Key words
green chemistry - mechanochemistry - solid-state synthesis - synthetic organic chemistry
- mechanoenzymology - sustainable chemistry - ball milling
1
Introduction
Mechanochemistry, that is chemical transformations initiated or sustained by mechanical
grinding or milling, or alternatively by twin-screw extrusion (TSE), with no or minimal
solvent usage, has expanded from a laboratory curiosity to a useful, rapidly developing
strategy for the preparation of molecules and amplification of their chemical reactivity.
Basically, mechanochemistry deals with physicochemical transformations induced by
mechanical energy that originates from impact, shear, compression, extension, etc.
Indeed, during the past 15 years a remarkable number of reports on novel solid-state
chemical transformations via grinding and milling have been recorded, especially across
organic and inorganic chemistry,[1] with special applications such as metal- and metal-organic-catalyzed mechanochemical
reactions,[2`]
[b]
[c] mechanochemically induced molecular rearrangements,[2d] preparation of active pharmaceutical ingredients (API),[2e–g] supramolecular chemistry,[2h] mechanosynthesis of heterocyclic rings,[2i] polymer chemistry,[2j]
[k] nanomaterials,[2l] valorization of biomass,[2m] and medicinal mechanochemistry,[2n] among others.[2o]
[p] Remarkably, a range of reactions previously not accessible in solution, can be carried
out by means of mechanochemical activation.
Eusebio Juaristi studied chemistry at Tecnológico de Monterrey (B.Sc., 1972) and at the University
of North Carolina at Chapel Hill (Ph.D., 1977). Juaristi became a postdoctoral associate
at the University of California in Berkeley (1977–1978) and research associate at
Syntex, Palo Alto, California (1978–1979) before returning to Mexico where he is now
Professor of Chemistry at CINVESTAV-IPN. Juaristi was Visiting Professor at the E.T.H.-Zurich,
1985–1986 and 1992–1993, at the University of California in Berkeley (1999–2000),
and at RWTH-Aachen, Germany (May–July 2013).
Scientific contributions: Physical organic chemistry with emphasis in conformational analysis and stereochemistry,
for example in the study of the anomeric effect. Juaristi has also worked in the areas of asymmetric synthesis, in particular on
enantioselective synthesis of β-amino acids. Other chemistry areas where Juaristi
has had influence include applications of computational chemistry, asymmetric organocatalysis,
and sustainable (‘green’) chemistry.
Awards: Medal of the Mexican Academy of Sciences for Young Scientists in 1988; National
Chemistry Award granted by the Mexican Chemical Society in 1994; and the Presidential
Medal in Sciences and Arts in 1998. In February of 2006 he became a member of ‘El
Colegio Nacional’, highest academic distinction in Mexico.
Focusing on organic synthesis, this short review presents illustrative examples of
salient developments in this exciting field, with the aim to demonstrate its potential
as an efficient and clean approach in chemical synthesis, enabled by synthetic procedures
that are based on solid state transformations rather than traditional chemistry in
solution.
Even though mechanochemical transformations were first recorded several millennia
ago,[3] they went mostly unnoticed until recently. Presumably, Aristotle’s statement in
the 4th century B.C. that ‘no reaction takes place in the absence of solvent’ led
to an erroneous chemistry paradigm which dictates that chemical substrates must be
dissolved in a solution to get close to each other through diffusion, so that their
functional groups can interact properly.
Importantly, mechanochemistry is now seen as an excellent method of green chemistry,
that greatly reduces or even totally avoids solvent use. Indeed, mechanochemistry
has been recognized by IUPAC as one of the 10 most promising technologies in the 21st
century.[4] In this regard, a now widely accepted representation consisting of three balls arranged
triangularly was proposed in 2016 by Rightmire and Hanusa for mechanochemistry in
chemical equations (Figure [1a]).[5]
Figure 1 (a) Representation of mechanochemical activation advanced by Hanusa. (b) Typical
grinding and milling equipment. (a) Mortar and pestle. (b) Retsch automated mortar. (c) Fritsch vertical shaker mill. (d) Fritsch vibrational mill. (e) Retsch vibrational ball mill. (f) Retsch vibrational ball mill with controlled temperature (Cryomill). (g) Retsch planetary ball mill. (h) Multiple-sample mill (Automaxion). (i) Twin-screw used for continuous mechanochemical extrusion. Reproduced with permission
from ref 2e. Copyright 2020 The American Chemical Society.
Mechanochemical reactions can be carried out in various types of instruments, either
in batch (vibrational or planetary mills) or continuous manner (twin screw extrusion,
TSE), that are often available in larger sizes. Both pieces of equipment are usually
operated with the addition of milling balls. The most commonly used instruments are
shaker and planetary mills, with increasing attention being paid to TSE (Figure [1b]).[6] These instruments are commercially available, and their advantages and limitations
have been discussed by several experts.[7] In shaker (vibrational) mills, reactor jars swing back and forth at the chosen frequency
(high-speed ball milling, HSBM). By contrast, in a planetary mill the jar spins around
a central axis, while rotating around its own axis in the opposite direction (ball
milling). Milling equipment (jars and balls) are usually made of stainless steel,
minerals (such as agate, zirconia, tungsten carbide), or polytetrafluoroethylene (Teflon).
On the other hand, jars of transparent material such as poly(methyl)methacrylate are
used to enable in situ monitoring (see Section 6.3).
Importantly, in addition to the choice of equipment, a variety of additives can affect
mechanochemical reactions. In fact, modified mechanochemical procedures with different
additives have resulted in improved reactivity (see Section 4.3).
Brief History of Mechanochemistry
2
Brief History of Mechanochemistry
One of the earliest recorded applications of mechanochemistry dates back to the 4th
century B.C. referring that grinding cinnabar with acetic acid afforded elemental
mercury.[3] Importantly, Takacs also pointed out that the addition of small amounts of vinegar
helps accelerate the process, apparently ‘lubricating’ the reaction.[3a] Indeed, a small amount of liquid helps induce a permanent mobile surface layer that
facilitated contact between the solid reagents.
This application of a liquid additive to accelerate the desired reaction between solid
reagents in the milling process is presently used in the modern mechanochemical technique
of liquid-assisted grinding (LAG), which is discussed in Section 4.3.
As already discussed, during the period between the 3rd century B.C. and the 18th
century A.D. reports concerning the use of mechanochemical grinding for the activation
of chemical reactions were very rare. However, during the 19th century the German
chemical industry developed rather big mills that were employed to grind materials
in the preparation of synthetic organic dyes. In an illustrative example, heliogen
blue is an intense sapphire dye that was prepared in these mechanical devices by milling
phthalonitrile and copper chloride (Scheme [1]).[8]
Scheme 1 Mechanochemical (mortar and pestle) preparation of heliogen blue by grinding copper
chloride and phthalonitrile[8]
Even after its formal introduction by Ostwald at the end of the 1800s, mechanochemistry
continued to be considered as anecdotic rather than reproducible chemistry. Thus,
this synthetic strategy was ignored while solution-based methods were well accepted.
This situation began to change when Toda and co-workers reported the intriguing observation
that neat grinding of an aromatic aldehyde and acetophenone in the presence of NaOH
under neat conditions gave the aldol condensation product (the anticipated chalcone)
in excellent yield, whereas the reaction performed in 50% aq EtOH afforded the chalcone
product in rather low yield (Scheme [2]).[9]
Scheme 2 Contrasting behavior in the aldol condensation reaction between p-methylbenzaldehyde and acetophenone; left-hand side, in 50% aq EtOH; right-hand side,
in the absence of solvent[9]
Subsequently, several applications of solvent-free, mortar and pestle enabled reactions
for chemical synthesis were reported by Chimni and co-workers.[10] Nevertheless, manual grinding by means of a mortar and pestle presents several inconveniences,
such as lack of reproducibility from lab to lab and even safety concerns. These practical
disadvantages motivated the development of automated ball-milling equipment that enable
the control of parameters such as frequency (intensity) of milling, securing higher
reproducibility in the process.[11] Furthermore, regarding experimental safety issues milling devices incorporate closed
containers, minimizing the exposure to potentially toxic or dangerous chemicals. Simultaneously,
automated mechanical milling, unlike hand grinding, allows for longer reaction times,
which are sometimes needed to attain very small particle sizes for the concomitant
activation of reagents in the solvent-free process.
Milling Equipment and Reaction Parameters
3
Milling Equipment and Reaction Parameters
The reactor jars and balls used for the milling process are generally made from inert
materials such as stainless steel, agate, zirconia, tungsten carbide, Teflon, etc.
Of course, these materials vary in their hardness and therefore can have an influence
on the amount of energy transferred to the reactants and thus their reactivity. For
instance, stainless steel and agate milling balls convey greater energy during the
milling process than Teflon. Milling media also differ in their chemical resistance,
and this fact must be taken into account when dealing with aggressive substrates.[3e] In this regard, stainless steel milling balls and containers may corrode in contact
with strong acids. Furthermore, wear of the milling container and milling balls during
the milling process can result in metal contamination, and this could impact the reaction
outcome.
In this context, while interference of the milling material with reaction substrates
is usually undesirable and therefore chemically inert milling materials, such as agate,
tungsten carbide, or zirconia, are frequently employed, a novel strategy is being
explored in which interaction of the milling jar and balls with the reagents is actually
desired.[3e] In particular, the milling tools may be able to act as the catalyst, facilitating
catalyst separation and reusability.[12] For example, milling jars and balls made of Cu, Ni, or Pd have been used for mechanochemically
catalyzed cross-coupling reactions.[13]
In relevant work in 2014, Borchardt and co-workers[14] devised a galvanostatic procedure for coating inert milling balls with a layer of
Pd. The modified milling balls were then successfully used as an in situ catalyst in the mechanochemically activated Suzuki reaction. Reaction yields higher
than 80% were achieved and the milling balls could be recycled several times.
Nevertheless, the phenomenon of leaching can be a serious handicap of mechanochemistry.
In 2023, Friščić and co-workers reported a remarkable contribution in this area using
state-of-the-art mills without balls.[15] Specifically, these researchers demonstrated the feasibility of direct mechanocatalysis
by resonant acoustic mixing (RAM), an emerging mechanochemical strategy that actually
avoids the use of milling media. The proof of concept of this pioneering concept was
accomplished by the effective synthesis of triazoles by means of copper-catalyzed
alkyne-azide click-coupling (CuAAC) activated by RAM.[15a]
In this regard, the modification of mechanochemical reactions by the presence of additives
has resulted in beneficial effects such as increased reactivity (see Section 4.3).
Another way to control a ball-milling reaction involves adjustment of the frequency
of milling, which has a direct effect on the motion and beating strength of the balls,
which in turn influence the progress of the reaction and therefore the structure of
the final products.[16]
As the result of its remarkable attributes, the area of mechanochemistry is presently
receiving significant attention.[1]
,
[17]
[18]
[19]
[20] Accordingly, the potential of mechanochemistry has been highlighted in numerous
review articles.[1i,21]
In this short review, we highlight some of the most relevant topics in current mechanochemically
enabled synthesis of organic compounds: (1) amino acid and peptide mechanosynthesis,
(2) asymmetric organic synthesis and asymmetric organocatalysis under mechanochemical
activation, (3) mechanoenzymology, (4) multicomponent reactions activated by mechanochemistry,
and (5) mechanosynthesis of representative heterocycles.
Attributes of Mechanochemistry That Propelled Its Present Renaissance
4
Attributes of Mechanochemistry That Propelled Its Present Renaissance
4.1
Enormous Attention Being Presently Paid to Sustainable Chemistry
Following the seminal 1998 monograph ‘Green Chemistry: Theory and Practice’, where Anastas and Warner advance the guiding principles of green chemistry,[22] an enormous amount of attention has been paid by the chemical community to the implementation
of more sustainable chemical procedures. In this regard, the increasing popularity
and success of mechanosynthesis can be ascribed in great measure to the fact that
mechanochemical reactions are usually carried out under solvent-free conditions or
with minimal volumes of organic solvents [liquid-assisted grinding (LAG); see Section
4.3].[23] This technique drastically minimizes waste production and therefore improves the
E factor of chemical transformations.[24] In particular, synthetic chemists now have access to mechanochemical equipment that
enables solvent-free synthesis.[25] Grinding reactions under solvent-free conditions are usually faster than solution-based
reactions owing largely to the increase in the surface area of contact on the solid
reactants, as a consequence of smaller particles being generated in the milling process.
Thus, mechanochemical processes are ‘greener’ since they avoid the usage of excess
solvent and concomitant purification protocols. In fact, ‘the best solvent is no solvent’[26] and solvent-free mechanochemical techniques are therefore most convenient to eliminate
or greatly reduce waste production. Furthermore, the mechanochemical solvent-free
environment enables the synthesis of otherwise elusive non-solvated compounds, as
well as rapid formation of products that in solution form slowly or not at all.
Furthermore, mechanochemical processes involve low energy consumption (see Section
4.2). Indeed, mechanochemical techniques have been commended for their convenient
application in ecologically friendly synthesis, fulfilling the principles of green
chemistry.[27]
The mechanochemical solvent-free environment enables the synthesis of otherwise elusive
non-solvated compounds, as well as rapid formation of products that in solution form
slowly or not at all.
As it was already mentioned, a major motivation for the present renaissance of mechanochemistry
is the attention paid to so-called green chemistry, with the concomitant need for
transformations that are cleaner, more efficient and safer.[22]
[26]
[28] The practical convenience of such development has been endorsed by the pharmaceutical
and food industries.[29] As already said, one way to develop more sustainable synthetic methods is by avoiding
or minimizing the use of solvents, which is a salient characteristic of solid-state
mechanochemical methodologies. Furthermore, solid state grinding usually requires
reduced reaction times, and in some instances provide products that are not accessible
in solution (see Section 4.5).[3e,30]
In this context, solvents are usually the major components in chemical processes,
frequently representing more than 90% of the reactant mixture.[29a]
[b] Furthermore, many solvents used in chemical reactions are potentially harmful to
human health and the environment.[31]
In summary, although the use of solvents in chemical reactions is by far the most
common practice,[32] solid-state mechanochemical transformations have demonstrated the feasibility to
induce chemical reactivity in the absence of bulk solvents.[33] Mechanochemical methods are therefore rather attractive for both academic and commercial
endeavors seeking more sustainable processes. This capacity is especially significant
in the present times, when environmental issues, pollution, and climate change are
most pressing.[34]
4.2
Reduced Energy Consumption
As already discussed, solid-state and solvent-free organic synthesis will become increasingly
important with regard to green or sustainable chemistry. Most important, energy consumption
is reduced significantly since used solvents do not have to be recovered and purified
for additional use or disposal.
While non-conventional energy sources for chemical reactions such as ultrasound and
microwave irradiation continue to attract the interest of many synthetic chemists,[35] mechanical milling can offer an energy advantage over their solution counterparts.[36] For instance, several studies by Ondruschka and co-workers of the energetics of
the Suzuki–Miyaura coupling showed significantly higher energy efficiency in a milling
process, as compared to traditional heating or microwave irradiation.[37]
In particular, Suzuki–Miyaura coupling of phenylboronic acid with 4-acetylphenyl bromide
affording 4-acetylbiphenyl was used as model reaction to evaluate the energy cost
of different activation techniques: microwave irradiation, planetary ball milling,
and vibrational ball milling. Results of these experiments are summarized in Table
[1] revealing lowest energy consumption under mechanochemical activation.[37b]
Table 1 Comparison of Amounts of Electrical Energy Necessary for the Performance of the Suzuki–Miyaura
reaction of 4-Acetylphenyl Bromide with Phenylboronic Acid[37b]
|
|
Activation mode
|
Yield (%)
|
E (kW)
|
|
microwave
|
80
|
40.0
|
|
planetary ball mill
|
89
|
1.7
|
|
vibrating mill
|
85
|
1.0
|
Generally, ball mills are rather efficient regarding energy consumption. For example,
a laboratory vibrational mill, such as the one depicted in Figure [1e], requires amounts of energy that are rather convenient, especially when considering
the typically short reaction times needed in mechanosynthesis.[38]
It is also worthwhile to recall that solvation frequently suppresses reactivity as
a consequence of the stabilization of the reagents. Thus, in addition to minimizing
the negative environmental impact of solvents, mechanochemistry may improve the reagent’s
reactivity, leading to reduced energy demand when solvation is prevented.[2f]
On the other hand, Yang, Chen, and co-workers have stressed the fact that ball-milling
activation transfers a rather significant amount of mechanical energy into the treated
materials, simultaneously ensuring a large surface area and intimate mixing between
reactants. This substantially reduces the energy barriers, and thus a smaller activation
energy is needed to initiate the reactions in thermal processes.[39]
4.3
Additive-Based Mechanochemistry
The usual way to carry out a mechanochemical reaction is by ‘neat grinding’, implying
that no additional substances (that is, inert solids or unreactive liquids) have been
added to the reactants. Nevertheless, the beneficial effect of added solvent on mechanochemical
reactions was reported in 2002.[40a] This method was eventually named ‘liquid-assisted grinding’ (LAG) by Friščić and
co-workers.[40b]
[c] The term ‘kneading’ is used when referring to manual grinding with a mortar and
pestle.[40d]
In this regard, mechanochemistry helps overcome solubility restrictions (see Section
4.4). LAG protocols use only minute amounts of solvents that function as catalytic
additives.[41]
In organic synthesis Eckert-Maksić, Friščić, and co-workers reported LAG for the high-yield
mechanosynthesis of more than 50 thioureas.[42] Regarding reaction selectivity, Browne and co-workers reported LAG-activated selective
fluorinations (mono- vis-a-vis difluorination).[43]
Thus, mechanochemical reactions are accelerated by the addition of small amounts of
organic solvents.[44] Apparently LAG facilitates more molecular mobility relative to neat grinding. Usually,
the choice of the appropriate additive is based on a process of trial and error. The
most commonly used solvents as for LAG include methanol, ethanol, propan-1-ol, ethyl
acetate, acetonitrile, and some ethers, such as THF and methyl-tert-butyl ether. The LAG process is characterized by the parameter η, that corresponds
to the volume of solvent in μL divided by the weight of sample weight in mg. Recommended
values for LAG fall in the η range of 0–2 μL mg–1. Higher η values are characteristic in the formation of slurries. By contrast, η
= 0 for neat grinding.
Importantly, the addition of chemically inert milling auxiliaries such as silica,
sand, sodium chloride, or sodium sulfate salts can be used as a means of supplying
the mechanochemical reactants from an inert support and facilitating the reaction.[1i]
[3e] Upon the addition of these milling auxiliaries, a more ‘dilute’ mixture of the milling
components can be formed, improving molecular contact and reactivity. It is worthwhile
mentioning that removal of inert additives, such as sand and silica, is easily carried
out during the workup procedure via filtration or centrifugation. In an interesting recent development, hydrotalcite
or hydroxyapatite minerals have also been used as additives fulfilling two functions,
as activating bases and as supporting material in ball-milling mechanosynthesis of
peptides.[45]
4.4
Handling of Insoluble Reactants
Solvent-free mechanochemical activation enables the manipulation of substrates exhibiting
poor or negligible solubility. Indeed, insoluble materials can react with no problem
under solvent-free reaction conditions. For example, James, Vyle, and co-workers have
reported that biomolecules, such as sugars and nucleosides, that are known to exhibit
low solubility in organic solvents are readily modified via ball-milling procedures.[46] More generally, reactions between solids that are not soluble in the common solvents
are well handled by means of mechanochemistry. Thus, mechanochemistry is frequently
able to overcome poor reactant solubility issues in reactions involving reactants
with poor solubility, enabling chemical reactions that otherwise would not be possible
in solution.
A salient example is the use of amino acids, peptides, and enzymes in synthetic organic
chemistry. These biomolecules generally present low solubility in organic solvents,
which limits their chemical manipulation and use in synthesis. Recently, however,
the use of mechanochemical techniques has helped overcome solubility limitations in
the synthesis and application of amino acids and peptides (see Section 5.1). Furthermore,
biocatalysts such as enzymes have recently been shown to perform well under ball-milling
conditions (see Section 5.3).
Emblematic here is the success achieved in reactions of fullerenes (notoriously insoluble
molecules in organic solvents) under ball-milling conditions. In particular, Komatsu
and co-workers found that a dimer of C120 is readily formed in reactions carried out under high-speed ball milling in the absence
of solvent (Scheme [3]).[47]
Scheme 3 Dimerization of fullerene C120 by means of solvent-free ball milling[47]
The possibility of overcoming solubility limitations in chemical synthesis has encouraged
the utilization of ball-milling techniques to enable chemical reactions that are challenging
or impossible under solution-based conditions.[48]
In this regard, Ito, Kubota, and co-workers[49] reported in 2021 a high-temperature ball-milling technique for solid-state palladium-catalyzed
Suzuki–Miyaura cross-coupling reactions via a high-temperature ball-milling technique. This ‘heat and beat’ strategy enabled,
among others, the reaction of insoluble aryl halides with polyaromatic compounds that
present extremely low solubility and are therefore scarcely reactive under conventional
solution-based conditions. Thus, induction-heated ball milling provides a practical
mechanochemical method for performing molecular transformations of insoluble organic
compounds that cannot be carried out by any other approach.[21g]
4.5
‘Impossible’ Reactions That Are Successful by Milling
The grinding, beating, and shearing forces involved in solid-state mechanochemical
processes can give rise to chemical reactivity that is not possible in thermal processes.[3a] Indeed, when mechanical forces rather than energy transferred by heat, activate
reactions, the mechanism of a reaction inside a ball mill can be different and sometimes
can lead to unexpected products.[8] Thus, mechanochemical activation has occasionally resulted in the discovery of new
chemical reactivity, expanding the scope of synthetic chemistry.[30]
[50]
[51] As for the explanation, it has been advanced that the locally high-energetic mechanical
process shifts the reactant’s atoms away from their equilibrium position, promoting
the irreversible and efficient formation of the reaction solid-state product.[52] Another attractive feature of mechanochemical protocols is the absence of laborious
workup protocols.
In an illustrative example showing pronounced differences between thermo- and mechanochemistry
in organic chemistry, Gomollón-Bell reported how the structure of copper complexes
depends on how they are made. In particular, copper derivatives form square-planar
complexes in solution, while ball milling provides octahedral structures, as discovered
by D. E. Crawford.[8]
4.6
Successful Handling of Air- and Water-Sensitive Reagents by Ball Milling
Mechanochemical techniques often overcome the need for inert environments when handling
air/moisture sensitive reagents. For instance, influential papers by Ito and co-workers[53a]
[b] and Browne and co-workers[53c–e] revealed that mechanochemistry allows carrying out reactions with sensitive organometallic
compounds in air. Indeed, the synthesis of palladium and zinc sensitive complexes,
that usually requires the use of a glove box and Schlenk lines, was efficiently accomplished
under simple ball-milling conditions.
In this regard, it is worthwhile mentioning that expensive protocols involving the
use of degassed and anhydrous solvents can be avoided through the use of mechanochemical
techniques.[53]
[54]
In this context, especially relevant is the mechanochemical activation of zero-valent
metals. Indeed, activating zero-valent metals is an important process in many synthetic
and catalytic chemical processes. In particular, the combination of ball milling and
chemical synthesis mediated by zero-valent metals provides a timely sustainable platform
for chemical synthesis, and catalysis.[55]
In this context, Grignard’s reaction is a classical, most helpful synthetic tool for
preparing valuable intermediates in the total synthesis of natural products, among
many other molecules. Nevertheless, the preparation of Grignard’s reagents is often
difficult to implement, requiring inert and anhydrous atmospheres. In this regard,
the groups of Harrowfield, Birke, Hanusa, Bolm, and Ito have independently reported
the mechanochemical activation of magnesium metal for the synthesis of Grignard reagents
via the insertion of magnesium metal into organic halides without the need for carefully
dried solvents.[56]
As can be anticipated, subsequent reaction of Grignard reagents with carbon dioxide
provides the corresponding carboxylic acids in moderate to good yields. Nevertheless,
this methodology works well with liquid bromide reagents, but rather poorly when the
halides are solid, insoluble substrates. Since neither prolonged time nor various
additives or LAG species afforded better results, increasing the temperature was considered.
Importantly, Ito and co-workers achieved that goal by means of a heat gun to reach
higher temperatures.[57] Such ‘heat and beat’ mechanochemical procedure has been successfully extended to
other mechanochemical processes.[58]
Salient Developments in the Mechanochemical Activation of Synthetic Organic Chemistry
5
Salient Developments in the Mechanochemical Activation of Synthetic Organic Chemistry
This short review aims to highlight salient achievements of mechanochemical activation
in (1) amino acid and peptide mechanosynthesis, (2) asymmetric organic synthesis and
asymmetric organocatalysis under ball-milling conditions, (3) mechanoenzymology, (4)
multicomponent mechanochemical reactions, and (5) mechanosynthesis of representative
heterocycles.
5.1
Amino Acid and Peptide Mechanosynthesis
Amino acids are essential components of relevant biomolecules such as peptides and
proteins, which in recent years have also been successfully used as organocatalysts
in asymmetric synthesis.[59]
Typically, the synthesis of α-amino acids in solution can be carried out by means
of the Strecker reaction[60] between amines, cyanides, and carbonyl compounds to afford rac-α-aminonitriles, which are then converted into rac-α-amino acids via hydrolysis.[61] In 2016, Bolm, Hernández, and co-workers described a mechanochemical procedure for
the corresponding mechanosynthesis, employing SiO2 as inert milling additive (Scheme [4]).[62]
Scheme 4 Mechanochemical Strecker reaction of α-aminonitriles from aldehydes, amines, and
cyanides[62]
On the other hand, in 2012 Lamaty and co-workers developed an enantioselective synthesis
of α-amino ester derivatives by asymmetric phase-transfer catalyzed alkylation of
precursor Schiff bases in a ball mill in the presence of a chiral cinchonidinium ammonium
salt (Scheme [5]).[63]
Scheme 5 Enantioselective alkylation of Schiff bases under solvent-free ball-milling conditions[63]
In 2015, Bolm, Soloshonok, and co-workers reported the asymmetric alkylation of glycine
residues by means of nickel(II) complex 1 (Scheme [6]).[17a]
Scheme 6 Mechanochemical asymmetric alkylation of chiral nickel(II) complex 1
[17a]
Scheme 7 Solvent-free peptide synthesis[64]
[65]
A relevant challenge in peptide synthesis is to reduce the amount of solvent used;
hence mechanochemistry can play an essential role for optimizing peptide synthesis.
In this regard, in 2009 Lamaty and co-workers reported that the opening of α-amino
acid N-carboxy anhydrides with α-amino acid esters under solvent-free conditions in a ball
mill affords α-peptides in good yield (Scheme [7]).[64]
[65] With base in this work and motivated by the significant interest in the chemistry
of β-amino acids and β-peptides,[66] Hernández and Juaristi reported the synthesis of α,β- and β,β-dipeptides in 2010
(Scheme [8]).[67] Importantly, comparison of the specific optical rotations of dipeptides prepared
in this work with data reported in the literature showed total agreement, indicating
that no significant racemization took place.
Scheme 8 Mechanosynthesis of α,β- and β,β-dipeptides[67]
The efficiency of this methodology was further confirmed through the mechanosynthesis
of the sweetener aspartame by milling of a mixture of the N-carboxy anhydride of aspartic acid and alanine methyl ester for 1 h at 30 Hz. The
desired dipeptide was obtained in 97% yield and removal of the protecting groups afforded
aspartame hydrochloride.[67] On the other hand, Hernández and Juaristi reported the mechanosynthesis of a protected
derivative of the pharmacologically active dipeptide (S)-carnosine in the ball mill (Scheme [9]).[67]
Scheme 9 Mechanosynthesis of protected dipeptide (S)-carnosine under solvent-free conditions[67]
In 2017, Landeros and Juaristi reported the high-yielding mechanosynthesis of various
α,α-, α,β-, and β,β-dipeptides from N-protected amino acids and amino acid methyl ester hydrochlorides in the presence
of HOBt and EDC as coupling reagents, and using Mg-Al hydrotalcite (HT) mineral as
green activating agent. The mechanochemical protocol offers important advantages,
such as easy workup, recovery and recyclability of the hydrotalcite activator, and
short reaction times.[45a]
The mechanosynthesis of long peptide chains is a challenging goal since coupling and
deprotection reactions become less efficient as the peptide chain length becomes longer.[68] The synthesis of Leu-enkephalin represents one of the most complex mechanosyntheses
registered to this date (Scheme [10]).[69]
The risk of epimerization represents a severe hurdle in amide coupling.[70] In this regard, Lamaty, Métro, and co-workers[71] examined the potential of ball milling to eliminate epimerization during peptide
coupling. In the process, it was observed that the mechanochemical procedure required
only one-third of this reaction time, probably as consequence of higher concentration
of the reagents in the ball mill, which shortens reaction times relative to the corresponding
reaction in solution.
Scheme 10 Solvent-free mechanosynthesis of Leu-enkephalin[69]
In this context, carbodiimide-activated coupling of amino acid residues has been carried
out conveniently by means of mechanochemistry.[72] On the other hand, Lamaty, Laconde, Colacino, and co-workers reported the use of
activated α-aminoacyl benzotriazole derivatives in peptide mechanosynthesis.[73]
Also relevantly, Užarević, Hernández, and co-workers reported the oligomerization
of glycine promoted by TiO2 (a mineral likely to be present in earth during prebiotic times) under mechanochemical
activation.[74]
5.2
Asymmetric Organic Synthesis and Asymmetric Organocatalysis under Ball-Milling Conditions
During the 21st century, asymmetric organocatalysis has become a rather efficient
and attractive way to prepare chiral compounds in enantiomerically enriched form.
The catalytic nature of this strategy fulfills some of the principles of so-called
‘green chemistry’, which is a major topic associated with the progress of chemistry
in the 21st century. Importantly, two papers published in 2012 advance the idea that
organocatalysis can be made even more sustainable when in combination with mechanochemistry.[10a]
[75]
From the beginning of asymmetric organocatalysis,[76] aldol reactions have been used as test reaction of the efficiency of novel organocatalysts.[77] In this context, the remarkable performance of (S)-proline as organocatalyst in asymmetric aldol reactions[76a] motivated the examination of the reaction under solvent-free conditions. Indeed,
Bolm and co-workers reported the successful asymmetric aldol reaction organocatalyzed
by (S)-proline under high-speed ball milling (HSBM).[78] Different aldehydes and ketones were used as substrates and the expected aldol products
were obtained in 42–99% yield, up to 99:1 diastereoselectivity, and 45–99% ee (Scheme
[11]). Relative to traditional reactions in solution, HSBM resulted in shorter reaction
times and cleaner reactions. Soon thereafter, (S
a)-Binam-(S)-prolinamide was successfully employed by Nájera and co-workers as a chiral organocatalyst
in the asymmetric aldol reaction under ball-milling conditions.[79]
Scheme 11 Solvent-free enantioselective aldol reaction organocatalyzed by (S)-proline in a ball mill[78]
Subsequently, the use of peptidic organocatalysts derived from (S)-proline was examined. In particular, dipeptidic organocatalysts (S,S)-Pro-Phe (A) and (S,S)-Pro-Trp (B) were tested by Juaristi and co-workers in the intermolecular aldol reaction under
ball milling activation (Scheme [12]).[80] These organocatalysts afforded the desired aldol product in high yield and excellent
diastereo- and enantioselectivity. Interestingly, the presence of water molecules
as additive apparently induces the formation of chiral micelles as consequence of
a hydrophobic effect, leading to a more rigid transition state and then high stereoselectivities
(see inset in Scheme [12]).[80]
Scheme 12 Enantioselective intermolecular aldol reaction organocatalyzed by dipeptidic organocatalysts
(S,S)-Pro-Phe and (S,S)-Pro-Trp by HSBM in the presence of water and benzoic acid as additives[80]
Considering that potential role that π–π stacking interactions could play in the robustness
of the transition state for the aldol reaction (cf. short distance between the aromatic
rings, see inset in Scheme [12]), it was reasoned that the replacement of the carbonyl amide segment by a thiocarbonyl
in organocatalysts A and B would afford more acidic N–H protons and consequently stronger hydrogen bonds between
the substrate and the organocatalyst; that is, a more rigid transition state. Accordingly,
the corresponding (S,S)-thiodipeptides were synthesized and evaluated in the same aldol reaction under similar
reaction conditions. As it turned out, thiopeptidic organocatalysts led indeed to
the formation of aldol products with higher diastereoselectivity, up to 98:2 anti/syn ratio.[81]
Machuca and Juaristi investigated further the putative stabilizing effect by π–π stacking
interactions in the suggested transition state. Specifically, the electron density
on the aromatic ring in the substrate aldehydes was systematically varied by the incorporation
of substituents with different electron-donating or electron-withdrawing capacity.
As anticipated, electron-deficient aldehydes afforded the aldol product in better
yields and with higher stereoselectivity relative to electron-rich analogues. This
observation is in line with the hypothesis that π–π stacking interactions play a significant
role in the resulting yields and stereoselectivities. Furthermore, the solvent-free
mechanochemical conditions are expected to enhance the rigidity of the transition
state leading to more selective reactions.[82a] Relevantly, when the reaction was evaluated under contrasting experimental protocols,
specifically, in solution, neat conditions with stirring, and solvent-free HSBM activation,
the highest selectivity (90:10 anti/syn ratio and 91:9 enantiomeric ratio) was achieved after 0.5 h of reaction under mechanical
activation in a ball mill. In the course of this work it was also established that
the stereogenic center in the (S)-proline residue is primarily responsible for the observed enantioinduction.[82b]
In 2004, Wang and co-workers reported the first example of Michael reactions performed
under HSBM solvent-free conditions, employing K2CO3, an achiral inorganic base, as catalyst. This mechanochemical reaction required less
than 1 h, and provided the expected racemic adducts in good yields and good anti/syn diastereoselectivity.[83] As it could have been anticipated, this report motivated the examination of chiral
organocatalysts that could lead to enantiomerically enriched products. In particular,
Michael additions organocatalyzed by chiral thioureas were deemed a particularly attractive
subject of study. Indeed, Toma, Šebesta, and co-workers investigated the effectiveness
of chiral pyrrolidine derivatives as organocatalysts in the asymmetric Michael reaction
between aldehydes and β-nitrostyrene.[84] As it turned out, α,α-diphenylprolinol derivative 2 afforded the enantioenriched Michael products in 44–97% yields, up to 95:5 diastereomeric
ratios, and up to 94% ee (Scheme [13]).
Scheme 13 Enantioselective Michael addition organocatalyzed by silylated α,α-diphenylprolinol
2 activated by ball milling[84]
Subsequently, Xu and co-workers evaluated the potential of chiral squaramide derivatives
as H-bond donor catalysts in the solvent-free Michael addition of 1,3-dicarbonyl nucleophiles
to 1-aryl-2-nitroalkenes employing a planetary ball mill.[85] On the other hand, Bolm and co-workers employed thiourea-based organocatalysts in
an organocatalytic asymmetric version for the Michael addition, under planetary-milling
conditions. For instance, α-nitrocyclohexanone added to various nitroalkene derivatives
to give the desired product in up to 95% yield, with a diastereomeric ratio of 98:2
and up to 98% ee. The reaction took place within 30 min (Scheme [14]).[86]
Scheme 14 Mechanochemically activated organocatalyzed asymmetric Michael addition reaction[86]
In 2020, Šebesta and co-workers reported an organocatalyzed mechanochemically activated
sequential asymmetric Mannich addition and diastereoselective fluorination sequence.
This reaction was catalyzed by chiral squaramide catalysts affording the desired products
as a single diastereomer in good yields and excellent enantiomeric purities.[87]
In this context, Mack and Shumba described the efficient activation of the Morita–Baylis–Hillman
(MBH) reaction by ball milling.[88] In this regard, chiral tertiary amines were explored as organocatalysts in the MBH
reaction of imine 3 with Michael acceptor ethyl acrylate (4). Best results were achieved with organocatalyst β-isocupreidine (5) delivering the aza-MBH product 6 with 64% ee (Scheme [15]).[89]
Scheme 15 Organocatalytic aza-Morita–Baylis–Hillman reaction using ball-milling technique[89]
With respect to enantioselective C-amination under solvent-free ball-milling conditions,
(S)-proline derivative 9 organocatalyzed the reaction of aldehydes 7 with azodicarboxylate 8 to give amine precursors 10 in good yields and high enantioselectivities (Scheme [16]).[90]
Scheme 16 Enantioselective C–N bond formation via hydrazination of aldehydes with azodicarboxylates under ball-milling conditions[90]
Highly enantioselective fluorination of β-keto esters employing a planetary ball mill
under solvent-free conditions was also accomplished by Xu and co-workers using supported
bis(azoline)-Cu(OTf)2 complexes 11 (Scheme [17]).[91]
Scheme 17 Enantioselective fluorination of β-keto esters[91]
In 2022, Šebesta and co-workers reported the high yielding, highly enantioselective
oxa-Diels–Alder reaction by using either a bifunctional aminothiourea or a monofunctional
quinine organocatalyst under LAG ball-milling conditions.[92]
5.3
Mechanoenzymology
The successful mechanosynthesis of amino acids and peptides (see Section 5.1) gave
evidence of the resilience of these biomolecules to the stressful conditions prevailing
in the milling process. The remarkable stability of amino acids and peptides under
mechanic stress was further evidenced by the remarkable degree of stereoselectivity
achieved in mechanochemical asymmetric reactions (see Section 5.2). These observations
paved the way for the use of mechanochemistry in combination with enzymic catalysis.
Indeed, in 2015 Gross and co-workers described the mechanochemical ring-opening polymerization
of ω-pentadecalactone catalyzed by immobilized Candida antarctica lipase B (CALB).[93] This development demonstrated that enzymic activity does prevail under stressful
mechanical milling.
Soon thereafter, seminal experiments of Hernández, Frings, and Bolm established the
catalytic capacity of biocatalyst Candida antarctica lipase B (CALB) to perform the kinetic resolution of racemic secondary alcohols under
mechanical milling. Again, this observation confirms the significant resistance of
peptide bonds in biomolecules to mechanical stress (Scheme [18]).[21h]
[94]
Scheme 18 Enzymatic kinetic resolution of racemic secondary alcohols catalyzed by immobilized
CALB under mechanochemical conditions;[21h]
[94]
E = enantioselectivity
Figure 2 Mechanoenzymology as a new branch of mechanochemistry. Reproduced with permission
from ref 95. Copyright 2021 Wiley-VCH.
These reports set the basis for the transition from synthesis and manipulation of
amino acids and peptides under mechanochemical activation to the application of biocatalysis
together with mechanochemistry to perform useful, enantioselective tasks. The new
field of mechanoenzymology was born (Figure [2]).[95]
Systematic studies involving mechanoenzymology with specific emphasis in the area
of sustainable medicinal mechanochemistry were then carried out by Juaristi and co-workers
using immobilized CALB as catalyst.[96] In particular, CALB enzyme was then used in the kinetic resolution of racemic β-amino
esters, β-amino alcohols, amines, and carboxylic acids (Scheme [19]); one of the driving forces in these studies being the difference of pharmaceutical
activity between enantiomers.[97]
Thus, these mechanoenzymatic strategies (Schemes 18 and 19) allowed, under appropriate
conditions (reaction time and frequency, additives, milling jar/balls material), the
preparation of enantioenriched and enantiopure active pharmaceutical ingredients or
their precursors, with superior results when compared with the same processes in solution.
These developments encourage the future examination of even more complex enzymes such
as transaminases, reductases, and monooxygenases, among other important enzymes.
In this context, the polymerization of ω-pentadecalactone was reported to afford high-molecular-weight
polymers.[98] Furthermore, non-immobilized enzymes have also been used together with mechanochemical
activation to carry out peptide bond formation. For instance, the mechanoenzymatic
oligomerization of α-amino acids was accomplished by means of protease papain.[99] Oligomerization of α-amino acids by means of a twin-screw extrusion has also been
recorded.[68b]
[99]
Scheme 19 Bioactive chiral compounds prepared in enantiomerically pure form via mechanoenzymatic kinetic resolution using immobilized CALB.
(a) Resolution of N-benzylated β3-amino esters.[96a] (b) Synthesis of enantiomerically pure (R)-rasagiline.
[96b] (c) Resolution of rac-ketorolac.[96c] (d) Resolution of β‑blocker propranolol.
[96d]
E = enantioselectivity. c = conversion.
Recently, the effectiveness of enzymes in mechanochemical depolymerization of biomaterials
has been actively explored by Auclair, Friščić, and co-workers.[100] Most interesting is the successful use of hydrolases, such as cellulases and chitinases,
in the depolymerization of feedstocks that are normally considered as biowaste (Figure
[3]).[100] For the implementation of this work, and aiming to increase the degree of depolymerization,
the authors developed the ‘reactive aging’ technique, which consists of cycles of
milling followed by aging.[100c] This protocol reduces mechanical stress on the biocatalyst and facilitates contact
between the enzyme and the substrate. This strategy offers great potential in the
depolymerization of plastic materials such as polyethylene terephthalate (PET).[101]
Figure 3 Some polymeric molecules suitable for mechanoenzymatic depolymerization[100]
On the other hand, lipases and proteases can also be employed in mechanoenzymatic
protocols to catalyze the polymerization of amino acids.[102] In a salient example, Hernández and co-workers[99] developed a mechanochemical papain-catalyzed polypeptide formation by means of a
chemoenzymatic protocol that overcame the low degree of polymerization found in traditional
solution procedures, as a consequence of premature precipitation of the oligopeptides
(Scheme [20]).
Scheme 20 Mechanoenzymatic papain-catalyzed oligopeptide formation by ball milling[99]
On the other hand, Arciszewski and Auclair focused on mechanoenzymatic reactions involving
polymers either as substrates or products.[103] Representative biopolymers were various proteins, DNA, and cellulose, or synthetic
polymers such as plastics.
Regarding mechanoenzymatic breakdown of natural polymers, it is worthwhile to emphasize
that there is an enormous interest in finding renewable, non-fossil-based feedstocks
to satisfy present and future needs for energy and basic chemicals. In particular,
natural polymers, such as cellulose, hemicellulose, and chitin, could provide suitable
abundant sources of clean energy if they can be broken down into useful products.
Particularly pertinent, biomass depolymerization is a challenging issue owing to the
poor solubility of the constituent polymers. This limitation can in principle be overcome
by means of solvent-free solid-state mechanochemical techniques (see Section 4.4).
In this context, chitinous biomass, that has been recorded as the most abundant nitrogen-containing
biopolymer on earth, is an attractive chemical feedstock for the production of useful
drugs and agrochemicals (Scheme [21]). In 2019, Friščić, Auclair, and co-workers reported the efficient mechanoenzymatic
breakdown of chitin to N-acetylglucosamine (GlcNAc) by a commercial chitinase (Scheme [21]).[100b]
Scheme 21 The mechanoenzymatic hydrolysis of chitin to generate N-acetylglucosamine[100b]
Mechanoenzymatic hydrolysis of synthetic polymers. Presently, only one tenth of the global annual plastic production (ca. 370 million
tons in 2019) is recycled after use, and the rest represents a serious problem, polluting
land, sea, and rivers. Thus, depolymerization is urgently needed for recycling plastics
in order to turn them into valuable materials. In this direction, Friščić, Auclair,
and co-workers recently reported that mechanoenzymatic procedures enable the direct
depolymerization of polyethylene terephthalate (PET) plastics by means of commercially
available Humicola insolens cutinase (Scheme [22]).[101a]
[104] This process was also efficient in the depolymerization of other plastics such as
terephthalates and polycarbonates, with better results relative to the corresponding
procedures in solution.
Scheme 22 Mechanoenzymatic procedure for the depolymerization of PET hydrolysis to give chemically
useful terephthalic acid[101a]
[104]
Mechanoenzymatic reactions with whole cell transaminases. In their ‘concept’ article in 2021 on mechanoenzymatic chemistry, Pérez-Venegas
and Juaristi wondered whether whole cells would be sufficiently stable to function
properly under milling conditions.[95] As it turns out, in 2022 Hailes and co-workers described the enantioselective amination
of various carbonyl substrates catalyzed by whole cell transaminases under mechanochemical
activation.[105] Relevantly, the transaminase-catalyzed conversion of prochiral aldehydes and ketones
into amino derivatives is totally enantioselective (Scheme [23]).
Scheme 23 Enantioselective mechanoenzymatic reductive amination of aldehydes and ketones with
transaminases[105]
When compared with traditional conditions in solution, the mechanoenzymatic whole
cell reactions afforded significantly higher yields of the products, despite hostile
conditions during ball milling; that is, high energy impacts, points of high local
temperature, and sites of high pressure inside the reactor jar.
In short, biocatalysts are closely linked to the future of organic synthesis, and
enzymatic processes may represent an important avenue in the future of mechanochemistry.
Here, one can envision a variety of relevant upcoming developments of mechanoenzymology,
for example making use of the many new enzymes that are being discovered by means
of modern tools such as protein engineering and bioinformatics. Indeed, one can expect
that the performance of engineered enzymes will exceed the efficiency of catalysts
traditionally used up to now in organic synthesis.[106] Nevertheless, as it was recently pointed out by Cossy,[107] present day synthetic chemists are better advised to learn molecular biology and/or
to strengthen their collaborations with molecular biologists.
In this context, the possibility of carrying out enzymatic cascades under milling
activation for the rapid production of complex compounds should be rather attractive
both at laboratory and industrial scale.[108]
[109]
5.4
Multicomponent Reactions Activated by Mechanochemistry
Multicomponent reactions are a powerful strategy for the synthesis of complex molecular
structures. Whereas in solution these reactions usually proceed through a series of
reversible processes under thermodynamic control, mechanochemical multicomponent reactions
are kinetically controlled.[110]
In a relevant contribution in the area of mechanochemistry, Menéndez and co-workers
reported that the three-component Hantzsch pyrrole synthesis proceeds efficiently
under ball-milling conditions (Scheme [24]).[111]
Scheme 24 Mechanochemically activated three-component Hantzsch pyrrole synthesis[111]
In this context, isocyanide-based multicomponent reactions have been well-studied
under traditional reaction conditions in solution.[112] By contrast, in 2016 Polindara and Juaristi revealed that Ugi 4-component reactions
(4-CR) employing tert-butyl isocyanide, aromatic aldehyde, chloroacetic acid, and propargylamine in the
presence of 2 mol% InCl3 proceeded satisfactorily in a ball mill (Scheme [25]).[113] The same team also disclosed a mechanochemical Passerini 3-component reaction (3-CR)
(Scheme [25]).[113]
Scheme 25 Mechanosynthesis of Ugi 4-CR and Passerini 3-CR adducts[113]
Boron dipyrromethene (BODIPY) dyes have attracted significant interest in view of
their useful photophysical properties.[114] Indeed, among many biological and medical applications BODIPY dyes have been employed
as emitting tags in bioimaging.[115] Accordingly, various synthetic routes have been developed to incorporate BODIPY
moieties in their structure. In particular, the Liebeskind–Srogl coupling reaction[116] is a rather convenient means for the preparation of BODIPY derivatives.
In this regard, the Polindara–Juaristi mechanochemical procedure described above,[113] was recently applied for the mechanosynthesis of several BODIPY dyes, including
BODIPY-Ugi adducts 12 and 13 (Scheme [26]).[117] Figure [4] depicts the X-ray diffraction structure and conformation of BODIPY-Ugi adduct 12.[117b]
Scheme 26 Ugi reaction in the mechanochemical preparation of BODIPY adducts 12 and 13
[117]
Figure 4 X-ray diffraction structure and conformation of BODIPY-Ugi adduct 12. Reproduced with permission from ref 117b. Copyright 2022 Wiley-VCH.
On the other hand, the multicomponent Strecker reaction is an emblematic procedure
for the synthesis of α-aminonitriles via condensation of aldehydes, ammonia, and hydrogen cyanide.[118] In 2016, Bolm, Hernández, and co-workers described a mechanochemical synthesis of
α-aminonitriles using representative starting materials and the milling auxiliary
SiO2 (see Scheme [4]); the expected α-aminonitriles were obtained in 70–97% yields.[62] In 2021, Bolm and co-workers reported Biginelli-type multicomponent reactions (MCRs)
with NH-free sulfonimidamides that gave 2,3-dihydro-1,2,6-thiadiazine 1-oxides in
high yields. The couplings are performed in a planetary ball mill under solvent-free
mechanochemical conditions. Acetic acid or ytterbium triflate are used as catalysts.[119]
5.5
Mechanosynthesis of Heterocycles and Modification of Heterocycles
The remarkable pharmacological activity of imidazolidine-2,4-diones, so called hydantoins,
motivated Porcheddu, Colacino, and co-workers to develop its efficient mechanochemical
preparation, which constitutes a representative example of the ecofriendly preparation
of pharmacologically active ingredients.[120]
Scheme 27 Mechanochemical preparation of substituted hydantoins[121]
Scheme 28 L-S Cross-coupling reaction under traditional reaction conditions (upper reaction)
and under mechanochemical activation (lower reaction)[123]
A systematic investigation of hydantoin synthesis by mechanochemistry starting from
a large variety of α-amino acid methyl ester hydrochlorides led to two general approaches
using potassium cyanate or isocyanates (Scheme [27]).[121]
Compared with solution synthesis, the reaction conditions are simpler, the yields
are significantly better, and the workup procedure is more simple.
Boron-dipyrromethenes (BODIPYs) are highly fluorescent compounds that are valuable
agents in photodynamic therapy, with further extensive applications in imaging and
ion sensing or as components of organic solar cells. A significant number of substituted
BODIPYs have been prepared via the cross-coupling reaction known as the Liebeskind–Srogl (L-S) protocol.[122] In 2020, Peña-Cabrera, Juaristi, and co-workers reported the effective L-S cross-coupling
reaction mediated by mechanical activation, eliminating the use of special reaction
conditions (Scheme [28]).[123]
The standard methodology for oligonucleotide synthesis with polymeric supports,[124] requires the use of large volumes of solvents for solubilization of the non-immobilized
reagents and for washing the solid support following reactions. In order to reduce
solvent usage, in 2021 Migaud and co-workers demonstrated the concept of using an
ionic liquid support in combination with liquid-assisted mechanochemistry for various
aspects of oligonucleotide synthesis (Scheme [29]).[125]
Scheme 29 One-pot mechanochemical preparation of a nucleoside on an ionic liquid support[125]
6
Future Directions
The number of mechanochemical applications has grown enormously in the last two decades;
nevertheless, mechanochemistry is still in a phase of study and development before
it can become the technique of choice in organic synthesis.[4]
[8] In this regard, the following sections discuss several areas of opportunity that
once fulfilled should help consolidate mechanochemistry as a practical strategy both
in academic and industrial settings. In this process, mechanochemistry will become
a synthetic approach fully supported on a robust conceptual basis.
6.1
Scaling-Up Mechanochemical Protocols
Mechanochemistry is increasingly adopted in academic laboratories in part because
it relies on essentially simple techniques involving grinding of substrates under
solvent-free conditions, avoiding high temperatures and bulk solvent usage. Thus,
mechanochemistry offers economic and environmentally friendly alternatives to synthetic
procedures in solution. Nevertheless, the milling technology developed in academic
settings confronts significant challenges before it can be fully adopted by industry.
For instance, chemical companies will need to replace traditional equipment with,
for example, ball mills and extruders satisfying requirements necessary for large-scale
production of the compounds and materials of interest.
In this regard, the vibrational mixer mill can handle grams of reactants, which is
suitable for most laboratory work, whereas planetary mills are available for larger
scales up to charges in the order of kilograms. For instance, the mechanochemical
Knoevenagel condensation between vanillin and barbituric acid was carried out in 80-g
batches by Stolle and co-workers by means of a planetary mill.[7c]
A convenient strategy for larger chemical reactions consists in modifying the process
from batch to continuous. In mechanochemistry, extruders are reactors where the reaction
substrates are ground together in a continuous manner through restricted spaces, so
that shear and compression forces provide the mechanical energy needed for activation
(Figure [5]). Thus, twin-screw extrusion (TSE) can be seen as a solid-state equivalent to solution-based
flow-reactors. Importantly, extruders operate under controlled reaction conditions
(reaction temperature, reagent feed-rate, and screw rotating speed) throughout the
process.
Figure 5 Continuous, solvent-free synthesis of perylene dyes by twin-screw extrusion. Reproduced
with permission from ref 126b. Copyright 2020 Wiley-VCH.
In this regard, James and co-workers have prepared metal organic frameworks at rates
of kilograms per hour.[126a] Similarly, James and co-workers reported the synthesis of various commercially relevant
perylene diimide dyes using TSE (Figure [5]).[126b] These dyes were obtained quantitatively without the need for product purification
with a throughput rate of about 1.5 kg per day, which is up to two orders of magnitude
greater than attained in solvent-based batch methods.
In another relevant development, scaling-up of the mechanoenzymatic oligomerization
of amino acids could be accomplished by extrusion techniques.[127] Furthermore, the potential of TSE methodology has been demonstrated for the continuous
manufacturing of various pharmaceutically active ingredients.[128] Similarly, Zhang, Niu, and co-workers have recently applied mechanochemical extrusion
for the conversion of poly(ethylene terephthalate) (PET) into porous carbon materials.[129] By contrast, in the area of peptide mechanosynthesis, Métro and co-workers developed
a continuous solvent-free synthesis of di- and tripeptides via extrusion.[130]
6.2
Temperature-Controlled Mechanochemistry
One limitation of present-day ball-milling methods is that the reaction temperature
in the milling jar is usually uncontrolled, and then subject to variations in sample
heating as the result of beating and friction.[126b] Indeed, Boldyreva, Browne, and others have pointed out that the amount of kinetic
energy present in the colliding milling ball(s) determines the maximum amount of energy
that can be transferred to the reagents per collision, and eventually dictates whether
or not a reaction takes place.[25]
[131]
The desirable goal to perform mechanochemical procedures at specific temperatures,
both above or below ambient temperature, is particularly challenging. Nevertheless,
as early as 2003, Kaupp and co-workers described double wall milling jars provided
with fittings that permitted the circulation of cooled or heated liquid during the
milling process. This equipment was successfully employed in the mechanochemical preparation
of heat-sensitive arylboronic esters.[132] Along similar lines, Kumar and Biswas[133] described cryo-mills that were used in combination with programmed pauses in the
grinding process to cool the jars with liquid nitrogen.
Presently, the challenging task for manufacturers of milling equipment is the production
and commercialization of milling apparatus with the capacity to control thermal energy
input between –100 °C and +100 °C. Advancing in this direction, the ‘GlenMills’ company
offers ‘Retsch’ ‘Cryogenic Milling’ apparatus where the grinding jar is continually
cooled with liquid nitrogen.[134]
In this context, different investigations have shown that increments in the temperature
of ball-milling reactions can result in significant acceleration of the mechanochemical
transformations, reducing the milling times from hours to minutes. In this regard,
Kubota, Ito, and co-workers recently reported the application of temperature-controlled
mechanochemistry to enable the mechanochemical nickel-catalyzed Suzuki–Miyaura coupling.
The temperature was controlled by means of a programmable jar heater.[16]
[135]
[136]
6.3
Understanding Mechanochemical Transformations
Despite the experimental simplicity of mechanochemical protocols, mechanochemistry
involves significant degrees of complexity. Indeed, milling containers are opaque,
‘black boxes’ that render it difficult to experimentally monitor reaction progress
and the concomitant molecular transformations. Furthermore, the profound differences
between conventional solution chemistry and solid-state chemistry render mechanochemical
transformations difficult to understand. In particular, the progress of mechanochemically
activated reactions involving two or more solid substrates depends on the generation
of interfaces between them, replacing the mediating role of the solvent.[137] Whereas in solution-based reactions the reactant molecules are able to approach
each other in order to react, in solid reactants the molecules are fixed, so that
displacement of the reactant molecules to the product phase is necessary. A suitable
mechanism is likely to involve the formation of a vapor or liquid bulk phase that
allows for mobility of the reacting molecules.[2c]
[138]
On the other hand, several spectroscopic and radiation diffraction techniques have
recently facilitated in situ monitoring of mechanochemical mechanisms, helping augment our understanding of solid-state
chemistry.[3e]
[139] In particular, the characterization of crystalline powders by means of powder X-ray
diffraction is feasible by comparison of the reagent and previously collected product
diffractograms, for instance from data deposited in the ‘Cambridge Structural Database’.
In cases where grinding results in sample amorphization, leading to a loss of diffraction
signals, FT infrared spectroscopy and Raman spectroscopy are suitable techniques that
do not depend on compound crystallinity. FT-IR and Raman spectroscopy help assess
changes in covalent bonding interactions (that is, bond scission or bond formation).
Further characterization analytical techniques such as solid-state NMR spectroscopy,
UV and visible light spectroscopy, and Mössbauer spectroscopy are also useful to monitor
and analyze mechanochemical reactions. In general, these measurements are carried
out ex situ, meaning that the milling process is stopped before isolation of aliquots of the
jar content for analysis.
6.4
Emerging Mechanochemical Techniques
Recently, mechanochemical activation is being combined with other energy sources that
are traditionally used in solution-based chemistry. In particular, newly developed
instrumental setups allow reactions that are not achievable by conventional mechanochemical
techniques. Salient areas of opportunity are photo-mechanochemistry, sono-mechanochemistry,
and electro-mechanochemistry. Advances in these areas are rather promising and represent
the future of solid-state reactivity through mechanochemistry.[140]
Regarding photo-mechanochemistry, the synergistic combination of photo- and mechanical
activations in organic synthesis offers an enormous potential. Nevertheless, mechanochemical
milling is usually conducted in non-translucent containers (e.g., agate, ceramics,
steels, and tungsten carbide), which poses an obstacle for light-irradiation procedures.
Recently, however, the monitoring of mechanochemical transformations have been accomplished
in translucent milling vessels (see Section 6.3) that have been used to carry out
photo-mechanochemical reactions.
In an illustrative example, Hernández designed a translucent milling vessel made of
poly(methyl methacrylate) (PMMA) to enable the photoborylation of arenediazonium salts
with bis(pinacolato)diboron (B2pin2) in the presence of the organic photocatalyst eosin Y, while having simultaneously
high-speed ball-milling activation.[141]
In this context, the synergistic combination of electrochemistry and mechanochemistry
can lead to new areas of opportunity in catalysis. For instance, Schumacher, Hernández,
and Bolm reported that mechanical forces transduced by ball milling can induce electrical
polarization in piezoelectric materials, thereby enabling chemical reactions influenced
by mechanical force and electric fields.[142] In particular, mechanical activation of piezoelectric BaTiO3 nanoparticles by ball milling enabled precise control over the oxidation state of
ligand-stabilized metal complexes, and its application in mechanically induced copper-catalyzed
atom transfer radical cyclizations. This strategy allowed for the efficient conversion
of monobromoacetamides into the corresponding lactams.[142]
In this context, photoredox catalysis is most useful in harnessing light energy to
accelerate bond-forming reactions. In 2019, Kubota and co-workers developed a method
for the redox-activation of small organic molecules in response to applied mechanical
energy through the piezoelectric effect. In particular, the milling of piezoelectric
materials via ball milling reduces arenediazonium salts in arylation and borylation
reactions.[143]
On the other hand, mechanochemical activation with simultaneous ultrasound irradiation
is also a rather attractive area of research. Actually, both techniques share some
striking similarities, and numerous sonochemical reactions can be rationalized in
purely mechanical terms. Cintas, Cravotto, and Calcio Gaudino examined potential synergistic
effects of tribochemical and sonochemical reactivity and demonstrated how strengthened
cavitation phenomena can determine the final molecular transformation.[144]
In this context, mechanochemical techniques are presently being applied in the rehabilitation
of old reagents. An illustrative example is the application of calcium-based heavy
Grignard reagents (R-CaX) in organic synthesis. In contrast with the ready application
of traditional Grignard reagents, the use of calcium ‘heavy Grignard reagents’ has
remained essentially unexplored as consequence of the lack of experimental procedures
to access such organocalcium under mild conditions.
Recently, it has been demonstrated that mechanochemical ball milling allows the generation
of organocalcium reagents from aryl halides and commercially available calcium metal.
Importantly, all experimental operations can be carried out in air. This operationally
simple protocol enables the development of novel cross-coupling reactions mediated
by arylcalcium nucleophiles. This method will allow synthetic chemists to readily
access the novel and unique reactivity of organocalcium nucleophiles.[145]
7
Conclusions
The present active search for cleaner and more economic ‘green’ processes in chemical
synthesis has propelled interest in solvent-free solid state synthetic procedures
using mechanochemistry. As this short review clearly demonstrates, the success recorded
in the field of organic mechanosynthesis during the last two or three decades has
been spectacular. Indeed, traditional organic synthesis, asymmetric organocatalysis,
multicomponent reactions, metal- and organometal-catalyzed processes, and techniques
combining mechanochemical activation with enzymatic catalysis can be conveniently
carried out in milling apparatus and extruders, in the absence of bulk solvent and
many times in faster and simpler ways, for example when handling air and water sensitive
substances or insoluble substrates.
Challenging developments such as implementation of large-scale industrial processes,
more efficient control of reaction parameters, and a better understanding of the mechanisms
involved in solid state mechanochemical transformations are occupying the attention
of chemists and chemical engineers involved in the area. Regarding scaling-up, better
control of the reaction’s parameters and reaction monitoring issues, manufacturers
of laboratory and industrial mills are advancing rapidly to satisfy such needs. It
is reasonable to anticipate that as the application of mechanochemistry in synthetic
goals increases, so will the employment of reliable techniques for monitoring mechanochemical
pathways, and with this the ability to explore successfully unchartered territories
and even more innovative applications.
