic
Sonochemistry; Luche, J.-L., Ed.; Plenum Press: New York, 1998; synthesis. Angew. Chem., Int. Ed. 2007, 46, 3002−3017.
Chapter 8, pp 301−329. (46) Szostak, M.; Spain, M.; Procter, D. J. Preparation of
(29) Crum, L. A. Comments on the evolving field of sonochemistry samarium(II) iodide: quantitative evaluation of the effect of water,
by a cavitation physicist. Ultrason. Sonochem. 1995, 2, S147−S152. oxygen, and peroxide content, preparative methods, and the activation
(30) Apfel, R. E. Acoustic cavitation. In Methods in Experimental of samarium metal. J. Org. Chem. 2012, 77, 3049−3059.
Physics; Edmunds, P., Ed.; Academic Press: New York, 1981; Vol. 19, (47) De Nicola, A.; Einhorn, J.; Luche, J.-L. An easy preparation of
Chapter 7, pp 355−411. hindered lithium amides. J. Chem. Res., Synop. 1991, 278.
(31) Gallego-Juárez, J. A.; Graff, K. F. Introduction to power (48) Ley, S. V.; Low, C. M. R. Ultrasound in Synthesis; Springer:
ultrasonics. In Power Ultrasonics. Applications of High-Intensity Heidelberg, 1989; pp 105−118.
Ultrasound; Gallego-Juárez, J. A., Graff, K. F., Eds.; Elsevier: (49) For an analysis and discussion of some representative examples,
Amsterdam, 2015; pp 1−6. see: Luche, J.-L.; Cintas, P. Can sonication modify the regio- and
J. Org. Chem. 2021, 86, 13833−13856
stereoselectivities of organic reactions? In Advances in Sonochemistry; and hydroxystannation of C-C multiple bonds. J. Org. Chem. 1994, 59,
Mason, T. J., Ed.; JAI Press, Ltd.: London, 1999; Vol. 5, pp 147−174. 8178−8186.
(50) Jayarajan, R.; Chandrashekar, H. B.; Dalvi, A. K.; Maiti, D. (70) Bowser, B. H.; Craig, S. L. Empowering mechanochemistry
Ultrasound-facilitated direct meta-C-H functionalization of arenes: a with multi-mechanophore polymer architectures. Polym. Chem. 2018,
time-economical strategy under ambient temperature with improved 9, 3583−3593.
yield and selectivity. Chem. - Eur. J. 2020, 26, 11426−11430. (71) Chen, Z.; Mercer, J. A. M.; Zhu, X.; Romaniuk, J. A. H.;
(51) Cintas, P.; Palmisano, G.; Cravotto, G. Power ultrasound in Pfattner, R.; Cegelski, L.; Martinez, T. J.; Burns, N. Z.; Xia, Y.
metal-assisted synthesis: from classical Barbier-like reactions to click Mechanochemical unzipping of insulating polyladderene to semi-
chemistry. Ultrason. Sonochem. 2011, 18, 836−841. conducting polyacetylene. Science 2017, 357, 475−479.
(52) Cintas, P.; Barge, A.; Tagliapietra, S.; Boffa, L.; Cravotto, G. (72) For recent studies of ladderane unzipping and polyladderene-
Alkyne-azide click reaction catalyzed by metallic copper under polyacetylene copolymers, see: (a) Chen, Z.; Zhu, X.; Yang, J.;
ultrasound. Nat. Protoc. 2010, 5, 607−611. Mercer, J. A. M.; Burns, N. Z.; Martinez, T. J.; Xia, Y. The cascade
(53) May, P. A.; Moore, J. S. Polymer mechanochemistry: unzipping of ladderane reveals dynamic effects in mechanochemistry.
techniques to generate molecular force via elongational flows. Chem. Nat. Chem. 2020, 12, 302−309. (b) Boswell, B. R.; Mansson, C. M.
Soc. Rev. 2013, 42, 7497−7506. F.; Cox, J. M.; Jin, Z.; Romaniuk, J. A. H.; Lindquist, K. P.; Cegelski,
(54) Cravotto, G.; Gaudino, E. C.; Cintas, P. On the L.; Xia, Y.; López, S. A.; Burns, N. Z. Mechanochemical synthesis of
mechanochemical activation by ultrasound. Chem. Soc. Rev. 2013, an elusive fluorinated polyacetylene. Nat. Chem. 2021, 13, 41−46.
42, 7521−7534. (73) Huang, W.; Wu, X.; Gao, X.; Yu, Y.; Lei, H.; Zhu, Z.; Shi, Y.;
(55) Li, J.; Nagamani, C.; Moore, J. S. Polymer mechanochemistry: Chen, Y.; Qin, M.; Wang, W.; Cao, Y. Maleimide-thiol adducts
from destructive to productive. Acc. Chem. Res. 2015, 48, 2181−2190. stabilized through stretching. Nat. Chem. 2019, 11, 310−319.
(56) Cintas, P.; Cravotto, G.; Barge, A.; Martina, K. Interplay (74) Shi, Z.; Song, Q.; Göstl, R.; Herrmann, A. Mechanochemical
between mechanochemistry and sonochemistry. In Polymer Mecha- activation of disulfide-based multifunctional polymers for theranostic
nochemistry-Topics in Current Chemistry, Vol. 369; Boulatov, R., Ed.; drug release. Chem. Sci. 2021, 12, 1668−1674.
Springer: Heidelberg, 2015; pp 239−284. (75) (a) Huo, S.; Zhao, P.; Shi, Z.; Zou, M.; Yang, X.; Warszawik, E.;
(57) Mason, T. J.; Cobley, A. J.; Graves, J. E.; Morgan, D. New Loznik, M.; Göstl, R.; Herrmann, A. Mechanochemical bond scission
evidence for the inverse dependence of mechanical and chemical for the activation of drugs. Nat. Chem. 2021, 13, 131−139. (b) For a
effects on the frequency of ultrasound. Ultrason. Sonochem. 2011, 18, commentary, see: Boulatov, R. The liberating force of ultrasound. Nat.
226−230. Chem. 2021, 13, 112−113.
(58) Nguyen, T. T.; Asakura, Y.; Koda, S.; Yasuda, K. Dependence (76) Lattwein, K. R.; Shekhar, H.; Kouijzer, J. J. P.; Van Wamel, W.
of cavitation, chemical effect and mechanical effect thresholds on J. B.; Holland, C. K.; Kooiman, K. Sonobactericide: an emerging
treatment strategy for bacterial infections. Ultrasound Med. Biol. 2020,
ultrasonic frequency. Ultrason. Sonochem. 2017, 39, 301−306.
46, 193−215.
(59) Boldyrev, V. V. Mechanochemistry and sonochemistry.
(77) Chettab, K.; Mestas, J.-L.; Lafond, M.; Saadna, D. E.; Lafon, C.;
Ultrason. Sonochem. 1995, 2, S143−S145.
Dumontet, C. Doxorubicin delivery into tumor cells by stable
(60) Nguyen, T. Q.; Liang, O. Z.; Kausch, H. H. Kinetics of
cavitation without contrast agents. Mol. Pharmaceutics 2017, 14, 441−
ultrasonic and transient elongational flow degradation: a comparative
447.
study. Polymer 1997, 38, 3783−3793.
(78) (a) Cádiz Bedini, A. P.; Muthmann, S.; Allgaier, J.; Bittkau, K.;
(61) For a good overview of theoretical interpretations of polymer
Finger, F.; Carius, R. Liquid hydridosilane precursor prepared from
mechanochemistry in sonicated solutions, see: Akbulatov, S.;
cyclopentasilane via sonication at low temperature without the action
Boulatov, R. Experimental polymer mechanochemistry and its of light. Ultrason. Sonochem. 2017, 34, 289−293. (b) For a
interpretational frameworks. ChemPhysChem 2017, 18, 1422−1450. commentary, see: Hidding, B. Sonochemistry of silicon hydrides.
(62) Hickenboth, C. R.; Moore, J. S.; White, S. R.; Sottos, N. R.; Science 2018, 360, 489−490.
Baudry, J.; Wilson, S. R. Biasing reaction pathways with mechanical (79) For recent perspectives on sonochemical methods towards
force. Nature 2007, 446, 423−427. sustainable chemistry, see: (a) Cravotto, G.; Borretto, E.; Oliverio,
(63) Ribas-Arino, J.; Marx, D. Covalent mechanochemistry: M.; Procopio, A.; Penoni, A. Organic reactions in water or biphasic
theoretical concepts and computational tools with applications to aqueous systems under sonochemical conditions. A review on
molecular nanomechanics. Chem. Rev. 2012, 112, 5412−5487. catalytic effects. Catal. Commun. 2015, 63, 2−9. (b) Draye, M.;
(64) Stauch, T.; Dreuw, A. Advances in quantum mechanochem- Kardos, N. Advances in green organic sonochemistry. Top. Curr.
istry: electronic structure methods and force analysis. Chem. Rev. Chem. 2016, 374, 74. (c) Wu, Z.; Tagliapietra, S.; Giraudo, A.;
2016, 116, 14137−14180. Martina, K.; Cravotto, G. Harnessing cavitational effects for green
(65) (a) Garcia-Manyes, S.; Beedle, A. E. M. Steering chemical process intensification. Ultrason. Sonochem. 2019, 52, 530−546.
reactions with force. Nat. Rev. Chem. 2017, 1, 0083. (b) Li, H.; (80) Jiménez-González, C.; Constable, D. J. C.; Ponder, C. S.
Walker, G. C. Twist and shout: single-molecule mechanochemistry. Evaluating the greenness of chemical processes and products in the
ACS Nano 2017, 11, 28−30. pharmaceutical industry-a green metrics primer. Chem. Soc. Rev. 2012,
(66) Andersen, J. M.; Mack, J. Decoupling the Arrhenius equation 41, 1485−1498.
via mechanochemistry. Chem. Sci. 2017, 8, 5447−5453. (81) (a) Fegade, S. L.; Trembly, J. P. Misinterpretation of Green
(67) (a) Gogate, P. R.; Prajapat, A. L. Depolymerization using chemistry. Ultrason. Sonochem. 2017, 37, 686−687. (b) Cintas, P.
sonochemical reactors: a critical review. Ultrason. Sonochem. 2015, 27, Ultrasound and green chemistry-further comments. Ultrason.
480−494. (b) McKenzie, T. G.; Karimi, F.; Ashokkumar, M.; Qiao, G. Sonochem. 2016, 28, 257−258.
G. Ultrasound and sonochemistry for radical polymerization: sound (82) There is some misuse and confusion about the terms “in-water”
synthesis. Chem. - Eur. J. 2019, 25, 5372−5388. and “on-water”, especially without a clear-cut mechanistic analysis. It
(68) (a) Berkowski, K. L.; Potisek, S. L.; Hickenboth, C. R.; Moore, is assumed that the first happens in the bulk aqueous medium and the
J. S. Ultrasound-induced site-specific cleavage of azo-functionalized latter denotes a transition structure located at the organic side of the
poly(ethylene glycol). Macromolecules 2005, 38, 8975−8978. (b) For organic−water interface: Li, C. J.; Chen, L. Organic chemistry in
a brief retrospective, see: De Bo, G. Polymer mechanochemistry and water. Chem. Soc. Rev. 2006, 35, 68−82.
the emergence of the mechanophore concept. Macromolecules 2020, (83) Ando, T.; Kimura, T. Ultrasonic organic synthesis involving
53, 7615−7617. non-metal solids. In Advances in Sonochemistry; Mason, T. J., Ed.; JAI
(69) See, for instance: Nakamura, E.; Imanishi, Y.; Machii, D. Press, Inc.: London, 1991; Vol. 2, pp 211−251 and references cited
Sonochemical initiation of radical chain reactions. Hydrostannation therein.
J. Org. Chem. 2021, 86, 13833−13856
(84) (a) Tuulmets, A.; Hagu, H.; Salmar, S.; Cravotto, G.; Järv, J. (99) Amaniampong, P. N.; Trinh, Q. T.; De Oliveira Vigier, K.; Dao,
Ultrasonic evidence of hydrophobic interactions. Effect of ultrasound D. Q.; Tran, N. H.; Wang, Y.; Sherburne, M. P.; Jérôme, F. Synergistic
on benzoin condensation and some other reactions in aqueous effect of high-frequency ultrasound with cupric oxide catalyst resulting
ethanol. J. Phys. Chem. B 2007, 111, 3133−3138. (b) Salmar, S.; in a selectivity switch in glucose oxidation under argon. J. Am. Chem.
Cravotto, G.; Tuulmets, A.; Hagu, H. Effect of ultrasound on the Soc. 2019, 141, 14772−14779.
base-catalyzed hydrolysis of 4-nitrophenyl acetate in aqueous ethanol. (100) Newnham, R. E. Properties of Materials. Anisotropy, Symmetry,
J. Phys. Chem. B 2006, 110, 5817−5821. Structure; Oxford University Press: Oxford, UK, 2005; pp 87−102.
(85) (a) Gulajski, L.; Sledz, P.; Lupa, A.; Grela, K. Olefin metathesis (101) Pardo, L. Piezoelectric ceramic materials for power ultrasonic
in water using acoustic emulsification. Green Chem. 2008, 10, 271− transducers. In Power Ultrasonics. Applications of High-Intensity
274. (b) Gulajski, L.; Tracz, A.; Urbaniak, K.; Czarnocki, S. J.; Ultrasound; Gallego-Juárez, J. A., Graff, K. F., Eds.; Elsevier:
Bieniek, M.; Olszewski, T. K. Ammonium-tagged ruthenium-based Amsterdam, 2015; pp 101−125.
catalysts for olefin metathesis in aqueous media under ultrasound and (102) Li, F.; Cabral, M. J.; Xu, B.; Cheng, Z.; Dickey, E. C.; LeBeau,
microwave irradiation. Beilstein J. Org. Chem. 2019, 15, 160−166. J. M.; Wang, J.; Luo, J.; Taylor, S.; Hackenberger, W.; Bellaiche, L.;
(86) Jaiswal, P. K.; Sharma, V.; Prikhodko, J.; Mashevskaya, I. V.; Xu, Z.; Chen, L.-Q.; Shrout, T. R.; Zhang, S. Giant piezoelectricity of
Chaudhary, S. On water ultrasound-assisted one-pot efficient Sm-doped Pb(Mg1/3Nb2/3)O3-PbTiO3 single crystals. Science 2019,
synthesis of functionalized 2-oxo-benzo[1,4]oxazines: first application 364, 264−268.
to the synthesis of anticancer indole alkaloid Cephalandole A. (103) Graff, K. F. Power ultrasonic transducers: principles and
Tetrahedron Lett. 2017, 58, 2077−2083. design. In Power Ultrasonics. Applications of High-Intensity Ultrasound;
(87) Rogozinska, M.; Adamkiewicz, A.; Mlynarski, J. Efficient “on Gallego-Juárez, J. A., Graff, K. F., Eds.; Elsevier: Amsterdam, 2015; pp
water” organocatalytic protocol for the synthesis of optically pure 127−158.
warfarin anticoagulant. Green Chem. 2011, 13, 1155−1157. (104) Hong, K.-S.; Xu, H.; Konishi, H.; Li, X. Direct water splitting
(88) Lee, J.; Kentish, S.; Matula, T. J.; Ashokkumar, M. Effect of through vibrating piezoelectric microfibers in water. J. Phys. Chem.
surfactants on inertial cavitation activity in pulsed acoustic field. J. Lett. 2010, 1, 997−1002.
Phys. Chem. B 2005, 109, 16860−16865. (105) Morosini, V.; Chave, T.; Virot, M.; Moisy, P.; Nikitenko, S. I.
(89) More, P. A.; Shankarling, G. S. Energy efficient Pfitzinger Sonochemical water splitting in the presence of powdered metal
reaction: a novel strategy using a surfactant catalyst. New J. Chem. oxides. Ultrason. Sonochem. 2016, 29, 512−516.
2017, 41, 12380−12383. (106) Vedadi, M. H.; Haas, S. Mechano-chemical pathways to H2O
(90) Kamble, S.; Kumbhar, A.; Rashinkar, G.; Barge, M.; Salunkhe, and CO2 spliting. Appl. Phys. Lett. 2011, 99, 154105.
R. Ultrasound promoted efficient and green synthesis of β-amino (107) (a) Wang, Z.; Pan, X.; Yan, J.; Dadashi-Silab, S.; Xie, G.;
carbonyl compounds in aqueous hydrotropic medium. Ultrason. Zhang, J.; Wang, Z.; Xia, H.; Matyjaszewski, K. Temporal control in
Sonochem. 2012, 19, 812−815. mechanically controlled atom transfer radical polymerization using
(91) Saleh, T. S.; Al-Bogami, A. S.; Mekky, A. E. M.; Alkhathlan, H.
low ppm of Cu catalyst. ACS Macro Lett. 2017, 6, 546−549. (b) Pan,
Z. Sonochemical synthesis of novel pyrano[3,4-e][1,3]oxazines: a
X.; Fantin, M.; Yuan, F.; Matyjaszewski, K. Externally controlled atom
green protocol. Ultrason. Sonochem. 2017, 36, 474−480.
transfer radical polymerization. Chem. Soc. Rev. 2018, 47, 5457−5490.
(92) Fillion, H.; Luche, J.-L. Cycloadditions. In Synthetic Organic
(108) Mohapatra, H.; Kleiman, M.; Esser-Kahn, A. P. Mechanically
Sonochemistry; Luche, J.-L., Ed.; Plenum Press: New York, 1998; pp
controlled radical polymerization initiated by ultrasound. Nat. Chem.
91−106 and references cited therein.
(93) (a) Bauld, N. L. Cation radical cycloadditions and related 2017, 9, 135−139.
(109) Mohapatra, H.; Ayarza, J.; Sanders, E. C.; Scheuermann, A.
sigmatropic reactions. Tetrahedron 1989, 45, 5307−5363. (b) Bauld,
N. L. Ab initio theoretical reaction path study of the cation radical M.; Griffin, P. J.; Esser-Kahn, A. P. Ultrasound promoted step-growth
Diels-Alder reaction. J. Am. Chem. Soc. 1992, 114, 5800−5804. polymerization and polymer crosslinking via copper catalyzed azide-
(c) Bauld, N. L.; Gao, D. The electron transfer chemistry of carbon- alkyne “click” reaction. Angew. Chem., Int. Ed. 2018, 57, 11208−
carbon multiple bonds. In Electron Transfer in Chemistry; Balzani, V., 11212.
Ed.; Wiley-VCH: Weinheim, 2001; Vol. 2, Part 1, pp 133−205. (d) (110) Kubota, K.; Pang, Y.; Miura, A.; Ito, H. Redox reactions of
For a cycloaddition involving a radical anion species, see: Roh, Y.; small organic molecules using ball milling and piezoelectric materials.
Jang, H.-Y.; Lynch, V.; Bauld, N. L.; Krische, M. J. Anion radical chain Science 2019, 366, 1500−1504.
cycloaddition of tethered enones: intramolecular cyclobutanation and (111) Pang, Y.; Lee, J. W.; Kubota, K.; Ito, H. Solid-state radical C-
Diels-Alder cycloaddition. Org. Lett. 2002, 4, 611−613. H trifluoromethylation reactions using ball milling and piezoelectric
(94) (a) Cabello, N.; Cintas, P.; Luche, J.-L. Sonochemical effects in materials. Angew. Chem., Int. Ed. 2020, 59, 22570−22576.
the addition of furan to masked ortho-benzoquinones. Ultrason. (112) Huang, G.; Chen, S.; Dai, C.; Sun, L.; Sun, W.; Tang, Y.;
Sonochem. 2003, 10, 25−31. (b) Avalos, M.; Babiano, R.; Cabello, N.; Xiong, F.; He, R.; Ma, H. Effects of ultrasound on microbial growth
Cintas, P.; Hursthouse, M. B.; Jiménez, J. L.; Light, M. E.; Palacios, J. and enzyme activity. Ultrason. Sonochem. 2017, 37, 144−149.
C. Thermal and sonochemical studies on the Diels-Alder cyclo- (113) Yoon, J.; Kim, J.; Tieves, F.; Zhang, W.; Alcalde, M.;
additions of masked o-benzoquinones with furans: new insights into Hollmann, F.; Park, C. B. Piezobiocatalysis: ultrasound-driven
the reaction mechanism. J. Org. Chem. 2003, 68, 7193−7203. enzymatic oxyfunctionalization of C-H bonds. ACS Catal. 2020, 10,
(95) For a recent critical review, see: Schmidt, F.; Cokoja, M. 5236−5242.
Supramolecular concepts for the biphasic epoxidation of olefins using (114) Takenaka, T. Bismuth-based piezoelectric ceramics. In
aqueous hydrogen peroxide. Green Chem. 2021, 23, 708−722. Piezoelectric and Acoustic Materials for Transducer Applications;
(96) Chatel, G.; Goux-Henry, C.; Mirabaud, A.; Rossi, T.; Kardos, Safari, A., Akdogan, E. K., Eds.; Springer: Boston, 2008; pp 103−130.
N.; Andrioletti, B.; Draye, M. H2O2/NaHCO3-Mediated enantiose- (115) For a previous study merging the action of piezoelectric
lective epoxidation of olefins in NTf2-based ionic liquids and under BiOCl and ultrasound, see: Shao, D.; Zhang, L.; Sun, S.; Wang, W.
ultrasound. J. Catal. 2012, 291, 127−132. Oxygen reduction reaction for generating H2O2 through a piezo-
(97) Cousin, T.; Chatel, G.; Kardos, N.; Andrioletti, B.; Draye, M. catalytic process over bismuth oxychloride. ChemSusChem 2018, 11,
High frequency ultrasound as a tool for elucidating mechanistic 527−531.
elements of cis-cyclooctene epoxidation with aqueous hydrogen (116) For another piezoelectric titanate activated by ultrasound to
peroxide. Ultrason. Sonochem. 2019, 53, 120−125. produce hydroxyl radicals, see: Ling, J.; Wang, K.; Wang, Z.; Huang,
(98) Calcio Gaudino, E.; Cravotto, G.; Manzoli, M.; Tabasso, S. H.; Zhang, G. Enhanced piezoelectric-induced catalysis of SrTiO3
Sono- and mechanochemical technologies in the catalytic conversion nanocrystal with well-defined facets under ultrasonic vibration.
of biomass. Chem. Soc. Rev. 2021, 50, 1785−1812. Ultrason. Sonochem. 2020, 61, 104819.
J. Org. Chem. 2021, 86, 13833−13856
(117) For leading approaches toward chemical automation, see: focusing effects on particle synthesis and clogging in microreactors.
(a) Li, J.; Ballmer, S. G.; Gillis, E. P.; Fujii, S.; Schmidt, M. J.; Lab Chip 2019, 19, 316−327.
Palazzolo, A. M. E.; Lehmann, J. W.; Morehouse, G. F.; Burke, M. D. (127) Aljbour, S.; Yamada, H.; Tagawa, T. Ultrasound-assisted
Synthesis of many different types of organic small molecules using an phase-transfer catalysis in a capillary microreactor. Chem. Eng. Process.
automated process. Science 2015, 347, 1221−1226. (b) Trobe, M.; 2009, 48, 1167−1172.
Burke, M. D. The molecular industrial revolution: automated (128) Banaszak-Léonard, E.; Mangin, F.; Len, C. Barton
synthesis of small molecules. Angew. Chem., Int. Ed. 2018, 57, decarboxylation under ultrasonic continuous flow. New J. Chem.
4192−4214. (c) Bédard, A.-C.; Adamo, A.; Aroh, K. C.; Russell, M. 2016, 40, 7414−7420.
G.; Bedermann, A. A.; Torosian, J.; Yue, B.; Jensen, K. F.; Jamison, T. (129) (a) Ingham, R. J.; Battilochio, C.; Fitzpatrick, D. E.; Sliwinski,
F. Reconfigurable system for automated optimization of diverse E.; Hawkins, J. M.; Ley, S. V. A systems approach towards intelligent
chemical reactions. Science 2018, 361, 1220−1225. and self-controlling platform for integrated continuous reaction
(118) For recent examples of optimization tools, see: (a) Klucznik, sequences. Angew. Chem., Int. Ed. 2015, 54, 144−148. (b) Fitzpatrick,
T.; Mikulak-Klucznik, B.; McCormack, M. P.; Lima, H.; Szymku, S.; D. E.; Battilocchio, C.; Ley, S. V. Enabling technologies for the future
Bhowmick, M.; Molga, K.; Zhou, Y.; Rickershauser, L.; Gajewska, E. of chemical synthesis. ACS Cent. Sci. 2016, 2, 131−138.
P.; Toutchkine, A.; Dittwald, P.; Startek, M. P.; Kirkovits, G. J.; (130) Kuhn, S.; Noël, T.; Gu, L.; Heider, P. L.; Jensen, K. F. A
Roszak, R.; Adamski, A.; Sieredzinska, B.; Mrksich, M.; Trice, S. L. J.; Teflon microreactor with integrated piezoelectric actuator to handle
Grzybowski, B. A. Efficient synthesis of diverse medicinally relevant solid forming reactions. Lab Chip 2011, 11, 2488−2492.
targets planned by computer and executed in the laboratory. Chem. (131) Kulkarni, K.; Friend, J.; Yeo, L.; Perlmutter, P. Surface
acoustic waves as an emerging source for drop scale synthetic
2018, 4, 1−11. (b) Shi, Y.; Prieto, P. L.; Zepel, T.; Grunert, S.; Hein,
chemistry. Lab Chip 2009, 9, 754−755.
J. E. Automated experimentation powers data science in chemistry.
(132) In solids, sound may propagate at speeds much greater than in
Acc. Chem. Res. 2021, 54, 546−555. (c) Angelone, D.; Hammer, A. J.
air or bulk liquids: (a) Kuznetsova, I. E.; Zaitsev, B. D.; Joshi, S. G.;
S.; Rohrbach, S.; Krambeck, S.; Granda, J. M.; Wolf, J.; Zalesskiy, S.; Borodina, I. A. Investigation of acoustic waves in thin plates of lithium
Chisholm, G.; Cronin, L. Convergence of multiple synthetic niobate and lithium tantalate. IEEE Trans. Ultrasonics Ferroelectrics &
paradigms in a universally programmable chemical synthesis machine. Frequency 2001, 48, 322−328. (b) Auld, B. A. Acoustic Fields and
Nat. Chem. 2021, 13, 63−69. (d) Shields, B. J.; Stevens, J.; Li, J.; Waves in Solids; John Wiley & Sons, Inc.: New York, 1973; Vol. I.
Parasram, M.; Damani, F.; Martinez Alvarado, J. I.; Janey, J. M.; (133) (a) Lin, S.-C. S.; Mao, X.; Huang, T. J. Surface acoustic wave
Adams, R. P.; Doyle, A. G. Bayesian reaction optimization as a tool for (SAW) acoustophoresis: now and beyond. Lab Chip 2012, 12, 2766−
chemical synthesis. Nature 2021, 590, 89−96. 2770. (b) Thompson, M.; Stone, D. C. Surface-Launched Acoustic
(119) (a) Gogate, P. R.; Sutkar, V. S.; Pandit, A. B. Sonochemical Wave Sensors; John Wiley & Sons, Inc.: New York, 1997.
reactors: important design and scale up considerations with a special (134) (a) Kelling, S.; Cerasari, S.; Rotermund, H. H.; Ertl, G.; King,
emphasis on heterogeneous systems. Chem. Eng. J. 2011, 166, 1066− D. A. A photoemission electron microscopy (PEEM) study of the
1082. (b) Patist, A.; Bates, D. Industrial applications of high power effect of surface acoustic waves on catalytic CO oxidation over
ultrasonics. In Ultrasound Technologies for Food and Bioprocessing; Pt{110}. Chem. Phys. Lett. 1998, 293, 325−330. (b) Mitrelias, T.;
Feng, H., Barbosa-Canovas, G., Weiss, J., Eds.; Springer: New York, Kelling, S.; Kvon, R. I.; Ostanin, V. P.; King, D. A. Effect of acoustic
2011; pp 599−616. excitation on the rate of CO oxidation over Pt{110}. Surf. Sci. 1998,
(120) (a) Cintas, P.; Mantegna, S.; Gaudino, E. C.; Cravotto, G. A 417, 97−106.
new pilot flow reactor for high-intensity ultrasound irradiation. (135) (a) Wu, C.; Zaitsev, V. Y.; Zhigilei, L. V. Acoustic
Application to the synthesis of biodiesel. Ultrason. Sonochem. 2010, enhancement of surface diffusion. J. Phys. Chem. C 2013, 117,
17, 985−989. (b) Crudo, D.; Bosco, V.; Cavaglià, G.; Grillo, G.; 9252−9258. (b) Von Boehn, B.; Foerster, M.; von Boehn, M.; Prat, J.;
Mantegna, S.; Cravotto, G. Process intensification in biodiesel Macià, F.; Casals, B.; Khaliq, M. W.; Hernández-Mínguez, A.; Aballe,
production with a rotor-stator type generator of hydrodynamic L.; Imbihl, R. On the promotion of catalytic reactions by surface
cavitation. Ultrason. Sonochem. 2016, 33, 220−225. acoustic waves. Angew. Chem., Int. Ed. 2020, 59, 20224−20229.
(121) (a) Fernandez Rivas, D.; Cintas, P.; Gardeniers, H. J. G. E. (136) García Lorca, F. Romancero Gitano-Poema del Cante Jondo;
Merging microfluidics and sonochemistry: towards greener and more Anaya: Madrid, 2006.
efficient micro-sono-reactors. Chem. Commun. 2012, 48, 10935−
10947. (b) Fernandez Rivas, D.; Kuhn, S. Synergy of microfluidics
and ultrasound. Process intensification, challenges and opportunities.
Top. Curr. Chem. 2016, 374, 70.
(122) Li, Y.; Liu, X.; Huang, Q.; Ohta, A. T.; Arai, T. Bubbles in
microfluidics: an all-purpose tool for micromanipulation. Lab Chip
2021, 21, 1016−1035.
(123) For a good overview of emerging strategies applied to the
preparation of pharmaceuticals, see: Campos, K. R.; Coleman, P. J.;
Alvarez, J. C.; Dreher, S. D.; Garbaccio, R. M.; Terrett, N. K.; Tillyer,
R. D.; Truppo, M. D.; Parmee, E. R. The importance of synthetic
chemistry in the pharmaceutical industry. Science 2019, 363,
No. eaat0805.
(124) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous flow
technology-a tool for the safe manufacturing of active pharmaceutical
ingredients. Angew. Chem., Int. Ed. 2015, 54, 6688−6728.
(125) Cantillo, D.; Damm, M.; Dallinger, D.; Bauser, M.; Berger, M.;
Kappe, C. O. Sequential nitration/hydrogenation protocol for the
synthesis of triaminophloroglucinol: safe generation and use of an
explosive intermediate under continuous-flow conditions. Org. Process
Res. Dev. 2014, 18, 1360−1366.
(126) (a) Jensen, K. F.; Reizman, B. J.; Newman, S. G. Tools for
chemical synthesis in microsystems. Lab Chip 2014, 14, 3206−3212.
(b) Dong, Z.; Fernandez Rivas, D.; Kuhn, S. Acoustophoretic
J. Org. Chem. 2021, 86, 13833−13856

Acs Joc 1c00805

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Acs Joc 1c00805

Uploaded by

Copyright:

Available Formats

pubs.acs.

Organic Sonochemistry: A Chemist’s Timely Perspective on

Cite This: J. Org. Chem. 2021, 86, 13833−13856 Read Online

ACCESS Metrics & More Article Recommendations

ABSTRACT: Sonochemistry, the use of sound waves, usually

than other activation protocols despite aﬀordable setups. Even if

© 2021 American Chemical Society https://doi.org/10.1021/acs.joc.1c00805

Herein, we concentrate on sono-organic methods and

■ WHAT IS CAVITATIONAL CHEMISTRY?

■ OPTIMIZATION AND MODES OF OPERATION.

■ SONOCHEMICAL REACTIVITY: CONVERGENT AND

Scheme 6. Semisynthetic Route to Enantiopure Milbemycin-β1a

Scheme 8. Direct and Selective Meta-C−H Substitution of Arenes Mediated by Ultrasound

Scheme 9. Alkyne−Azide 1,3-Dipolar Cycloadditions Activated by Sonication Using Metallic Copper

thermally forbidden mechanisms may become mechanochemi-

Scheme 12. Formation of Polyladderene-Polyacetylene

Scheme 17. Synthesis of β-Amino Carbonyl Compounds by

Scheme 16. Sonochemical Syntheses of Heterocyclic Drugs

Scheme 18. Mismatched Cavitational and Thermal Eﬀects

The use of surfactants can increase the solubility of organic

Figure 4. Schematic representation of direct (left) and inverse (right)

has the origin in the lack of a center of symmetry in the crystal

σ = c Eε (4) causing the liberation of H2 and O2 from water (Figure 5).

Scheme 24. Mechanoredox Arylation Mediated by a SET

precatalyst to its active Cu(I) form that activates the alkyl

Figure 6. Sonication-induced catalytic C−H oxyfunctionalization

should involve the reaction of electrons from the piezoelectric

■ FLOW AND AUTOMATION: THE PRESENT AND

Perspective, we are concerned with acoustoﬂow synthesis at

by collapse contribute to break and dissolve solid particles

■ CONCLUSIONS AND OUTLOOK

You might also like