Mechanochemistry — the process where mechanical forces such as grinding, milling, or shearing drive chemical transformations — is as old as the mortar and pestle. However, the discipline is far from old-fashioned. Mechanochemical reactions are typically carried out without solvents, offering a greener approach to synthesis.
Operating under solid-state or near-solid-state conditions, mechanochemistry also enables entirely new chemical transformations. In many cases, these reactions would be inaccessible via solution-based methods. As green chemistry gains traction, this method is an increasingly important way to reduce waste and improve safety in the development of chemicals, pharmaceuticals, and more.
The surge in interest is evident in publication trends, as we found by examining the CAS Content CollectionTM, the largest human-curated repository of scientific information, accessible through CAS IP Finder, powered by STNTM (see Figure 1).
A steady increase in journal articles highlights mechanochemistry’s growing academic appeal, driven by interest in sustainable and environmentally responsible chemistry research. In contrast, the relatively low number of patent filings indicates limited commercialization, likely due to the current challenges in understanding how mechanical grinding activates different molecular groups for chemical reactions. Let’s explore how the field is evolving and its role in the larger field of green chemistry:
How mechanochemistry works
The choice of technique for a mechanochemical reaction directly impacts energy input, reaction efficiency, scalability, and sustainability, making it a critical determinant of process performance. Our analysis reveals that milling is the most prevalent technique for mechanochemical reactions (see Figure 2).
This dominance is attributed to milling’s ability to precisely control reaction parameters, such as milling frequency and the medium-to-sample weight ratio, within an enclosed system, thereby enhancing efficiency, versatility, and suitability for numerous reactions and research applications.
Mill designs are based on their motion patterns, with shaker and planetary mills being the most used. Shaker mills are typically used for small samples, where milling jars oscillate back and forth at a frequency that determines milling intensity. Planetary mills rotate jars around a central axis while spinning on their own axis, generating strong centrifugal forces that mimic gravity in industrial roller mills and provide a direct link to scale-up.
The next most common technique is grinding, which generally refers to a simpler, open-to-atmosphere mechanical process that provides limited control over reaction parameters. However, this is the cheapest and simplest approach and can be mimicked on the gram-scale with a simple mortar and pestle.
Ultrasonication uses high-frequency sound waves to drive chemical transformations through efficient agitation, enhanced dissolution, improved mass and heat transfer, and reagent sonolysis via cavitational collapse. These localized extreme conditions are effective for heterogeneous reactions, enabling them without bulk heating. This makes ultrasonication a versatile method for promoting reactions under mild overall conditions.
Newer mechanochemical techniques have appeared in a smaller number of publications:
- Reactive extrusion, particularly twin-screw extrusion (TSE), offers a scalable and continuous approach to mechanochemical processing by enabling precise control through reactor design and optimization of other continuous variables. While organic synthesis via TSE remains in its early stages, its potential is increasingly recognized. IUPAC identified reactive extrusion as one of the ten emerging technologies in chemistry with the potential to make our planet more sustainable.
- Liquid-assisted grinding (LAG) is an emerging technique that plays a crucial role in the success of mechanochemistry. By introducing a small amount of liquid (liquid additive : weight of reactants η ≈ 0-1 μL/mg), LAG enhances reactant mixing, accelerates reaction rates, improves selectivity and yield, facilitates energy transfer, and enables or directs transformations that are not achievable through neat grinding alone. Manipulating liquid additives in LAG offers a significant control on mechanochemical reactions. Additionally, LAG is efficient in screening inclusion compounds, cocrystals, polymorphs, and in organic mechanochemistry. Ion- and liquid-assisted grinding (ILAG) evolved from LAG, incorporates a small amount of salt (≤ 5 mol%) to activate the system. A related yet distinct approach is ionic liquid-assisted grinding (IL-AG), which uses an ionic liquid as the additive instead of conventional solvents or salts.
- Resonance acoustic mixing (RAM) uses low-frequency acoustic energy for mixing and inducing reactions without the need for milling media or solvents. RAM utilizes a simplified reactor design that minimizes contamination risk. It has found applications in organic synthesis and photochemical processes, offering a clean and efficient approach to mechanochemical transformations.
Mechanochemistry and advanced manufacturing across industries
Mechanochemistry has evolved into a versatile approach with applications spanning multiple domains. We analyzed concept data based on class codes and categorized them according to their respective applications (see Figure 3). Our findings indicate that mechanochemistry is widely applied in materials science, with significant contributions to energy storage, electronics, environmental applications, catalysis, and biomedical fields.
The dominance of material chemistry stems from its suitability for solid-state synthesis, eco-friendly processing, and the design of advanced materials. Additionally, historical development of mechanochemistry within mineral and materials engineering has concentrated infrastructure and expertise in these domains.
We conducted an in-depth analysis to gain comprehensive insights into each area and identified the top ten concepts within each category (see Figure 4). Solid electrolytes have emerged as the dominant focus of mechanochemistry in energy storage and conversion, as evidenced by the highest number of publications in this concept. This trend is likely driven by the growing popularity of solid-state batteries, which offer superior safety, durability, environmental friendliness, and exceptionally high energy density.
Semiconductors and ceramic insulators are dominant concepts in electronics and optoelectronics, as both are indispensable for device performance, miniaturization, and reliability. They enable high-speed, high-efficiency, and durable electronics and optoelectronics, which are central to modern technologies like smartphones, solar cells, and LEDs.
Biomass is prevalent in environmental applications because it addresses many sustainability challenges, including waste management, renewable energy production, and carbon footprint reduction. Integrating mechanochemistry with biomass valorization and processing further enhances sustainability.
In recent years, photocatalysis has emerged as a pivotal area in catalytic processes due to its sustainability and high efficiency. Building on this, mechano-photocatalytic reactions have attracted significant scientific interest as an advanced step toward greener technologies, now recognized as one of the most prominent catalytic approaches within mechanochemistry. Mechanocatalytic processes also play a crucial role in enabling diverse organic transformations.
Mechanochemistry is revolutionary in biomedical applications and the synthesis of various therapeutic agents. These include pharmaceutical formulation, which involves polymorph control, co-crystal formation, and co-amorphous systems to enhance drug solubility and stability. Additionally, mechanochemistry supports nanomedicine by producing functionalized pharmaceutical nanoparticles for targeted drug delivery.
Another significant usage of mechanochemistry lies in the concept of porous and separation materials, with a predominant emphasis on metal–organic frameworks (MOFs). MOFs are distinguished by their exceptional combination of high porosity, tunable architecture, and chemical versatility, making them highly sought-after materials for diverse scientific and industrial applications. They can be synthesized in one-pot methods, making them an ideal target for mechanochemical development through the reduction of solvents.
Mechanochemistry also features applications in construction materials and surface coatings, with a predominant focus on cement and plastic films respectively. Plastic films and spray coating can also be generated from polymers produced via mechanochemical pretreatment of lignocellulosic biomass.
Making organic chemistry more sustainable
Mechanochemistry is one of the modern tools for technology-enhanced synthesis, fostering synergy between traditional organic chemistry and advanced technological innovations. Organic synthesis traditionally relies on dissolving reactants in organic solvents to facilitate reactions, which raises the question of whether such transformations can be achieved through mechanochemical approaches, thereby eliminating large volumes of solvent.
While this strategy is highly desirable from a sustainability perspective, it remains challenging because organic synthesis is deeply rooted in solution-phase techniques that ensure molecular-level precision, stereo/chemoselectivity, and stabilization. Ongoing efforts to overcome these limitations have successfully expanded the scope of mechanochemistry to include numerous organic transformations such as organocatalytic reactions and metal-catalyzed transformations, olefin metathesis, C─H activation, coupling reaction, and click reaction.
使用 CAS SciFinder®（世界中の情報源から化学および関連科学データを収集）を用いて反応データを分析し、メカノケミカルなアプローチで現在行われている変換反応の傾向について洞察を得ました（図5を参照）。
同様の傾向を調査している研究者は、 CAS SciFinderの人工知能を活用した検索機能を使用することで、 有機化学反応データのパターンを特定できます。
配位反応が主要な変換タイプであり、それに続いてアルコールやアミンのアルデヒドへの付加、マイケル付加、活性化された二重結合または三重結合への有機金属の付加を含む付加反応が続きます。どちらの反応タイプも本質的に固体状態の条件と適合しており、機械的活性化によって提供される密接な混合とエネルギー入力の恩恵を受けています。
エステル化、アシル化、アルキル化といった反応タイプは、有機合成において最も一般的な官能基変換の一部です。図6は、上位10種類の反応タイプの年ごとの成長を示しており、メカノケミカル条件下で実施される反応数の一貫した増加を強調しています。
図6： 上位10種類の反応タイプの成長。出典：CAS Content Collection。
メカノケミストリーのスケールアップには、プロセス自動化が不可欠です
メカノケミストリーは、溶媒を使用しない革新的な化学合成手法として、その重要性がますます高まっています。この分野は、材料科学、高分子化学、有機・無機合成、生化学など、幅広い領域で広く採用されるようになりました。メカノケミストリーには多岐にわたる利点がありますが、その可能性を商業的な成功へとつなげるには、スケールアップの課題を克服することが不可欠です。そのため、反応手法の進歩やメカノケミカル技術の開発を通じて、これらの課題に取り組む努力が続けられています。
例えば、メカノ触媒は、機械的エネルギーと触媒作用を組み合わせることでエネルギー効率を高め、従来の溶液法では到達できなかった反応を実現します。これは、有機合成、材料開発、重合など、あらゆる領域で同様の影響力を持っています。前述の通り、LAGもメカノケミカルな反応性を高める強力な手法として注目されており、溶媒フリーの条件下では困難な反応を促進します。連続処理はスケールアップと工業化を実現するための鍵であり、押出機を用いたメカノケミストリーが重要なソリューションとして浮上しています。TSE技術の統合により、多くのメカノケミカル変換を大規模に実行することが可能になりました。
メカノケミストリーは大きな成功を収めていますが、その反応機構や理論的基盤についての包括的な理解は、まだ発展途上の段階にあります。したがって、メカノケミカルプロセスを効果的に計画し、成功させるためには、この方向での集中的な研究が不可欠です。さらに、人工知能を統合することでプロセスの自動化や選択を支援し、より効率的で経済的に実行可能な工業規模のメカノケミカル生産への道を開くことができます。
要するに、メカノケミストリーは単なるトレンドではなく、持続可能な化学生産に向けたパラダイムシフトです。継続的な研究と技術革新により、学界と産業界の両方で進歩を促進し、主流の工業プロセスとなる準備が整っています。
