Speeding Up Your Organic Synthesis with Ball Mills

Ball Mills are systems developed for refining particles or desagglomeration of aggregated species.

This capability makes ball mills a useful tool for up- and down-stream processes in a range of applications in the pharmacy, food technology, chemical industry etc.

Reactive Milling

The specific surface area of particles is increased while performing particle refinement to a defined size. This increase is normally accompanied with increasing number of surface defects, which are centers for reactivity. Thus, comminution of particles results in a chemical activation of solids which can cause reactions between solids. This is called reactive milling.

For quite a while, the use of reactive milling by ball mills was limited to inorganic synthesis as well as in the design and synthesis of advanced materials with exotic properties that are complex or unfeasible to synthesize using classical methods.

Planetary ball mills are often used for such reactions. Figure 1 shows the operating principle of planetary ball mills, where rotation of grinding bowls mounted on a sun disc that rotates in the opposite direction accelerates grinding balls. Frictional forces are generated due to the resulting trajectories of the grinding balls, affecting processes between the grinding balls as well as between the wall of the grinding bowl and the balls. The transformation and dissipation of the kinetic energy into thermal energy induces chemical reactions between the solids, causing the so-called reactive milling or mechano- chemical reactions.

Planetary Ball Mill PULVERISETTE 7 premium line (Fritsch GmbH) and general operating principle of Planetary Ball Mills.

Planetary Ball Mill PULVERISETTE 7 premium line (Fritsch GmbH) and general operating principle of Planetary Ball Mills.

Figure 1. Planetary Ball Mill PULVERISETTE 7 premium line (Fritsch GmbH) and general operating principle of Planetary Ball Mills.

Application of Ball Mills in Organic Synthesis

The use of ball mills as reactors in organic synthesis is also driven by the concepts of process intensification and sustainable chemistry. Reaction conditions in the impact zones of grinding balls are extreme as predicted by theoretical models. However, several literatures support the possibility of this type of synthesis using ball mills, yielding outstanding and surprising results with regard to chemical reactivity or selectivity when compared to traditional solution-based synthesis.

Since reactions in ball mills are carried out without using solvents, ball mills are increasingly gaining interest in a number of fields. Research efforts led to the development of new reaction procedures to synthesize organic molecules in planetary ball mills without using solvents. This had extended the scope of reactions, including sophisticated techniques for carbon- carbon bond formation through Pd-catalyzed cross-couplings and methods to form hetrocycles from building blocks on hand such as azides and alkynes.

Scheme 1

Such metal-catalyzed reaction protocols performed in planetary ball mills are briefly explained by Scheme 1 (Figure 2). Aryl bromides (Ar-Br) were cross-coupled with phenylboronic acid in the solid state, forming corresponding biphenyls with a yield of 18% to 98% based on the substituents present in the first coupling partner. Plain Pd(OAc) 2 was used as the catalyst to perform these reactions in the presence of KF-Al2O3 as the basic reagent. It was possible to fine-tune the yields by varying the molar ratio of KF and Al2O3 and the water content being adsorbed on the surface of the reagents.

Metal-catalyzed reactions carried out in planetary ball mills at lab-scale.

Figure 2. Metal-catalyzed reactions carried out in planetary ball mills at lab-scale.

The same catalyst was used for the Sonogashira cross-coupling of aryl iodides with terminal alkynes furnished alkynes using two different substituents at the carbon-carbon triple bond. Here again, the yields are based on the characteristic of the coupling partners. Moreover, the use of diazabicyclo octane (DABCO) as a solid base facilitated to carry out this kind of solid-state reaction effectively in a planetary ball mill.

The reaction yielded surprising results with respect to the selectivity for the cross-coupling product, which is more than 95% irrespective of the type of substituent. In addition, the reaction was performed in heterogeneous phase under aerobic conditions. For reaction conditions such as homo-coupling, it is normal to observe side reactions. However, in this case, such side reactions were not at all observed, or the level of respective products was less than the detection limit.

Besides Suzuki and Sonogashira cross-coupling, publications describing solvent-free techniques for the Heck reaction are also available. A Cu-catalyzed alkyne-azide cycloaddition (CuAAC), which is a prototype for Click-reactions, is also illustrated by Scheme 1. Characterized by easy accomplishment, high selectivity and high yield. However, azides are generally shock-sensitive materials and therefore precautionary measures need to be taken while performing such reactions in ball mills.

Phlegmatization of the reaction mixture with quartz sand as milling auxiliary forms the corresponding 1,4-substituted 1,2,3-triazoles with a yield range of 80% to 98%. The functionalization of an azido-sugar and of a polystyrene was also performed using the reaction protocol. The modification of the polystyrene with a terminal alkyne allowed the reaction with n-decyl azide. Surprisingly, the polymer chain was not disintegrated during the last reaction. This result encouraged the use of planetary ball mills to perform polymerization with promising results for potential applications.

Technological Parameters

In addition to chemical characteristics, technological parameters also significantly affect the reactions in ball mills. The impact of these variables on the outcome of the reaction was investigated by selecting different model reactions from various fields of organic synthesis. Besides yielding valuable data, Suzuki cross-coupling enables the oxidative cleavage of β-pinene affording nopinone and the dehydrogenation of γ-terpinene to p-cymene. The last example in particular is a true option for ozonation at low temperatures.

Investigation of the technological parameters reveals that the type of ball mill, whether it is a mixer ball mill or planetary ball mill, does not influence the outcome of the reaction. However, variables such as the size and count of the grinding balls, the milling material and the filling degree of the grinding bowls play an important role. In contrast to particle refinement, the role of the grinding ball size may not be significant until the cumulative mass of the grinding balls remains unchanged.

Selecting the appropriate milling material is imperative considering the amount of transferrable kinetic energy as the transferred wear energy is decided by the density of the material. In addition, it is necessary to consider the chemical aspects of the material, such as the mechanical stability and chemical resistance. The filling degree of the grinding bowls plays a key role with respect to the number of collisions and impacts during ball milling. Low filling degree results in deterioration of the grinding media, whereas grinding bowls completely filled with the feed material hamper the movement of the grinding balls.

Process Parameters

Process parameters such as reaction time and operating frequency also play a crucial role in experiments carried out in ball mills relating to organic synthesis. The relationship of those variables to either the reaction rate (time) or the wear energy (frequency) is highly imperative to successfully complete reactions in ball mills.

Studying the impact for different model reactions does not help in drawing general conclusions due to different kinetic prerequisites for the individual transformations. The energetic assessment of process technologies or reaction protocols can be made by calculating the energy intensity for the synthesis of a single mole of a product of interest. This assessment reveals that synthesis in ball mills is better than syntheses in classical heating baths and microwave ovens and comparable to ultrasound-assisted reactions (Table 1).

Table 1. Comparison of different possibilities for energy entry regarding yield and energy intensity Em fort the model oxidation of p-toluidine to its azo-compound

energy entry device condition yield [%] Em [kWh mol-1]
mechanical Planetary Ball Mill
Mixer Ball Mill
ultrasound (24 kHz, 200 W)
radiation-based heating bath
microwave (multimode)

a milling material: agate, 20 min, 800rpm ≙ 13.3 Hz.
b 20 min at 20 °C with maximal power input.
c 60 in at 80 °C.
d 30 min at 80 °C, maximal power input = 300 W.

The effective transfer of energy from the power socket into a product of interest has been proven for a number of examples. When different ball mills are compared with respect to their gross power input and the degree of efficiency to convert this energy into kinetic energy, the results confirm the superior efficiency of large-scale planetary ball mills. The significant increase in efficiency is accompanied with higher net power input. This means that the amount of energy wasted for auxiliary parts of the machine is significantly less from a relative point of view. The last aspect in particular is critical for scaling up organic syntheses in ball mills.


The results presented in this article have proven the applicability of planetary ball mills as reactors for organic syntheses. The high mixing efficiency of ball mills is exploited for chemical reactions performed in the solid state and in the absence of a solvent. In addition, the continuous particle refinement in ball mills yields surfaces with high activity, thus leading to increased reactivity and selectivity. This paves the way for further advances and applications of ball mills in organic syntheses.

The reaction time is another advantage of ball mills as it is usually limited to several minutes and in the same level as microwave-assisted processes. Reaction rate is considerably higher due to high concentration of substance in comparison with transformations in a solution. Thermal energy is directly generated in the grinding bowls, thus allowing low energy intensities of reactions in ball mills. However, some tasks such as temperature regulation need to be addressed in the future. Several papers discussing organic syntheses in ball mills disprove Aristotle’s philosophy, ‘No coopora nisi fluida.’ Ball mills indeed expand the toolbox used for organic synthesis.

This information has been sourced, reviewed and adapted from materials provided by FRITSCH GMBH - Milling and Sizing.

For more information on this source, please visit FRITSCH GMBH - Milling and Sizing.


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