Download PDF
Synlett 2024; 35(20): 2331-2345
DOI: 10.1055/a-2422-0992
account
Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

Mechanochemistry: A Resurgent Force in Chemical Synthesis

Nirmalya Mukherjee∗
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Dedicated to Professor Brindaban C. Ranu on his 75th birthday.

Abstract

Mechanochemistry, a solvent-free approach that harnesses mechanical energy, is emerging as a transformative technique in modern chemistry. It has emerged from a niche technique to a versatile tool with broad applications. By inducing physical and chemical transformations, it enables the synthesis of complex molecules and nanostructured materials. Recent advancements have extended its applications beyond simple physical transformations to encompass catalytic processes, unlocking new possibilities for selective synthesis and product design. This account delves into the fundamentals of mechanochemistry and its applications in organic synthesis, also beyond traditional synthetic routes. Mechanochemistry offers new avenues for molecular and materials discovery, expanding the scope of accessible chemical space.

1 Introduction

2 Organic Synthesis in Ball Mills

3 Combination with Different Energy Sources

4 Advantages of Mechanochemistry

5 Future of Mechanochemistry

6 Conclusion


#

Key words

mechanochemistry - organic synthesis - solvent-free reactions - catalysis - green chemistry

Biographical Sketch

Zoom Image

Nirmalya Mukherjee is an organic chemist with a strong focus on catalysis and methodology development. Raised in Kolkata, India, he obtained his doctorate in 2016 under the guidance of Professor B. C. Ranu and Professor A. Sarkar. Following postdoctoral research with Professor K. Grela in Warsaw, Poland, he joined the group of Professor O. F. Wendt at Lund University, Sweden, in 2019. His academic journey continued at KTH Royal Institute of Technology, Sweden, where he collaborated with Professor P. Dinér from 2021 to 2024. Mukherjee’s research interests span a broad spectrum, encompassing organic synthesis, catalysis, methodology development, metathesis, mechanochemistry, photochemistry, and electrochemistry.

1

Introduction

Mechanochemistry,[1] a technique that harnesses mechanical energy to drive chemical reactions, is experiencing a resurgence in popularity.[2] Traditionally relegated to niche applications, it has gained prominence due to its potential to circumvent the limitations of conventional solution-phase synthesis. By eliminating or minimizing the use of solvents,[3] mechanochemistry offers a more sustainable and efficient approach to chemical production. Moreover, it has opened new avenues for synthetic exploration, enabling the creation of molecules and materials that were previously unattainable.[4]

This paradigm shift has been driven by the development of advanced milling equipment and in-situ analytical techniques,[5] which facilitate a deeper understanding of mechanochemical processes. As a result, mechanochemistry is evolving from a laboratory curiosity to a robust and reliable synthetic tool with far-reaching implications across various chemical disciplines.

1.1

A Brief History and Resurgence

The earliest documented mechanochemical reaction, dating back to the 4th century BC, involved grinding cinnabar with acetic acid in a copper vessel to produce elemental mercury, possibly marking the first method to extract a metal from a compound (Figure [1]).[6] Aristotle’s statement, often translated as ‘no reaction proceeds in the absence of solvent’, contrasts with the many solventless mechanochemical reactions known today.[7] An alternative translation suggests that ‘liquids are the type of bodies most liable to mixing’.[8] During the Middle Ages, mechanochemistry was employed in mining and metallurgy.

Zoom Image
Figure 1 The evolution of mechanochemistry: a historical overview

In the 1820s, Michael Faraday conducted mechanochemical experiments, reducing AgCl to Ag using Zn, Cu, Sn, or Fe.[9] Carey Lea’s work in the 1890s demonstrated that mechanochemical reactions could yield different products than thermal ones, such as the decomposition of mercury and silver halides to their elements.[10] This work marked the emergence of mechanochemistry as a distinct subdiscipline in chemistry, with Wilhelm Ostwald later classifying it alongside thermochemistry, electrochemistry, and photochemistry.[11] Early solvent-free organic mechanochemical reactions, like the cocrystallization by Ling and Baker in 1893, further expanded the field.[12]

Mechanochemistry’s resurgence, driven by the principles of green chemistry,[13] aims to provide cleaner, safer, and more efficient transformations, crucial for the pharmaceutical and chemical industries.[14] Mechanochemistry is distinguished by its ability to induce chemical transformations through milling or grinding, eliminating the need for dissolving reactants in bulk solvents. Unlike traditional laboratory techniques that utilize stirrers and heaters, mechanochemical methods employ automated ball mills and replace beakers and flasks with jars containing milling media (Figure [2]). This enclosed, solvent-free environment offers defined parameters for optimizing reactivity, such as milling frequency and medium-to-sample weight ratio, milling materials, etc.,[15] unlike manual grinding which is open to environmental factors and also associated with reproducibility problems.[16] Among various mill designs, shaker and planetary mills are the most widely used.[11] [17] Shaker mills, where jars move back and forth at a set frequency to determine milling intensity, are commonly used for small sample sizes, such as in pharmaceutical solid screening. Planetary mills, on the other hand, rotate jars around a central axis while spinning them on their own axes, creating centrifugal forces that mimic gravity effects seen in industrial roller mills, facilitating scale-up. Milling balls and jars are typically made from materials like stainless steel, zirconia, tungsten carbide, or poly(tetrafluoroethylene) (Teflon). Transparent poly(methyl methacrylate) (PMMA) jars are also used to enable in-situ monitoring.

Zoom Image
Figure 2 A brief introduction of ball mills

Modern mechanochemical techniques, such as ball milling and liquid-assisted grinding (LAG), offer precise control over reactivity without the need for bulk solvents. The success of mechanochemistry is largely attributed to innovative techniques involving catalytic additives to control reactivity. Among these, LAG stands out for its role in positioning mechanochemistry as a practical alternative to solution synthesis.[18] This is evident from the concept of a solvent-free research laboratory[19] and intricate multistep mechanochemical routes for producing pharmaceutically and biologically significant targets.[20] LAG employs a minimal amount of liquid to speed up reactions and facilitate transformations that are not possible with dry grinding. The definition of LAG is based on the impact of the liquid additive-to-reactant weight ratio (η) on mechanochemical reactivity.[21] Neat grinding corresponds to η = 0, typical solution reactions correspond to η > 10 μL/mg, and LAG operates in the range of approximately 0–1 μL/mg. Within this range, reactivity remains independent of reactant solubility, differentiating LAG from slurry reactions where low solubility can impede reactivity.

The high efficiency of LAG has been demonstrated in various applications, including the screening of inclusion compounds, cocrystals, salts, solvates, and polymorphs, as well as in organic mechanochemistry.[22] By altering the liquid additive in LAG, researchers can effectively control mechanochemical reactions, making this particularly valuable for screening solid drug forms.[23] The reactivity in LAG is notably independent of solubility, which can be attributed to the formation of mobile surface layers or the continuous saturation of a minimal amount of liquid with reactants. The exact mechanism behind the structure-directing effects in LAG remains unclear, but recent studies suggest it may be influenced by factors such as liquid polarity, the η ratio, and specific interactions between the liquid and the reactants (Figure [3]).[21] This advancement has broadened the scope of mechanochemistry, making it a viable alternative to traditional solution-based synthesis and facilitating the development of novel materials and pharmaceuticals.[24]

Zoom Image
Figure 3 Description of key parameters

# 1.2

Terminology

The term mechanochemistry is often broadly applied to any chemical reaction induced mechanically, such as by grinding.[25] This is the context in which it is used in this account. However, some argue that this broad application is incorrect and that the term should only refer to cases where mechanical energy directly breaks strong bonds, such as in polymers or single molecules, creating reactive centers (often radicals) that undergo further reactions.[26] [27] This narrower definition would exclude grinding reactions that primarily proceed due to increased contact surface area between reactants. The IUPAC defines a mechanochemical reaction as a ‘chemical reaction that is induced by the direct absorption of mechanical energy’, noting that typical methods include shearing, stretching, and grinding, which generate reactive sites, usually macroradicals, in polymer chains undergoing mechanochemical reactions.[25] While this note provides specific guidance for polymers, the basic definition is broad and does not restrict the atomic-scale mechanism, justifying the general use of the term.

Mechanochemistry employs mechanical energy to induce chemical transformations, often bypassing the need for solvents. While traditionally associated with solvent-free conditions, the term’s interpretation is nuanced. While intentional solvent exclusion is a key advantage, trace amounts of residual solvents or moisture can influence reaction outcomes. Furthermore, the term ‘solvent-free’ does not preclude the formation of condensates during the reaction itself. Therefore, while mechanochemistry offers significant environmental benefits, a more nuanced understanding of solvent involvement is crucial for accurate interpretation and optimization of reaction conditions.[1c]


# 1.3

Principles of Mechanochemistry

Chemical reactions initiated by various forms of energy can produce unique products and open up reaction pathways that are unattainable through other methods. Mechanochemical reactions, in particular, are defined as chemical reactions induced by the direct absorption of mechanical energy. This mechanical energy, derived from sources such as impact, tension, and friction, can be generated through manual grinding, ball milling, pan milling, ultrasonication, and hydrodynamics.[28] These energies then cause substances to undergo phase and structural changes, crystalline transformations, reductions in crystallinity, surface activation, and mechanochemical reactions.[29]

During mechanochemical processes, energy variations related to crystal fragmentation, high defect densities, and elevated macroscopic temperatures often occur, leading to the breaking of chemical bonds and the creation of free radicals.[5b] [30] From a kinetic standpoint, mechanochemical reactions can be explained by collision theory.[31] The kinetic energy produced during these reactions facilitates the wear, fracture, and refinement of the microstructure of the chemical system. Crucially, the specific surface area of materials can be significantly increased by the formation of new interfaces during fracture, enhancing the likelihood of contact between different components. Since reactions typically occur on the surface or boundaries of these components,[32] kinetic energy accelerates chemical reactions.[33] Additionally, the outcomes of mechanochemical experiments are often unpredictable, making such methodology an ideal approach for discovering new chemical reactions.


# 1.4

Mechanistic Aspects

Mechanistic studies in mechanochemistry do not yet provide a clear or comprehensive understanding due to the diversity of reaction types, conditions, and materials involved, ranging from metals and metal oxides to molecular crystals. The inhomogeneous nature of solid–solid reactions, the difficulty of observing materials undergoing mechanochemical reactions at microscopic or molecular levels, and the lack of studies on some reaction types add to the complexity. Different mechanistic models have been developed, each with limited applicability, and more than one model may apply to a given reaction.

Mechanochemical processes have been primarily explored within the context of inorganic materials, with theories such as the hot spot and magma–plasma models attempting to explain the underlying mechanisms.[11] [34] These models propose localized regions of intense heat generation during milling, capable of driving chemical transformations. While these theories provide valuable insights into inorganic systems, their applicability to organic and metal–organic mechanochemistry remains less clear. The complex nature of these compounds and the milder reaction conditions typically employed suggest that different mechanisms may predominate.

Mechanochemical cocrystallization can occur through various pathways,[18] including surface diffusion, vapor-phase transport, and amorphous intermediate formation. Liquid-assisted grinding enhances cocrystallization by increasing molecular mobility, with the choice of liquid influencing product outcome. In metal–organic mechanochemistry, reaction pathways are more diverse, ranging from paste-like intermediates to consistently flowing powders. The presence of hydrates or the formation of condensates can impact reaction behavior, necessitating a nuanced understanding of these factors for successful reaction optimization.

While mechanochemistry has made significant progress, a comprehensive understanding of its underlying mechanisms remains a challenge. In-situ characterization techniques, such as synchrotron-based X-ray powder diffraction and Raman spectroscopy, have been instrumental in overcoming the limitations of traditional ex-situ analysis.[35] [36] These techniques have enabled real-time monitoring of mechanochemical processes, providing crucial insights into reaction pathways and intermediate formation.

In-situ characterization techniques have facilitated the exploration of mechanochemical reaction kinetics and the influence of temperature, previously challenging due to the dynamic nature of milling processes.[37] Studies on metal–organic framework synthesis have revealed unexpected first-order kinetics, suggesting a potential ‘pseudofluid’ reaction environment where reactant collisions, driven by milling frequency, govern reaction rates.[38]

In-situ diffraction studies have demonstrated that mechanochemical reaction pathways can be significantly influenced by temperature variations.[39] These findings challenge the prevailing hot spot theory by indicating that milder temperatures can drive mechanochemical transformations. The observed temperature dependence of reaction rates suggests that the localized high-energy environments associated with hot spots may not be essential for all mechanochemical processes, particularly in the realm of organic and metal–organic compounds.

To fully understand and optimize mechanochemical processes, future research should encompass a comprehensive range of reaction conditions and outcomes, including both successful and unsuccessful attempts. By systematically investigating various parameters and identifying reaction limitations, researchers can develop a more robust understanding of the underlying mechanisms and expand the scope of mechanochemical applications.


#
# 2

Organic Synthesis in Ball Mills

Historically, organic synthesis has predominantly relied on solution-phase methods. However, a paradigm shift is underway with the emergence of mechanochemistry as a viable alternative. While ball milling has gained traction in recent years,[26a] [40] the field is still in its developmental stages compared to established solution-based techniques. This nascent field offers exciting opportunities to explore novel reaction pathways and optimize synthetic processes, particularly in areas such as stoichiometry, catalysis, asymmetric synthesis, and metathesis. The following sections highlight selected examples to show the progress and opportunity of ball millings in organic synthesis.

2.1

Metal-Free Organic Reactions in Ball Mills

Mechanochemistry is a versatile platform for metal-free organic transformations, such as the Knoevenagel condensation, Michael addition, Wittig reaction, peptide synthesis, and many more. The Knoevenagel condensation, a key C–C bond forming reaction, has been successfully adapted to solvent-free mechanochemical conditions. Kaupp’s pioneering work in 2003 demonstrated the efficient synthesis of α,β-unsaturated carbonyl compounds through ball milling (Scheme [1]),[41] highlighting the potential of mechanochemistry for waste-free and energy-efficient organic transformations. The inherent frictional heating generated during milling was found to be crucial for driving the reaction to completion, outperforming microwave-assisted methods in terms of energy consumption.

Zoom Image
Scheme 1 Mechanochemical Knoevenagel condensation

Bräse and co-workers reported an efficient mechanochemical synthesis of xanthones, a structural motif prevalent in natural products. By optimizing reaction parameters such as time, reactant ratios, and milling conditions, they achieved a 66% yield of tetrahydroxanthenone through a domino oxa-Michael–aldol reaction (Scheme [2]).[42] While the yields were lower compared to solution-based methods, this study highlighted the potential of mechanochemistry for complex multistep transformations and its ability to influence product selectivity.

Zoom Image
Scheme 2 Mechanochemical oxa-Michael–aldol reaction

The mechanochemical synthesis of alkenes via the Wittig olefination has been demonstrated, showcasing the potential of solvent-free conditions for this important transformation. Balema, Pecharsky, and co-workers successfully generated various phosphonium ylides under mechanochemical conditions, achieving high yields of phosphoranes and olefins (Scheme [3]).[43] This work highlighted the unique reactivity profile of solids, where weaker bases like K2CO3 can facilitate deprotonation, emphasizing the need for re-evaluating traditional concepts of acidity and basicity in solvent-free environments.

Zoom Image
Scheme 3 Mechanochemical Wittig reaction

Thioglycosides, essential for oligosaccharide synthesis and enzyme inhibition, have been successfully prepared via solvent-free mechanochemical methods. Patil and Kartha have demonstrated the synthesis of various thioglycoside derivatives, including alkyl, aryl, and glycosyl analogues, in high yields (Scheme [4]).[44] This approach eliminated the need for aromatic solvents, toxic thiols, and phase transfer catalysts, highlighting the potential of mechanochemistry for efficient and environmentally friendly carbohydrate synthesis.

Zoom Image
Scheme 4 Mechanochemical synthesis of thioglycosides

Vyle and co-workers have demonstrated the potential of mechanochemistry for processing biologically relevant molecules like nucleosides (Scheme [5]).[45] By eliminating the need for toxic solvents, such as DMF and pyridine, ball milling offers a greener approach to protecting group manipulations. The successful introduction of the TBDMS protecting group to phenols and nucleosides highlights the versatility of this technique. Furthermore, the ability to perform one-pot double protections, such as O-silylation and N-benzylation, underscores the efficiency of mechanochemical methods in handling complex biomolecules.

Zoom Image
Scheme 5 Solventless mechanochemical protection of nucleosides

Amide synthesis is a critical transformation in organic chemistry. Traditional methods often rely on expensive transition-metal catalysts or toxic reagents. To address these limitations, solvent-free mechanochemical approaches have emerged. Gao and Wang have demonstrated the synthesis of amides from aryl aldehydes and anilines using Oxone as a catalyst and oxidant, with a stoichiometric amount of magnesium sulfate employed as an additive (Scheme [6]).[46] This mechanochemical method outperformed solution-based alternatives in terms of yield and selectivity, highlighting the potential of mechanochemistry for sustainable amide synthesis.

Zoom Image
Scheme 6 Mechanochemical oxidative amidation

The chemistry of peptides has seen significant advancement in recent decades. Despite established methods like stepwise synthesis in solution and solid-phase peptide synthesis,[47] a major challenge remains the large volume of solvents required, especially for large-scale peptide production. There is an ongoing need for more efficient and environmentally friendly peptide synthesis methods, particularly when scaling up production. The field of green chemistry has rapidly evolved, focusing on areas such as alternative feedstocks, safer chemicals, and the use of substitute solvents like aqueous, ionic, and supercritical fluids to reduce reliance on volatile organic solvents and manage waste.[48] Another promising approach involves conducting reactions without solvents, utilizing techniques like mixing, grinding, or ball milling in solid-state chemistry. Lamaty and co-workers have demonstrated the synthesis of di- and tripeptides via solvent-free ring-opening polymerization of N-carboxyanhydrides using sodium bicarbonate as a base (Scheme [7]).[3d] [49] This study showcased the potential of mechanochemistry for peptide synthesis, while maintaining high yields and stereochemical integrity.

Zoom Image
Scheme 7 Solvent-free mechanochemical peptide synthesis

Kaupp and co-workers pioneered the mechanochemical arylaminomethylation reaction, utilizing iminium salts generated from hexahydro-1,3,5-triazines and HCl (Scheme [8]).[50] This solvent-free approach led to the efficient synthesis of (phenylaminomethyl)naphthols. While further exploration of the substrate scope is warranted, these initial findings demonstrate the potential of mechanochemistry for amine-based C–C bond formation reactions.

The synthesis of organochalcogenides, particularly selenides and tellurides, is challenged by the instability and toxicity of the reagents, as well as difficulties in controlling reaction conditions such as stereochemistry and reactivity. Additionally, mechanistic uncertainty and environmental concerns add to the complexity, especially when scaling up or ensuring product stability. Thus, the synthesis of chalcogenides involving stable and easily available diaryl dichalcogenides is widely employed to overcome these challenges.[51a] Ranu and co-workers have introduced a solvent-free mechanochemical approach for synthesizing organochalcogenides, employing aryldiazonium tetrafluoroborates and diorgano dichalcogenides (Scheme [9]).[51b] [c] Neutral alumina and potassium hydroxide facilitated this transformation, yielding a diverse range of products with high efficiency. This mechanochemical process yielded a wide range of organosulfides, -selenides, and -tellurides with high yields and excellent tolerance for various functional groups. This method bypassed the need for traditional solvents and showcased the potential of mechanochemistry for constructing C–X bonds. Literature reports suggest a strong correlation between mechanical force and disulfide reduction, as evidenced by single-molecule force spectroscopy and computational studies.[52] It is hypothesized that the S–S bond in proteins typically elongates or weakens under mechanical force. By analogy, the synthesis of organochalcogenides, particularly organosulfides, likely involves the mechanochemical activation of disulfides under ball-milling conditions.

Zoom Image
Scheme 8 Mechanochemical arylaminomethylation of β-naphthol
Zoom Image
Scheme 9 Synthesis of organochalcogenides under ball milling

Expanding upon this work, the same group developed a solvent-free mechanochemical synthesis of S-aryl dithiocarbamates. By combining carbon disulfide, amines, and aryldiazonium tetrafluoroborates in the presence of basic alumina, they achieved the high-yielding production of a variety of dithiocarbamate derivatives (Scheme [10]).[51b] This method showcased the versatility of mechanochemistry for constructing C–S bonds under mild and metal-free conditions. While product isolation required traditional solvent-based purification techniques, the core synthetic process remained solvent-free.

Zoom Image
Scheme 10 Mechanochemical synthesis of S-aryl dithiocarbamates

Mechanochemical C–H functionalization has emerged as a promising avenue for organic synthesis. Ranu and co-workers have demonstrated the direct chalcogenation of 2-naphthols and bicyclic heteroarenes using di(hetero)aryl disulfides and diselenides under solvent-free conditions (Scheme [11]).[53] This metal-free approach, employing basic alumina as a grinding aid, yielded a diverse array of chalcogenated products. The method’s versatility was highlighted by its tolerance for electron-donating and -withdrawing substituents on the aryl ring. While product purification required conventional solvent-based techniques, the core synthetic transformation was accomplished efficiently and sustainably under mechanochemical conditions. It was suggested that the reaction does not follow a radical pathway, as the introduction of the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) neither produced any significant effect on the reaction nor led to the formation of a TEMPO adduct. This supports the conclusion that the reaction proceeds via an ionic mechanism, where naphthoate ion reacts with diaryl dichalcogenide to form the final product.

Zoom Image
Scheme 11 Mechanochemical synthesis: α-chalcogenation of bicyclic (hetero)arenes

# 2.2

Metal-Catalyzed Organic Transformations in Ball Mills

Metal-mediated transformations in solvent-free environments have been documented since the 1980s. One notable example is the work by Toda and co-workers who synthesized 2,2′-binaphthols (BINOLs) with yields up to 95% by gently heating pre-ground mixtures of 2-naphthols with iron(III) salts at 50 °C.[54] An early instance of metal-catalyzed milling reactions includes a palladium-catalyzed Heck-type coupling of aryl halides with protected aminoacrylates.[55] Today, metal-catalyzed mechanochemistry encompasses a wide range of popular transformations adapted to solvent-free environments,[56] including Suzuki–Miyaura,[57] Heck,[58] Buchwald–Hartwig,[59] and Sonogashira coupling,[60] and rhodium- and gold-catalyzed C–H activation.[61]

Most examples of catalytic mechanochemistry still rely on catalysts originally developed for solution chemistry. However, mechanochemistry offers a distinct reaction environment that can support alternative catalytic designs, potentially simplifying previously challenging reactions. This was exemplified by the Mack group, who replaced conventional catalysts with metal surfaces. For example, use of a milling setup made entirely of copper enabled efficient Sonogashira coupling without the need for a CuI cocatalyst, with no significant change (Scheme [12]).[60]

Zoom Image
Scheme 12 Mechanochemical Sonogashira coupling in a Cu milling assembly

The concept of using the milling assembly itself as a catalyst has been extended to other processes. For example, the Borchardt group developed ligand- and solvent-free Suzuki–Miyaura reactions utilizing palladium balls as both the milling media and the catalyst (Scheme [13]).[62] This innovative approach demonstrates the potential of mechanochemistry to streamline and simplify catalytic processes by integrating the catalyst directly into the milling equipment, thereby eliminating the need for additional reagents and solvents.

Zoom Image
Scheme 13 Mechanochemical Suzuki–Miyaura coupling with Pd balls

1,2,3-Triazoles, versatile heterocyclic compounds, have found wide-ranging applications in the agrochemical, corrosion inhibitor, dye, materials, photostabilizer, and pharmaceutical industries. Stolle and co-workers pioneered the solvent-free mechanochemical synthesis of triazoles from azides and alkynes, demonstrating the potential of this technique for accessing diverse triazole derivatives.[63] Moreover, the successful mechanochemical polymerization of triazoles without compromising polymer integrity highlights the potential of this approach for materials science applications (Scheme [14]).

Zoom Image
Scheme 14 Mechanochemical polymerization of 1,12-diazidododecane and bis-ethynyl compounds

Ranu and co-workers have presented an alternative method for synthesizing 1,4-disubstituted 1,2,3-triazoles through a straightforward one-pot three-component reaction. This process involves reacting alkyl halide or arylboronic acid, sodium azide, and terminal alkynes on a Cu/Al2O3 catalyst surface via ball milling under solvent-free conditions (Scheme [15]).[64] Typically, no chromatographic separation or purification is required, and no toxic organic solvents are involved throughout the procedure. This approach eliminates the need to handle hazardous organoazides and provides a simple route to obtain aryl,alkyl- and aryl,aryl-substituted 1,2,3-triazoles. X-Band EPR spectrum and XPS studies confirmed that copper remained in the +2 oxidation state during the entire reaction cycle.

Zoom Image
Scheme 15 Cu/Al2O3-catalyzed mechanochemical one-pot synthesis of 1,2,3-triazoles

The functionalization of C–H bonds using mechanochemistry is an area experiencing rapid growth. Bolm and co-workers have described several mechanochemical C–H functionalization strategies employing iridium-, ruthenium-, and rhodium-based catalysts to modify sp2 carbons, achieving high yields and chemoselectivity (Scheme [16]).[61] [65] Das and co-workers have reported a method for the mechanochemical regioselective arylation of indoles using a palladium(II) catalyst, achieving up to 99% isolated yields in 37 examples (Scheme [17]).[66] However, examples involving reactions at sp3 centers are still uncommon. One notable instance is an intermolecular C(sp3)–H amination using the Du Bois Rh2(esp)2 catalyst with stoichiometric PhI(OAc)2 oxidant, yielding 40–95% in 25 examples.[67]

Zoom Image
Scheme 16 Ru- and Rh-catalyzed mechanochemical C–H functionalization
Zoom Image
Scheme 17 Mechanochemical regioselective arylation of indoles

# 2.3

Metathesis in Ball Mills

Mechanochemistry has emerged as a powerful tool for olefin metathesis reactions, enabling efficient and solvent-free synthesis of complex molecules. By adapting commercially available catalysts to solid-state conditions, Friščić and co-workers have achieved high yields and reaction rates for both cross-metathesis and ring-closing metathesis (Scheme [18]).[68] The ability to process solid reactants without the need for extensive solvent purification represents a significant advancement in green chemistry. Moreover, the potential for scaling up these reactions through the use of planetary milling opens new avenues for industrial applications.

Zoom Image
Scheme 18 Ring-closing metathesis under ball milling

In continuation of this, the same group recently showed mechanochemical ring-opening metathesis polymerization (ROMP), which has emerged as a promising green alternative to conventional solution-based methods (Scheme [19]).[69] By harnessing the energy of ball milling, this approach enables the polymerization of a wide range of monomers, including those traditionally challenging due to solubility issues. The ability to produce mechano-exclusive polymers, such as those from immiscible monomers, highlights the unique potential of this technique. While the underlying mechanism mirrors solution-phase ROMP, the solvent-free environment introduces new opportunities for polymer design and synthesis.

Zoom Image
Scheme 19 Mechanochemical ring-opening metathesis polymerization

In contrast, the number of examples of organometallic complexes assembled via mechanochemistry is relatively limited. However, recent publications have made significant contributions to the synthesis of simple N-heterocyclic carbene (NHC) complexes of Pd, Cu, and Au, as well as the synthesis of NHC ligand precursors (Scheme [20]).[70] A mechanochemical one-pot, two-step procedure has been developed to synthesize various NHC precursors. This innovative method allows for the production of widely used compounds such as IPr·HCl, IMes·HCl, Io-Tol·HCl, and ICy·HCl in significantly higher yields compared to traditional solvent-based methods, while also drastically reducing environmental impact.[71] This solventless mechanochemical approach begins directly from anilines and avoids the isolation of 1,4-diazadiene (DAD) intermediates, reducing DAD hydrolysis and preventing solvent compatibility issues between synthetic steps often encountered in solution-based strategies.

Zoom Image
Scheme 20 Synthesis of NHC ligand precursors under mechanochemical conditions

A mechanochemical approach to the synthesis of sophisticated multiligand carbene–alkylidene complexes of ruthenium has not been reported until recently. This is likely due to the relative fragility of these complexes and their sensitivity to heat generated during grinding. In a key study on mechanochemical olefin metathesis, it was found that Ru catalysts were unstable when steel jars and balls were used.[68] Additionally, the solution-phase synthesis of these complexes is also problematic, as oxygen, moisture, Brønsted bases, and other reagents or solvents used during synthesis can compromise the quality of the final product. Fogg and co-workers have demonstrated that various batches of commercial catalysts may contain Ru nanoparticles that can lead to unwanted side reactions.[72]

Zoom Image
Scheme 21 Synthesis of Ru carbene organometallic complexes

Grela and co-workers have described the first mechanochemical synthesis of nine contemporary ruthenium catalysts used for olefin metathesis, marking the first reported example of the formation of Ru carbene organometallic complexes in the solid state (Scheme [21]).[73] They demonstrated that three key organometallic transformations commonly used in the synthesis of second- and third-generation Ru catalysts in solution – phosphine ligand (PCy3) exchange with in-situ formed NHC ligand, PCy3 to pyridine ligand replacement, and benzylidene ligands interchange – can be successfully conducted under mechanochemical conditions, yielding the nine contemporary Ru olefin metathesis catalysts with high purity. This mechanochemical approach not only reduces the amount of organic solvent required (none for synthesis, only for purification) and is scalable, but also enables transformations that were previously considered impossible in the solution phase (also see Section 4.2).


# 2.4

Asymmetric Reactions in Ball Mills

Proline-catalyzed aldol reactions are among the most-studied organocatalytic asymmetric C–C bond forming reactions. These reactions proceed via enamine intermediates formed in situ from one of the carbonyl components and the catalyst. Typically, highly polar solvents such as DMSO, DMF, or water are used, which are difficult to remove postreaction. Bolm and co-workers were the first to conduct solvent-free aldol reactions under ball-milling conditions (Scheme [22]).[74] Using 10 mol% proline and nearly equimolar amounts of starting materials, they achieved excellent yields (mostly over 90%) of anti-aldol products with high diastereo- and enantioselectivity (up to 99% ee). Various factors affecting yield and stereochemistry were studied, demonstrating the superiority of ball milling over conventional stirring. In a similar approach, Guillena, Nájera, and co-workers explored direct aldol reactions between ketones and aldehydes under solvent-free conditions, using a combination of BINAM–prolinamide (5–10 mol%) and benzoic acid (10–20 mol%).[75] The aldol products achieved up to 98% ee and were obtained in yields up to 90%.

Zoom Image
Scheme 22 Mechanochemical asymmetric aldol reaction

Recently, Bolm and co-workers examined the phase behavior of proline-catalyzed aldol reactions between solid substrates under solvent-free conditions.[76] They discovered a significant nonlinear relationship between the ee of the catalyst (proline) and that of the aldol product, suggesting it originated from the ternary phase behavior of scalemic proline. Further studies led to the discovery of enantio-enrichment by iterative retro-aldol/aldol reactions catalyzed by an achiral or racemic base.


#
# 3

Combination with Different Energy Sources

Mechanochemistry, the application of mechanical energy to drive chemical reactions, has emerged as a powerful and sustainable alternative to traditional solution-phase synthesis. While ball milling remains the predominant technique, recent advancements have expanded the scope of mechanochemistry by integrating additional energy sources such as heat, light, sound, and electricity. These combined approaches, often termed ‘mechanochemistry 2.0’, offer unprecedented opportunities for accessing novel chemical space and enhancing reaction efficiency.[77]

3.1

Thermo-mechanochemistry

Mechanochemical processes are inherently influenced by temperature, with factors like friction and plastic deformation contributing to heat generation within the milling chamber. While localized hot spots can occur, the bulk temperature of the reaction mixture typically rises gradually due to energy dissipation.[34] [78] This temperature increase can impact reaction kinetics and product formation, necessitating precise temperature control for optimal results.

Cryomilling, a technique involving milling at subambient temperatures, has been employed in various fields, including biology and materials science.[79] By preventing thermal-induced recrystallization and enhancing material fragility, cryomilling facilitates efficient particle size reduction and selective transformations.

Recent advancements in mechanochemical equipment have enabled controlled heating during milling, expanding the synthetic toolbox. By coupling mechanical energy with thermal energy, researchers can access new reaction pathways and improve product yields and selectivity. While challenges remain in designing and optimizing these combined systems, the potential benefits for chemical synthesis are significant. For instance, the mechanochemical Suzuki–Miyaura cross-coupling of insoluble aryl halides using a palladium catalyst was performed at various temperatures by heating the milling vessel with a heat gun (Scheme [23]).[80] This reaction does not proceed at room temperature, but milling at higher temperatures resulted in complete conversion and, in some instances, produced compounds that are not achievable through traditional solution-based methods.

Zoom Image
Scheme 23 Suzuki–Miyaura cross-coupling under thermo-mechanochemical conditions

Understanding the interplay between mechanical force and thermal energy is crucial for developing effective mechanochemical processes. By carefully controlling temperature and other reaction parameters, researchers can unlock the full potential of this versatile technique.


# 3.2

Photo-mechanochemistry

Light is a crucial driver of chemical reactions, both in nature and in the laboratory. Examples of light-dependent phenomena include photosynthesis, the ozone photolysis cycle, photovoltaics, and radical polymerizations. In synthetic chemistry, light can initiate reactions that are not possible through thermal activation by generating radical or excited-state species that are significantly more reactive than ground-state ones. Combining mechanical activation with light-energy activation offers exciting new synthetic possibilities.

As early as 1987, Toda and co-workers used a test tube shaker to demonstrate that mechanochemistry could induce the cocrystallization of several diols with carbonyl-containing coformers.[81] When complexes containing chalcone as the coformer were irradiated during milling, a stereoselective [2+2] cycloaddition was achieved, with the diol dissociating from the product during milling and acting as a catalyst. More than 20 years later, efficient and rapid [2+2] photodimerization of trans-1,2-bis(4-pyridyl)ethylene using functionalized resorcinol as a catalyst was reported (Scheme [24]).[82] This procedure involved cycles of grinding with a pestle and mortar followed by UV light irradiation. This mild grinding method greatly increased turnover, leading the authors to suggest that automated mechanochemical processes, such as a ball mill combined with UV light, could shorten reaction times and reduce catalyst amounts. They later achieved shortened cycloaddition times by irradiating an open vortex shaker with UV light during milling.[83] However, in-situ UV irradiation in classic mixer or planetary mills remains challenging due to the opacity of materials commonly used for milling vessels to UV light.

Zoom Image
Scheme 24 Different reactivity between photo-mechanochemical and mechanochemical conditions

The synergistic effects of light, mechanical force, and temperature have been explored in photo-mechanochemical reactions. For instance, the photoborylation of aryldiazonium salts was achieved through ball milling in a PMMA vessel equipped with LEDs.[84] This study revealed the interplay between photocatalysis, mechanochemistry, and thermal effects, as the reaction proceeded differently under neat and liquid-assisted conditions.


# 3.3

Electro-mechanochemistry

The integration of electrical energy with mechanical force has emerged as a promising approach for driving chemical transformations. While electrochemistry and mechanochemistry have been independently studied for decades, their combined application is a relatively new frontier. Initial efforts focused on electrical discharge assisted mechanical milling, where high-voltage discharges were generated within the milling chamber to induce chemical reactions.[85] This technique has demonstrated success in various applications, including materials synthesis and the activation of inert substances.

Beyond electrical discharge, the use of dielectric barrier discharge (DBD) plasma coupled with mechanical milling has shown potential for enhancing reaction efficiency. By generating reactive species and creating a unique reaction environment, DBD plasma assisted mechanochemistry has enabled the synthesis of materials with improved properties.[86]

The integration of piezoelectric materials into mechanochemical processes represents another emerging area.[87] These materials, capable of converting mechanical energy into electrical energy and vice versa, offer opportunities for self-powered and self-regulated chemical reactions. By understanding the interplay between mechanical force, electrical energy, and chemical reactivity, scientists can unlock new possibilities for materials synthesis and chemical transformations.

While significant progress has been made, the field of electro-mechanochemistry is still in its infancy. Developing specialized equipment and establishing a comprehensive theoretical framework are essential for realizing the full potential of this approach.


# 3.4

Sono-mechanochemistry

Sonochemistry, utilizing high-frequency sound waves to induce chemical reactions through cavitation, has been employed alongside mechanochemistry to enhance synthetic outcomes.[88] By combining the mechanical forces of milling with the energetic effects of ultrasound, developed hybrid systems are capable of overcoming limitations inherent to individual techniques. This synergistic approach has shown promise in various applications, including materials synthesis, where it has enabled faster reaction rates, improved product yields, and access to unique material properties.

While the precise mechanisms underlying these combined processes remain under investigation, it is evident that the integration of ultrasound and milling offers a powerful tool for expanding the scope of mechanochemical synthesis.


#
# 4

Advantages of Mechanochemistry

4.1

New Synthetic Opportunities

Mechanochemistry is being increasingly recognized as a tool for both green chemistry and materials discovery. Beyond enhancing reaction efficiency, it offers unique opportunities to access products unattainable through conventional methods. For instance, while the synthesis of monodisperse metal nanoparticles usually requires high dilution to control particle growth and aggregation, it was recently shown that milling with capping agents enables the solvent-free synthesis of monodisperse gold nanoparticles with sizes between 1 and 2 nm.[89]

Additionally, mechanochemistry was employed for the solvent-free exchange of hydrophobic to hydrophilic ligands on 8 nm superparamagnetic iron oxide nanoparticles without altering their size or magnetic properties.[90] This capability to synthesize and modify monodisperse nanoparticle systems in a solvent-free environment exemplifies the unexpected synthetic opportunities that mechanochemistry can offer.


# 4.2

New Reaction Discovery

There is a modest yet steadily increasing number of reports detailing chemical transformations achievable through mechanochemistry that are either difficult or impossible to accomplish in solution.[4d] [91] One remarkable early example is the dimerization of C60 when milled with KCN, which unexpectedly resulted in the formation of dumbbell-shaped C120 rather than the anticipated hydrocyanation product.[4c] Similarly, milling C60 with 4-(dimethylamino)pyridine yields isomers of trimeric C180.[92]

More recently, to explore whether the milling method could offer new possibilities for some ‘problematic’ Ru catalyst syntheses, a direct ligand exchange between Gre-I and the SIMes ligand was attempted. Previous attempts to directly synthesize the nitro-activated catalyst Gre-II from its first-generation precursor in solution had been unsuccessful,[93] likely due to the low stability of Gre-I under the strongly basic conditions needed for the in-situ generation of the free NHC ligand. However, in the solid state, 36% Gre-II was obtained through direct metalation of SIMes.[73]


# 4.3

Synthesis of Impossible Molecules

An intriguing aspect of mechanochemistry is its ability to produce molecules previously thought impossible to isolate. The synthesis of tris(allyl)aluminum complexes, which proved challenging in solution, often resulting in solvates and adducts, was successfully achieved via mechanochemical means.[94] By milling AlCl3 with the potassium salt of bis(trimethylsilyl)allyl anion, the elusive compound was successfully obtained as an off-white powder. When dissolved, this product forms oily mixtures, underscoring its inaccessibility through solution-based methods.

Mechanochemistry has enabled the isolation and characterization of previously elusive intermediates. For example, aryl N-thiocarbamoyltriazoles, proposed intermediates in thiourea synthesis, were successfully isolated and characterized through mechanochemical methods (Scheme [25]).[95] Liquid-assisted grinding facilitated the isolation of transient reaction intermediates which could be synthesized quantitatively, allowing their identification as the elusive aryl N-thiocarbamoyltriazoles. These compounds, unstable in solution, could be stabilized in the solid state, demonstrating the unique capabilities of mechanochemistry for studying reaction intermediates.


# 4.4

Stoichiometric Control

A surprising aspect of mechanochemical reactions is their exceptional control over stoichiometry, enabling the precise and targeted synthesis of stoichiometrically distinct cocrystals and coordination polymers simply by adjusting the reaction mixture composition.[19a] [23b] [96] This level of control is significantly superior to that observed in analogous solution- or melt-based experiments, where achieving product selectivity often requires a large excess of a reactant and is challenging to regulate.

This precise stoichiometric control extends to covalent reactions, where it has been utilized as an efficient method for desymmetrization. For instance, milling aromatic diamines with 1 or 2 equivalents of an aryl isothiocyanate results in the clean and selective formation of mono- or bis(thioureas).[4a] Similarly, milling mesitylene with varying amounts of Oxone and a sodium halide leads to selective mono-, di-, or trihalogenation.[97]


#
# 5

Future of Mechanochemistry

The previous sections highlight the clear advantages mechanochemistry offers over traditional solvent-based synthesis, such as the discovery of new or improved reactivity and the potential reduction or elimination of solvents. However, challenges like difficulty in real-time reaction monitoring, limited mechanistic understanding, and scalability issues limit its broader adoption. Additionally, the lack of standardized protocols and equipment complicates its generalization.

To integrate mechanochemistry into modern synthetic chemistry, further research is needed to improve reaction monitoring, develop scalable methods, and establish standardized procedures. These areas, critical for advancing the role of mechanochemistry in mainstream synthetic applications, are discussed in the following sections.

5.1

Purification of Product

As noted in earlier sections, even if the mechanochemical reaction itself is solvent-free, solvents may still be required for purification, such as for removing nonvolatile byproducts or residual starting materials. While mechanochemistry cannot eliminate the need for solvents in all cases, it can offer advantages in specific situations, such as: (i) reducing overall solvent use, especially toxic ones; (ii) lowering energy consumption; (iii) providing improved reactivity or access to products not achievable via traditional methods; (iv) yielding analytically pure products without additional purification; or (v) producing acceptable impurities for the intended use, or when impurities are removed in a subsequent step. The future of mechanochemistry likely involves its integration into these scenarios, with sustainably sourced, less harmful solvents used as needed.

Moreover, the typical approach to synthesis often begins with the question, ‘Which solvent should I use?’ rather than considering whether a solvent is necessary at all. For mechanochemistry to gain broader acceptance, a shift in this mindset is essential, potentially as important as addressing the technical challenges associated with the method.[98]


# 5.2

Problems Related to Scalability

Most of the syntheses described earlier have been carried out on small laboratory scales, ranging from a few hundred milligrams to a few grams. Although large-scale milling equipment is available and commonly used in bulk material processing, the scalability of mechanosynthesis has not been widely explored, and the process is often perceived as challenging to scale-up. However, recent successful production-scale syntheses of drug/carrier composites (20–50 kg) by Vectorpharma S.p.A. are both significant and encouraging.[99] Additionally, the use of continuous flow mechanochemistry, such as cocrystallization in twin-screw extruders, suggests promising new approaches to large-scale mechanosynthesis that extend beyond traditional ball-milling techniques.[100]

Zoom Image
Scheme 25 Mechanochemical synthesis of aryl N-thiocarbamoyltriazoles

# 5.3

Proper Mechanistic Investigation

As noted in earlier sections, a thorough mechanistic understanding of mechanochemical reactions necessary for a highly predictive synthesis approach is still developing; thus, much mechanosynthesis is currently performed on a trial-and-error basis. Nevertheless, there are emerging guidelines for successful molecular mechanosynthesis. For instance, using lower-melting reactants when possible, employing liquid-assisted grinding, and generating internal solvents are recommended practices. Additionally, fundamental reactivity principles from solution-based chemistry often apply to mechanochemistry as well. A straightforward example is acid–base reactions: stronger acids and bases tend to enhance the likelihood of reactions occurring under mechanochemical conditions.[101] Moreover, a proper mechanistic investigation with in-situ real-time monitoring will not only aid in understanding the reaction pathways under mechanochemical conditions but also help in making mechanochemistry a more widely applicable field within synthetic organic chemistry.


# 5.4

Process Optimization

Ball mills typically lack the features that synthetic chemists commonly expect, such as temperature monitoring and temperature control (though it is worth noting that some systems with these capabilities have been developed and are even commercially available). Additionally, in-situ monitoring using spectroscopy or diffraction techniques is not standard. The advancement of in-situ analysis holds promise for enhancing mechanistic understanding, optimizing processes, and broadening the application of mechanochemical methods.


#
# 6

Conclusion

Mechanochemistry, the application of mechanical energy to drive chemical reactions, has experienced a resurgence in recent decades. Originating from ancient practices, this technique has evolved from a niche approach to a versatile tool with broad applications. Initially focused on inorganic materials, mechanochemistry has expanded into organic and supramolecular chemistry, demonstrating its potential for a wide range of synthetic transformations.

While mechanochemistry has demonstrated synthetic capabilities often rivalling or surpassing traditional methods, a deeper mechanistic understanding remains elusive. Transitioning from qualitative observations to a quantitative framework requires advanced instrumentation, theoretical modelling, and systematic experimentation. By unravelling the complex interplay of energy, materials, and mechanical forces, researchers can establish a predictive model for mechanochemical outcomes. Solvent-free or minimal-solvent conditions enhance efficiency and sustainability but necessitate a nuanced understanding of solvent effects and their role in reaction pathways.

Recent advancements have expanded the capabilities of mechanochemistry beyond traditional milling techniques. The integration of additional energy inputs, such as light, heat, sound, or electricity, with mechanical force holds immense potential for unlocking new reaction pathways and enhancing product yields and selectivity. While these combined approaches are still in their early stages, they offer a promising avenue for future research and development in mechanochemistry.

Additionally, the development of in-situ monitoring techniques has enabled real-time observation of mechanochemical processes, providing crucial insights into reaction mechanisms and kinetics. These advancements are essential for optimizing reaction conditions and expanding the applicability of mechanochemistry across various chemical domains.


#
#

Conflict of Interest

The author declares no conflict of interest.

Acknowledgment

The author thanks Dr. Amit Saha, Department of Chemistry, Jadavpur University, for his helpful discussion.


Corresponding Author

Nirmalya Mukherjee
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Department of Chemistry, Organic Chemistry
Teknikringen 30, 100 44 Stockholm
Sweden   

Publication History

Received: 31 July 2024

Accepted after revision: 25 September 2024

Accepted Manuscript online:
25 September 2024

Article published online:
31 October 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Zoom Image
Figure 1 The evolution of mechanochemistry: a historical overview
Zoom Image
Figure 2 A brief introduction of ball mills
Zoom Image
Figure 3 Description of key parameters
Zoom Image
Scheme 1 Mechanochemical Knoevenagel condensation
Zoom Image
Scheme 2 Mechanochemical oxa-Michael–aldol reaction
Zoom Image
Scheme 3 Mechanochemical Wittig reaction
Zoom Image
Scheme 4 Mechanochemical synthesis of thioglycosides
Zoom Image
Scheme 5 Solventless mechanochemical protection of nucleosides
Zoom Image
Scheme 6 Mechanochemical oxidative amidation
Zoom Image
Scheme 7 Solvent-free mechanochemical peptide synthesis
Zoom Image
Scheme 8 Mechanochemical arylaminomethylation of β-naphthol
Zoom Image
Scheme 9 Synthesis of organochalcogenides under ball milling
Zoom Image
Scheme 10 Mechanochemical synthesis of S-aryl dithiocarbamates
Zoom Image
Scheme 11 Mechanochemical synthesis: α-chalcogenation of bicyclic (hetero)arenes
Zoom Image
Scheme 12 Mechanochemical Sonogashira coupling in a Cu milling assembly
Zoom Image
Scheme 13 Mechanochemical Suzuki–Miyaura coupling with Pd balls
Zoom Image
Scheme 14 Mechanochemical polymerization of 1,12-diazidododecane and bis-ethynyl compounds
Zoom Image
Scheme 15 Cu/Al2O3-catalyzed mechanochemical one-pot synthesis of 1,2,3-triazoles
Zoom Image
Scheme 16 Ru- and Rh-catalyzed mechanochemical C–H functionalization
Zoom Image
Scheme 17 Mechanochemical regioselective arylation of indoles
Zoom Image
Scheme 18 Ring-closing metathesis under ball milling
Zoom Image
Scheme 19 Mechanochemical ring-opening metathesis polymerization
Zoom Image
Scheme 20 Synthesis of NHC ligand precursors under mechanochemical conditions
Zoom Image
Scheme 21 Synthesis of Ru carbene organometallic complexes
Zoom Image
Scheme 22 Mechanochemical asymmetric aldol reaction
Zoom Image
Scheme 23 Suzuki–Miyaura cross-coupling under thermo-mechanochemical conditions
Zoom Image
Scheme 24 Different reactivity between photo-mechanochemical and mechanochemical conditions
Zoom Image
Scheme 25 Mechanochemical synthesis of aryl N-thiocarbamoyltriazoles