During the last decade numerous protocols have been published using the method of ball milling for synthesis all over the field of organic chemistry. However, compared to other methods leaving their marks on the road to sustainable synthesis (e.g. microwave, ultrasound, ionic liquids) chemistry in ball mills is rather underrepresented in the knowledge of organic chemists. Especially, in the last three years the interest in this technique raised continuously, culminating in several high-quality synthetic procedures covering the whole range of organic synthesis. Thus, the present tutorial review will be focused on the highlights using this method of energy transfer and energy dissipation. The central aim is to motivate researchers to take notice of ball mills as chemical reactors, implementing this technique in everyday laboratory use and thus, pave the ground for future activities in this interdisciplinary field of research.

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The scale-up of the Knoevenagel-condensation between vanillin and barbituric acid carried out in planetary ball mills is investigated from an engineering perspective. Generally, the reaction proceeded in the solid state without intermediate melting and afforded selectively only one product. The reaction has been used as a model to analyze the influence and relationship of different parameters related to operation in planetary ball mills. From the viewpoint of technological parameters the milling ball diameter, dMB, the filling degree with respect to the milling balls' packing, ΦMB,packing, and the filling degree of the substrates with respect to the void volume of the milling balls' packing, ΦGS, have been investigated at different reaction scales. It was found that milling balls with small dMB lead to higher yields within shorter reaction time, treaction, or lower rotation frequency, rpm. Thus, the lower limit is set considering the technology which is available for the separation of the milling balls from the product after the reaction. Regarding ΦMB,packing, results indicate that the optimal value is roughly 50% of the total milling beakers' volume, VB,total, independent of the reaction scale or reaction conditions. Thus, 30% of VB,total are taken by the milling balls. Increase of the initial batch sizes changes ΦGS significantly. However, within the investigated parameter range no negative influence on the yield was observed. Up to 50% of VB,total can be taken over by the substrates in addition to 30% for the total milling ball volume. Scale-up factors of 15 and 11 were realized considering the amount of substrates and the reactor volume, respectively. Beside technological parameters, variables which influence the process itself, treaction and rpm, were investigated also. Variation of those allowed to fine-tune the reaction conditions in order to maximize the yield and minimize the energy intensity.

A solvent-free method for the Sonogashira coupling reaction was established under ball milling conditions without the use of copper or additional ligands. Pd(OAc) 2 or Pd(PPh 3 ) 4 in combination with 1,4-diazabicyclo[2.2.2]octane (DABCO) were chosen as catalysts and base, respectively. The reaction was investigated using a variety of aryl halides and acetylenes and with different amounts of the Pd-catalyst and DABCO. Results indicated that the employment of Pd(OAc) 2 in combination with SiO 2 as a grinding auxiliary preferentially induces the transformation of aryl iodides to the corresponding Sonogashira coupling products. In contrast, both the substitution of SiO 2 by Al 2 O 3 or replacement of Pd(OAc) 2 with Pd(PPh 3 ) 4 enable the reaction of aryl bromides with phenylacetylenes. The selective reaction of bis-ethynyl compounds to double-coupled products and the influence of further common bases on the reaction was also scrutinized, confirming the high reactivity of DABCO as a base for solvent-free transformations.