Advances in synthesis: general discussion
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Advances in synthesis: general discussion Alexander Angerhofer, Matej Bal´ aˇ z, Viktor Balema, Ana M. Belenguer, Richard G. Blair, Elena Boldyreva, Carsten Bolm, Lars Borchardt, Adam B. Braunschweig, Duncan L. Browne, Stephen Craig, Lamis El Wenni, Franziska Emmerling, Michael Ferguson, Cecilia Fiore, Tomislav Friˇ sˇ ci´ c, Kimichika Fukushima, Felipe Garc´ ıa, Lori Gonnet, Sven Gr¨ atz, Rafael A. Hernandez R., Hajime Ito, Stuart L. James, Deniz Karabiyikli, Jeung Gon Kim, Koji Kubota, Fr´ ed´ eric Lamaty, Giulio I. Lampronti, Jamie Leitch, Stipe Lukin, James Mack, Lucia Maini, Sharmarke Mohamed, Audrey Moores, Karthik Nagapudi, Francesco Puccetti, Mi Tian and Qian Yu DOI: 10.1039/d2fd90081e Richard G. Blair opened discussion of the introductory lecture by Elena Boldyreva: I have read quite a few of the articles out of the Institute of Solid State Chemistry and Mechanochemistry. The biggest challenge I have faced is in translating the mill choice to one I can implement in my laboratory. I do not doubt that you are using commercially available mills, they are just not available in the United States. For instance the AGO-2 mill is described as a planetary mill, but only one image exists when searching the internet. Can you recommend a paper that summarizes the mill technologies used at the institute? Elena Boldyreva replied: A review on mechanochemistry in Siberia was recently published by a former director of this institute, who is no longer related to it, but is affiliated with Novosibirsk State University. 1 AGO is described in detail in the book by Avvakumov (one of the co-designers of this high-energy planetary mill), 2 and in the recent revised edition of this book from 2022. 3 1 V. V. Boldyrev, Mechanochemistry in Siberia, Herald Russ. Acad. Sci., 2018, 88(2), 142–150. 2 E. G. Avvakumov, Mechanical methods of the activation of the chemical processes, Publishing House of the Siberian Branch of Russian Academy of Sciences, Nauka, Novosibirsk, 1979. 3 E. G. Avvakumov, Mechanical methods of the activation of the chemical processes, Publishing House Lenand, 2022, ISBN 978-5-9710-9392-3. Richard G. Blair enquired: For years there has been a disconnect between Western and Russian mechanochemistry researchers. A summary of milling approaches comparing work at the Institute of Solid State Chemistry and Mechanochemistry to commonly used methods today would be very useful. Does such 150 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Faraday Discussions Cite this: Faraday Discuss.,2023,241,150 DISCUSSIONS Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online View Journal | View Issue
a document exist? Perhaps there is interest in pursuing this –I would be interested in assisting. Elena Boldyreva answered: Thank you for your question. I do not think, that “there has been a disconnect between Western and Russian mechanochemistry researchers”. On the contrary, from the very beginning, since the middle of the 20th century, “Russian mechanochemistry”was closely related to research done in many countries in the world, researchers exchanging visits, performing joint experiments, publishing jointly research papers, books, even developing jointly technologies. Professor Boldyrev had strong connections with all the important research groups throughout the world. He supervised several PhD students from abroad. As examples, I can mention Vladimir Sepelak (now at KIT in Germany), or Giuseppe Intini from Italy. I myself supervised Adam Michalchuk as a PhD student; he learned mechanochemistry originally in Novosibirsk, and then moved to Germany. We kept on working and publishing together, as long as this was not forbidden to him by German rules for political reasons. I have many international collaborations. Russia was always well represented at the international meetings on mechanochemistry, including the last but one INCOME that took place in Koˇ sice in 2017. The only sad exception was the last INCOME in 2022 in Cagliari: the organizers declined the attendance of Russian researchers, even virtually, for political, not scientic reasons. Also my own lecture there was not allowed, though prepared. As far as your suggestion of preparing a comparative review document is concerned. Such a single document does not exist. However, there are several recent reviews by professor Boldyrev and myself (in Russian and in English), as well as a recent revised edition of a monograph by Avvakumov (in Russian), that give an overview of the past and current activities in this eld. See for example ref. 1or2. I need to add that many key players in mechanochemistry from the Institute of Solid State Chemistry and Mechanochemistry either moved to other institutions (Boldyrev, Ivanov, Urakaev, Boldyreva, Bychkov), passed away (Pavlyukhin), or retired (Avvakumov). There is also much research in mechanochemistry done at other institutes and universities in Novosibirsk and in Russia. Professor Boldyrev and myself currently have no relationship with the Institute of Solid State Chemistry and Mechanochemistry, but we are quite active in the eld of mechanochemistry at Novosibirsk State University. If you are interested in a collaboration with us on preparing the review document you mention, or in other respects, we can discuss the details. This may be a good idea. 1 V. V. Boldyrev, Mechanochemistry in Siberia, Herald Russ. Acad. Sci., 2018, 88(2), 142–150. 2 A. A. Michalchuk, E. V. Boldyreva, A. M. Belenguer, F. Emmerling and V. V. Boldyrev, Tribochemistry, mechanical alloying, mechanochemistry: what is in a name?, Front. Chem., 2021, 9, 685789. Tomislav Friˇ sˇ ci´ copened a general discussion: The data and effects related to mechanochemistry presented at this meeting leave a very complex picture, which can confuse or drive away researchers who want to use mechanochemistry as a tool for synthesis and reaction discovery. How can we simplify this for synthetic chemists? Should we divide different types of instrumentation based on Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 151 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
activation energy or based on what type of chemical systems it might be best suited for? How can we bring mechanochemical methodology to something that is broadly accessible, similar to how synthetic chemists perceive solution techniques? Richard G. Blair responded: Perhaps it would be useful to develop a generic mechanochemical reactor design that's useful for 90+% of the work. I am thinking along the lines of condensers used in organic chemistry. There are quite a few designs but common use is limited to one or two. More involved work requires moving to different condenser designs. James Mack said: There is a lot detail in understanding a mechanochemical reaction, no different than trying to understand traditional solution based reactions. However in solution based reactions there are many assumptions made, like the ideal gas law, when we all know there is no such thing as a ideal gas. Our community needs to take a similar approach to simplify our process so that we can move forward and not get caught up in semantics. Tomislav Friˇ sˇ ci´ cadded: I fully agree –simpler models that are easy to grasp and use should come in advance of more in-depth studies, as they provide an opportunity to make generalizations and make the eld more accessible to nonexperts. Tomislav Friˇ sˇ ci´ copened discussion of the paper by Richard G. Blair: While your approach is able to detect impact, how could it be used (or modied for this purpose) to detect energy input related to shear.? Richard G. Blair replied: Since both shear and compressive forces can give rise to signals it may be difficult to decouple the two. If one had a system that was mostly shear that would be a start. The second challenge would be coupling of the shear motion through a vial. In such a case direct contact between the system and the piezoelectric element may be needed. Offhand, it might be interesting to make a stack of piezoelectric elements/lms (see Fig. 1 here). Lars Borchardt opened discussion of the paper by Carsten Bolm: As in your mentioned publication in Green Chemistry, 1 the reaction takes place in a steel vessel. Can you prove/exclude that the formation of radicals is involved which might initiate the reaction? 1 D. Kong, M. M. Amer and C. Bolm, Green Chem., 2022, 24, 3125, DOI: 10.1039/d2gc00820c. Carsten Bolm answered: In our previous very related study on stainless-steel initiated allene additions in a ball mill, 1 we tested TEMPO and BHT as radical traps. There, TEMPO led to a complete inhibition of the product formation, and BHT reduced the product yield signicantly. Furthermore, small quantities of trapping products were detected with both reagents. Thus, we really do believe that radicals are involved. In this particular case, we have not done such inhibitory studies, but the analogy is apparent. Faraday Discussions Discussions 152 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
1 D. Kong, M. M. Amer and C. Bolm, Green Chem., 2022, 24, 3125, DOI: 10.1039/d2gc00820c. Lars Borchardt asked: It is known from the mechanochemical synthesis of polymers that due to collision of milling balls at vessel walls radicals are formed. Do you observe this radical formation and can you potentially quench it? Carsten Bolm replied: Our control experiments show that such radical formations are not relevant here. If they occur and the radicals are then quenched rapidly, we do not know. Karthik Nagapudi requested: In your talk you said that relying on the piezo effect could be dangerous –could you explain more? Carsten Bolm responded: The term “dangerous”referred to the fact that we have to be very careful with the data interpretation. As noted in our article (https:// doi.org/10.1039/d2fd00075j), we became highly critical and performed many test reactions to ensure that the results were really based on the electron transfer (ET) effects of the piezoelectric materials. The community should be most sensitive to avoid (the danger of) mis-interpretations. Matej Bal´ aˇ zcommunicated: At the end of your talk, you mentioned the word “dangerous”. Did you mean it in terms of terminology that researchers tend to incorrectly assign the role of piezoelectricity in organic reactions, or did you mean Fig. 1 Proposed scheme for a stack of piezoelectric elements/films to detect energy input related to shear. Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 153 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
it in such a way that performing such reactions can be dangerous because of the possibility of some exothermic effects like explosion, etc.? Carsten Bolm communicated in reply: Working on organic reactions initiated by piezoelectric materials under mechanochemical conditions we became very critical and realized the necessity of performing many test reactions to ensure that the results were really based on the suggested effect. There is a signicant danger of mis-assignment, and I hope that the community remains sensitive. Ana M. Belenguer continued discussion of the paper by Richard G. Blair: In your manuscript (https://doi.org/10.1039/d2fd00084a) you claim that the most common failure mode of the piezoelectric setup was cracking of the solder joint. Have you resolved this problem? Richard G. Blair replied: Yes, we have solved this problem by potting the electronics in high strength epoxy. Ana M. Belenguer enquired: Are the balls made of 414 stainless-steel? How important is the material for the ball? Richard G. Blair answered: The balls are made of 440C (X105CrMo17). This is a martensitic steel that has been heat treated to Rockwell C60. It is important to choose a steel that is as hard as possible to reduce plastic deformation and loss of energy. Any commercially available ball bearing will be hardened to reduce ball wear. Richard G. Blair opened discussion of the paper by Felipe Garc´ ıa: Your discussion on scale up is a bit pessimistic. You will nd that energy consumption per unit of reactant goes down as the scale goes up. This is due to a change in the motors used and efficiencies of running large 3-phase motors. Check out mills by Netzsch. Felipe Garc´ ıareplied: We have not had the opportunity to attempt any upscaled reaction using a 3-phase motor. Considering that the term upscaling can be interpreted differently in different areas of the chemical sciences (see ref. 1), in the areas that we have worked, metal complexes 2 and perovskite materials, 3 upscaling represents a scale of 1 kg or less, which generally does not require 3phase motor equipment. We will look into examples in the future where we could compare 2-phase vs. 3-phase mechanochemical equipment in terms of consumption. 1 E. Colacino, V. Isoni, D. Crawford and F. Garc´ ıa, Trends Chem., 2021, 3, 335–339. 2 V. K. Singh, A. Chamberlain-Clay, H. C. Ong, F. Le´ on, G. Hum, M. Y. Par, P. Daley-Dee and F. Garc´ ıa, ACS Sustainable Chem. Eng., 2021, 9, 1152–1160. 3 Z. Hong, D. Tan, R. A. John, Y. K. E. Tay, Y. K. T. Ho, X. Zhao, T. C. Sum, N. Mathews, F. Garc´ ıa and H. S. Soo, iScience, 2019, 16, 312–325. Stephen Craig addressed Richard G. Blair and Carsten Bolm: Are there hypotheses for why barium titanate seems to be the preferred piezo material for mechanoredox transduction systems? Faraday Discussions Discussions 154 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
Richard G. Blair answered: The piezoelectric constant alone does not fully describe a material’s electrical characteristics. I think we are not looking at the right parameter. It may be a combination of the piezoelectric coefficient and something like electrical conductivity. Carsten Bolm responded: In both our previous work 1 and the current one (https://doi.org/10.1039/d2fd00075j) we tested a series of piezoelectric materials (such as tet-BaTiO 3 , cub-BaTiO 3 , ZnO, and SrTiO 3 ) and, indeed, tet-BaTiO 3 was the best. There might be chemical reasons, but we should also not forget that we optimized the systems with tet-BaTiO 3 . Thus, it could well be that the other piezoelectric materials perform better when focusing on their application in greater detail. 1 C. Schumacher, J. G. Hern´ andez and C. Bolm, Angew. Chem., Int. Ed., 2020, 59, 16357. Audrey Moores continued discussion of the paper by Carsten Bolm: Thanks a lot for your word of caution on the piezo effect, can you recommend guidelines to check for this, as an author, but also as a reviewer/editor of such research discovery? Carsten Bolm answered: That is very difficult, and I hesitate to generalize. Each system will require adequate test reactions, and I can only recommend each scientist (being author, editor, or reviewer) to perform as many of those as possible. Misinterpretations will be highly misleading, and it is in the interest of all of us to avoid such unproductive pathways. Alexander Angerhofer asked: Have you tried to test the radical reactions using spin traps (for example PBN) combined with EPR spectroscopy? If not, what might be the challenges for carrying out spin trapping in the ball mill? Carsten Bolm replied: We have not used spin traps in this particular system, but we applied TEMPO and BHT in our previous very related study on stainlesssteel initiated allene additions in a ball mill. 1 There, TEMPO led to a complete inhibition of the product formation, and BHT reduced the product yield signi- cantly. Furthermore, small quantities of trapping products were detected with both reagents. 1 D. Kong, M. M. Amer and C. Bolm, Green Chem., 2022, 24, 3125, DOI: 10.1039/d2gc00820c. Viktor Balema remarked: We detected radicals in a polystyrene (PS) polymer aer ball milling it in a SPEX Mill 8000. 1 1 V. P. Balema, I. Z. Hlova, S. L. Carnahan, M. Seyedi, O. Dolotko, A. J. Rossini and I. Luzinov, New J. Chem., 2021, 45, 2935–2938, DOI: 10.1039/d0nj05984f. Carsten Bolm responded: Many thanks for the hint to your article. I nd it rather remarkable that you could “reform”styrene from PS and that you were able to detect “stable radicals”. For sure that is worth studying in more detail and I look forward to seeing the results from your intended mechanistic studies (as mentioned in the last sentence of your article). Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 155 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
Sharmarke Mohamed continued the general discussion: A number of authors have reported changes in reaction yield or outcome of a mechanochemical reaction by simply changing the material that the jar/balls are made of (i.e., stainless steel to plastic) during ball-milling. It is clear that changing the milling media affects the friction, surface–reactant interactions and possibly other factors during the ball-milling operation. However, I wonder which of these factors would you say are most important in affecting the yield and chemical products of the reaction as you change the milling media? Is it the changes in the surface effects induced by changing the milling media or changes in the mechanical forces (i.e., shearing etc.) inside the jar due to changes in the material type? Felipe Garc´ ıareplied: Based on our experience, all the factors that you have mentioned matter; there are several reviews discussing parameters –in addition to the one mentioned in my earlier reply, ref. 1, 2 and 3 provide good entry-level discussion as well as their applications to a wide range of materials. 4 We have observed that the jar material plays an important role, which we attribute to increasing mechanical forces. For instance, in the area of polyaromatic systems 5,6 or main group frameworks. 3 However, we have not performed detailed studies to rule out any of the other parameters you mentioned as the prevailing factor. 1 N. R. Rightmire and T. P. Hanusa, Dalton Trans., 2016, 45, 2352–2362, DOI: 10.1039/ c5dt03866a. 2 D. Tan and F. Garc´ ıa, Chem. Soc. Rev., 2019, 48, 2274–2292, DOI: 10.1039/c7cs00813a. 3 Y. Sim, Y. X. Shi, R. Ganguly, Y. Li and F. Garc´ ıa, Chem.–Eur. J., 2017, 23, 11279–11285. 4 T. Friˇ sˇ ci´ c, C. Mottillo and H. M. Titi, Angew. Chem., Int. Ed., 2020, 59, 1018–1029. 5 T. Yong, G. B´ ati, F. Garc´ ıa and M. C. Stuparu, Nat. Commun., 2021, 12, 5187. 6G.B ´ ati, D. Cs´ ok´ as, T. Yong, S. M. Tam, R. R. S. Shi, R. D. Webster, I. P´ apai, F. Garc´ ıa and M. C. Stuparu, Angew. Chem., Int. Ed., 2020, 59, 21620–21626. Elena Boldyreva responded: You have already listed most of important factors yourself. I suggest that you read our recent paper on this topic, where we discuss the possible effects. 1 Depending on the system and the mechanical device, either surface effects, or changes in mechanical forces can prevail. Oen, both are important. 1 E. Losev, S. Arkhipov, D. Kolybalov, A. Mineev, A. Ogienko, E. Boldyreva and V. Boldyrev, Substituting steel for a polymer in a jar for ball milling does matter, CrystEngComm, 2022, 24(9), 1700–1703, DOI: 10.1039/d1ce01703a. Tomislav Friˇ sˇ ci´ casked: A very abstract question –are there other processes apart from shear and impact that we should be considering when contemplating mechanochemical reactions? Richard G. Blair answered: Although shear and impact are the fundamental processes driving the reaction, there are other material related processes that are important. Key in this are the mechanical characteristics of the material being milled. This is especially important if solids are being used as piezoelectric sources, catalysts, or even milling aids. For instance, the plastic deformation limit of the material allows optimizing a process for inducing defects. We have seen an increase in catalytic efficiency over defects when the catalyst material is being milled with forces above its plastic deformation limit. Faraday Discussions Discussions 156 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
In designing milling media the coefficient of restitution is easily measured and gives a gauge of the energy lost in impacts with the container walls. Ultimately this is related to the mechanical properties of the milling media and vial. It may not be as important in soorganic reactions, but inorganic reactions really benet from using materials with high coefficients of restitution. This idea warrants further study and perhaps discussions with materials and mechanical engineers. Felipe Garc´ ıareplied: Shear and impact are potentially major contributors to the mechanochemical process, however, despite a lot of effort being devoted to temperature control during the mechanochemical process (ref. 1–6, etc.), there is less emphasis on friction and heat ow (and its dissipation) 7 –which ultimately could affect the effectiveness of shear and impact forces. 1 J. Andersen and J. Mack, Green Chem., 2018, 20, 1435–1443, DOI: 10.1039/c7gc03797j. 2 N. Cindro, M. Tireli, B. Karadeniz, T. Mrla and K. Uˇ zarevi´ c, ACS Sustainable Chem. Eng., 2019, 7, 16301–16309, DOI: 10.1021/acssuschemeng.9b03319. 3G.B ´ ati, D. Cs´ ok´ as, T. Yong, S. M. Tam, R. R. S. Shi, R. D. Webster, I. P´ apai, F. Garc´ ıa and M. C. Stuparu, Angew. Chem., Int. Ed., 2020, 59, 21620–21626, DOI: 10.1002/anie.202007815. 4 S. Immohr, M. Felderhoff, C. Weidenthaler and F. Sch¨ uth, Angew. Chem., Int. Ed., 2013, 52, 12688–12691, DOI: 10.1002/anie.201305992. 5K.U ˇ zarevi´ c, V. ˇ Strukil, C. Mottillo, P. A. Julien, A. Puˇ skari´ c, T. Friˇ sˇ ci´ c and I. Halasz, Cryst. Growth Des., 2016, 16, 2342–2347, DOI: 10.1021/acs.cgd.6b00137. 6 Y. Gao, C. Feng, T. Seo, K. Kubota and H. Ito, Chem. Sci., 2022, 13, 430–438, DOI: 10.1039/ d1sc05257h. 7K.U ˇ zarevi´ c, N. Ferdelji, T. Mrla, P. A. Julien, B. Halasz, T. Friˇ sˇ ci´ c and I. Halasz, Chem. Sci., 2018, 9, 2525–2532, DOI: 10.1039/c7sc05312f. Carsten Bolm responded: I consider shear and impact as the “initiators”for other phenomena which result from them (such as local heating, piezoelectric effects, mixing, .). As such, shear and impact represent the basis that we shall explore in more detail. James Mack commented: Traditionally in organic chemistry, reactions are categorized by reaction class, but since the materials are so important in these processes and reaction rates, we need to categorize mechanochemical reactions by reaction class but also by materials used. Stuart L. James responded: Interesting idea, makes sense especially where the milling medium takes part. Stuart L. James added: It could also be interesting to look at the same reaction type with different substrates, and look at the effects of different melting points and different polarities (by analogy to solvent polarity) on reactivity. Adam B. Braunschweig continued discussion of the paper by Richard G. Blair: The use of piezoresistors in your reaction vessels to measure forces is a very interesting reaction setup. I was wondering if you had used these sensors to try to measure activation parameters, such as activation energy or free energy of activation. Richard G. Blair responded: We have not yet. It is a good idea. I think looking at the distribution of forces (voltages) as a function of reaction yield may enable Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 157 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
such an analysis. However, higher data acquisition rates will need to be utilized as the 10 kHz sampling rate we currently use does not fully capture all impact events. Stuart L. James remarked: I would highlight James Mack's Chem. Sci. paper from 2017 –I think it's very helpful in understanding how the Arrhenius equation relates to milling reactions. 1 1 J. M. Andersen and J. Mack, Chem. Sci., 2017, 8, 5447–5453, DOI: 10.1039/c7sc00538e. Cecilia Fiore continued the general discussion: The catalytic effect of materials of the jar: in previous work, we had a reverse situation, a one-pot reaction could go in two steps with the intermediate formation and the addition of a third component as a second step. Zirconium oxide worked well to complete the reaction, stainless steel instead stopped the reaction at the rst (intermediate) step. We considered the catalytic effect of the jar material but it still remains unclear what happened. Referees were asking for weighing of the jars and balls to investigate the possible loss of materials. How would you answer this kind of request? Richard G. Blair responded: I have encountered this issue as well, especially in catalysis work where belief oen supersedes proof. We have chosen mechanically equivalent blanks. 1 Which might work in your situation by using other vial materials. You can also use ICP/MS to measure the amount of metals leached into the reaction material. Fe(SCN) 63− is a great way to measure iron in the sample. It is sensitive to ppm levels. Just use nitric acid to digest the samples. 2 I hesitate to recommend this as you would contaminate your zirconia vial with steel. But you could use steel balls in a zirconia vial. 1 D. J. Nash, D. T. Restrepo, N. S. Parra, K. E. Giesler, R. A. Penabade, M. Aminpour, D. Le, Z. Li, O. K. Farha, J. K. Harper, T. S. Rahman and R. G. Blair, ACS Omega, 2016, 1, 1343–1354, DOI: 10.1021/acsomega.6b00315. 2 S. M. Hick, C. Griebel and R. G. Blair, Inorg. Chem., 2009, 48, 2333–2338, DOI: 10.1021/ ic8022437. Stuart L. James answered: I'm not sure if weighing would be accurate enough to be sure if some material came off, and it wouldn't have to give a catalytic effect anyway. Sounds like a tricky one. Carsten Bolm replied: I assume that we had the same reviewers (as we were asked the same questions). In order to shine light into the “catalytic mystery”we performed many control experiments (with jars and balls made of various materials, metal additives, .), and all data were conclusively pointing to the reported results. For sure, the jar/ball material has a major impact, but I am not sure that, for example, weighing the jar (as suggested by your reviewers) will give clear answers. We also discussed with analytical chemists, and my conclusion was that nding the “real catalyst”will be very challenging (and at least beyond the scope of our current report). We might come back to such investigations in the future, but honestly, I am not sure that we could nd a satisfying answer –neither for the reviewers nor –and even more so –for us. Faraday Discussions Discussions 158 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
Tomislav Friˇ sˇ ci´ canswered: When working at synchrotron sources, we oen use poly(methyl)methacrylate (PMMA) milling vessels that need to be recycled due to large volume and intensity of work. We typically do this through sonication in a mixture of aqueous HCl and methanol, followed by washing with water, methanol, manual wiping and then drying in a lab oven around 40 °C. If the jars get worn, then we usually sandpaper them to high polish before re-use. This works for most systems we worked on at synchrotron sources (metal oxides, carbonates, hydroxides, MOFs, organic molecules). Richard G. Blair replied: We use a mix of 100% ethanol and kaolinite. Typically, a mixture of about 1 gram of kaolinite per 30 mL of ethanol is utilized. A vial to be cleaned is lled half way with this mixture and the media then milled for 15– 30 minutes. We have found this is the most effective way to clean metallic and WC vials. It is superior to using glass as it does not abrade the vials or media. The mixture can be reused. Acetal is produced during the cleaning process due to the interaction of the ethanol with the kaolinite. This mechanochemical process may aid in the cleaning process. Matej Bal´ aˇ zresponded: In our experiments, we use cleaning with sea sand and subsequently with ethanol as a standard procedure. Jeung Gon Kim enquired: Stainless steel is the most popular material for mechanochemistry. However, there are a variety of SUS of very different properties. The most popular SUS is SUS304 which is not durable enough for ball milling reactions based on my experiences. Can you share your knowledge about how to choose the right SUS for ball milling? Tomislav Friˇ sˇ ci´ canswered: We typically go for hardest available materials –I believe that the milling jars designed by Form-Tech Scientic follow the same design, whereas other manufacturers (in my practical experience) provide also soer materials. However, we are these days looking at resolving these issues through investigating media-free methods, such as SpeedMixing, 1 accelerated ageing 2 or resonant acoustic mixing (RAM). 3 1 Y. Teoh, G. Ayoub, I. Huski´ c, H. M. Titi, C. W. Nickels, B. Herrmann and T. Friˇ sˇ ci´ c, Angew. Chem., Int. Ed., 2022, 61, e202206293, DOI: 10.1002/anie.202206293. 2 I. Huski´ c, C. B. Lennox and T. Friˇ sˇ ci´ c, Green Chem., 2020, 22, 5881–5901, DOI: 10.1039/ d0gc02264k. 3 L. Gonnet, C. B. Lennox, J.-L. Do, I. Malvestiti, S. G. Koenig, K. Nagapudi and T. Friˇ sˇ ci´ c, Angew. Chem., Int. Ed., 2022, 61, e202115030, DOI: 10.1002/anie.202115030. Richard G. Blair responded: There is a need to minimize media wear and maximize impact energy. The best way to assess this is through measuring the coefficient of restitution of the media of choice on the material for the vial. This can be easily measured with a high speed camera. Some cell phone cameras can take video at 1000 fps and higher. 400 series stainless steels offer a compromise between the need for corrosion resistance and hardness. However, they need to be properly heat treated to achieve optimal properties. 440C is oen chosen as it is a commonly available alloy that can be heat treated to a very high level of hardness (Rockwell C60 –which is about as hard as you can get in a steel). For comparison Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 165 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
304 steels are much soer (B85) resulting in signicant peening and loss of energy to vial deformation. 316 steel is slightly harder (B95). Some chemical inertness is sacriced when using a 400 series steel. However, I have found that in the absence of water these steels can hold up to very aggressive reagents –such as iodine and liquid bromine. James Mack replied: As Richard Blair addressed, need to use a stainless steel source that can be hardened. Type 440C is the one we have found to be best. Sharmarke Mohamed continued discussion of the paper by Carsten Bolm: With reference to the paper by Prof. Bolm, I can see that the argon (Ar) environment for the ball milling reaction is achieved by evacuating the air inside the milling jar and ushing it with Ar inside a glovebox several times. I am assuming the glovebox was only used to evacuate the air inside the jar and that the actual milling equipment is being used outside the glovebox? Can you comment on whether this method is a reliable approach for performing ball milling reactions under an inert atmosphere? Have you tried this with other reactions and if so, how are the reported yields? It is of course very convenient to just ush out the air inside the milling jar inside a glove box and replace the air with an inert gas. But this assumes that the inert gas inside the jar does not leak over time during the ball milling operation. Carsten Bolm answered: That is a very good point. However, we have already applied this strategy (of lling the jars in the glove box under inert gas and performing the milling outside) several times, and even when working with very sensitive compounds there was no obvious problem. Two points might be of relevance here: rst, our vials are rather gas-tight, and leaking –in and out –is only a minor issue, and second, mechanochemical reactions (as also nicely demonstrated by Ito, Kubota and co-workers) are less airand moisture-sensitive than analogous ones performed under standard solution-phase conditions. Although not relevant here I wish to add that we very frequently perform reactions with gases (such as CO 2 ) with vials having inand outlets, and also there, the use of alternative atmospheres is no problem at all. Stuart L. James remarked: I think this work points to an interesting future in which the milling media are not just passive and inert, but actively get involved in the reaction. This is a way in which mechanochemistry could differentiate from conventional synthesis. Matej Bal´ aˇ zcontinued the general discussion: It seems to me that organic mechanochemistry papers are being published in high-impact factor (IF) journals. Do you share the same view? If yes, do you have any thoughts on why papers on inorganic mechanochemistry (which is by the way the precursor of organic mechanochemistry) are not so successful? Tomislav Friˇ sˇ ci´ creplied: I am not sure if division across inorganic or organic chemistry is of relevance; most journals perceived to be of high impact are intended for publication of results regardless of a particular discipline. The distribution of papers across journals, I would believe, depends on the author's Faraday Discussions Discussions 166 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
choice and selection of topics, which sometimes transcend organic or inorganic chemistry, such as nanoparticle systems, MOFs, hybrid perovskite materials, supramolecular materials (such as cocrystals) etc. Elena Boldyreva answered: The IF of a journal reects the number of interested readers of the journal, not of a specic paper. The IFs of organic and coordination chemistry journals are in general higher than the IFs of chemical engineering, materials science, or mining journals. If one looks at the citations and downloads of individual papers, one can nd also very “successful”inorganic mechanochemistry papers published. Another reason, as I see it, is the organic chemistry community members are better in promoting their work. As a more “mature” eld, inorganic mechanochemistry tends to be more “modest”in presenting results, not claiming extraordinary “novelty”, not caring about attractive titles, etc. Rafael A. Hernandez R. responded: No, I do not agree. I have encountered papers in inorganic chemistry that are published in high IF journals. I will have to search in more detail for the applications of these inorganic compounds in different elds. Duncan L. Browne opened discussion of the paper by Koji Kubota: For the reactions where PTFE was added, was there any temperature monitoring of those reactions? Perhaps the heat generated from polymer motion is heating the reaction mixture and supplementing the mechanical energy with thermal energy. Is there an observable temperature change when comparing reactions with and without PTFE? I appreciate this is somewhat difficult when the reaction is also being heated externally. Koji Kubota answered: Thank you very much for the question. There was no observable temperature change during the reaction in the presence of PTFE, suggesting that the heat generated from the polymer motion may not be the reason for the observed acceleration effect. Jeung Gon Kim remarked: In the paper (https://doi.org/10.1039/d2fd00121g), the temperature, 120 °C, was crucial for reactivity. I think it is closely related to polymer morphology. High molecular weight PTFE has a glass transition around 110–120 °C, thus chains could move more freely, then could help mixing. Koji Kubota responded: Thank you very much for the suggestion. We agree that polymer morphology may be the reason for the acceleration effect by the addition of PTFE that was only observed at high temperature. We will carry out additional experiments to check such possibility. Carsten Bolm enquired: In your cross-coupling system, you used a highly uorinated polymer as activator. Have low molecular weight compounds with a high uorine content the same effect? Koji Kubota replied: Thank you very much for the question. We carried out some reactions in the presence of uorinated small molecules, but no acceleration effect was observed. Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 167 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
Carsten Bolm opened discussion of the paper by Fr´ ed´ eric Lamaty: What was the temperature in the cross-coupling by C–H-bond activation? Fr´ ed´ eric Lamaty responded: We tried to adapt the heating system developed by Prof. Ito and Dr Kubota. 1 The heat gun was set to a temperature of 200 °C. At the end of the reaction the temperature inside was measured by IR aer opening the reactor, with a value of 92 °C. 1 T. Seo, N. Toyoshima, K. Kubota and H. Ito, J. Am. Chem. Soc., 2021, 143, 6165–6175. Richard G. Blair continued discussion of the paper by Koji Kubota: Have you looked at uorine-containing oils or oligomers such as the Krytox line of oils? Additionally, small particle size PTFE is highly toxic, is there concern about the toxicity of the reaction byproducts. Koji Kubota replied: Thank you very much for the question and the suggestion. We haven't used such uorine-containing oils as additives for mechanochemical cross-coupling. We honestly didn't know that small particle size PTFE is so toxic. Since PTFE is insoluble in common organic solvents, products and by-products can be easily separated from PTFE. Lars Borchardt enquired: This is fantastic work. You are using Pd salts in a steel (Fe) vessel; since Pd is more noble than Fe it potentially can be reduced (redox chemistry) and thus coated/deposited on the vessel wall. Do you observe any of such phenomena e.g. detect Pd at the milling vessel? Koji Kubota responded: Thank you very much for the question. Such phenomena would be possible but we have never observed it. Audrey Moores questioned: Did you see an effect of polymer type? You can derive rheological metrics from different polymers and see if mechanical effects can be called for; do you see an effect of MW in PTFE? Koji Kubota replied: Thank you very much for the question. Unfortunately, we haven't checked an effect of MW in PTFE. A more systematic study will be carried out to elucidate the acceleration mechanism. Francesco Puccetti asked: Polymers can degrade under mechanical forces, for example by chain breakage and recombination. Under your milling conditions, is there a loss of uorine from the PTFE polymer which could help the reaction to proceed, along with the CsF already added? Did you check the chemistry of the polymer aerwards? Koji Kubota responded: Thank you very much for the question. That's a very interesting idea, but unfortunately we did not check whether uorine species are generated during the reaction. We'll explore such possibility as a follow-up project. Faraday Discussions Discussions 168 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
Qian Yu continued discussion of the paper by Fr´ ed´ eric Lamaty: Is there any difference in sample synthesis without solvent and with liquid? For example in the surface structure of the samples? Are liquids added in the experiments? Fr´ ed´ eric Lamaty answered: In the Faraday Discussions publication (https:// doi.org/10.1039/d2fd00096b), experiments are initially carried out in a total absence of solvent. Some liquid (or sometimes solid) additives are used to improve conversion and yields. We did not investigate the surface of the structure thus obtained. Carsten Bolm asked: The way sydnones are depicted, they have a signicant charge distribution. Is that effect real, and how strong is their binding to metals? Fr´ ed´ eric Lamaty replied: In 2019, 1 we tried to rationalize data from the literature and it seems that studies based on X-ray diffraction analysis, IR measurements and electronic density calculations demonstrate that (i) the exocyclic C–Obondhas indeed a double bond character, (ii) the pelectrons are unequally delocalized on the sydnone ring, and (iii) the N2–N3 and N3–C4 bonds have partial double bond character. With this representation, the exocyclic oxygen displays a partial negative charge of −0.35. Bond lengths between this oxygen and the metal in metal complexes (with a modied sydnone ligand bearing an exocyclic nitrogen), are very close to the ones obtained with salen complexes. 1 X. Bantreil, N. P´ etry and F. Lamaty, Dalton Trans., 2019, 48, 15753, DOI: 10.1039/ c9dt03115d. Jamie Leitch continued discussion of the paper by Koji Kubota: You have been using the heat gun approach for some time now to conduct milling reactions at elevated temperatures. As mills cannot be very reliable, have you seen increased heat stress and malfunction over the years? Furthermore, do you alternate the heating between the 2 mill arms in subsequent experiments? E.g. in experiment A do you heat the le-hand milling arm, and in experiment B the right hand arm? Or always the same arm? Koji Kubota responded: Thank you very much for the question. We have never seen a case where the ball mill broke during the heating process. We have used both arms for heated ball milling reactions. Lucia Maini asked: The reactions described in the paper (https://doi.org/ 10.1039/d2fd00121g) take place at high temperature. Are there any phase transitions of your reagents that could increase their reactivity? Do your reactants show a high thermal expansion which could improve their reactivity? Koji Kubota replied: Thank you very much for the question. We have observed that, in some cases, melting of solid reactants under heated ball-milling conditions can enhance reactivity. But this is not the case in all heated mechanochemical reactions. Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 169 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
James Mack enquired: All of the molecules you are using have appendages on them which helps to increase solubility, have you tried polyaromatic hydrocarbons without appendages? Do they work as well? Koji Kubota responded: Thank you very much for the question. Of course, we have tried the reactions with polyaromatic hydrocarbons without bulky alkyl substituents. The reactions looked like they worked well, but the extremely low solubility of the product prevented the purication and characterization. So, we decided to focus only on substrates with bulky alkyl substituents to increase the solubility of the products. Jeung Gon Kim queried: You addressed that the formation of amorphous phase is a key to reactivity. Did you ever monitor a phase transition of your poorly soluble substrates? DSC or PXRD would give you evidence. Koji Kubota replied: Thank you very much for the question. We carried out PXRD analysis of the crude reaction mixtures and observed that the signals became much broader aer the reaction, suggesting that PTFE could weaken intermolecular interactions between the solid substrates and promote efficient cross-coupling. Viktor Balema asked: Did you try milling then heating as an alternative for hot milling? This may work in an interesting way. Koji Kubota responded: Thank you very much for the question. We checked such a possibility. The ball milling of the reaction mixture was carried out at room temperature and then the jar was placed in an oven at 120 °C. We found that no reaction took place, conrming that high-temperature ball milling is crucial for the reaction. We haven't tried cryo-milling for the reaction. Cecilia Fiore continued discussion of the paper by Fr´ ed´ eric Lamaty: General topic: contamination by metals aer ball milling reactions. When you get your product, what do you do as a rst thing? Do you purify your mixture (ltration, chromatography, etc.) or do you directly take NMR? Is there a loss of material during the purication process? Fr´ ed´ eric Lamaty replied: To evaluate the conversion of an organic reaction we use HP liquid chromatography. In any case (not only reactions carried out by ballmilling), we always lter the sample on a PTFE lter. Less oen, 1 H NMR is used and indeed in some cases contaminants such as iron (if stainless steel jars or balls are used) may hamper the quality of the spectrum. Hence we lter either on a cotton pad (usually this is enough to remove particles) or PTFE lter. Regarding the nal product, usually they have been ltered at some point, precipitated, recrystallized or, in the last resort, puried by chromatography on silica gel. These operations remove most of the impurities arising from the milling actions. Lamis El Wenni asked: Is the iron contamination from the mill? Does the Zr ball also contaminate? Faraday Discussions Discussions 170 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
Fr´ ed´ eric Lamaty answered: Any jar or balls, from any material, will contaminate the sample. Abrasion is inevitable. It is noteworthy that the level of contamination depends on the choice of the material of the jar/material of the balls when different materials are used. We evaluated in 2015 contamination of an amidation product obtained by milling in various jars with various balls (stainless steel, ZrO 2 , PTFE, agate). 1 Interestingly, new stainless steel jars release a large amount of contaminants. 1 T.-X. M´ etro, J. Bonnamour, T. Reidon, A. Duprez, J. Sarpoulet, J. Martinez and F. Lamaty, Chem.–Eur. J., 2015, 21, 12787, DOI: 10.1002/chem.201501325. Sven Gr¨ atz enquired: In mechanochemistry in general but for the synthesis of active pharmaceutical ingredients (APIs) in particular, referees are overly strict when it comes to abrasion. How do you deal with this situation and can you give a recommendation regarding a best practice to detect and declare abrasion in API synthesis? Fr´ ed´ eric Lamaty responded: See the two previous replies. The best way for evaluation of metallic contaminants in APIs remains (as for classical synthesis) ICP-MS. 1 1 T.-X. M´ etro, J. Bonnamour, T. Reidon, A. Duprez, J. Sarpoulet, J. Martinez and F. Lamaty, Chem.–Eur. J., 2015, 21, 12787, DOI: 10.1002/chem.201501325. Matej Bal´ aˇ zcontinued the general discussion: In inorganic mechanochemistry, the desired phase is oen not obtained directly aer milling, but a subsequent thermal treatment is necessary. What about applying such an approach for organic mechanochemistry? Tomislav Friˇ sˇ ci´ cresponded: I would suggest that different mechanochemical activation methodologies should be equally applicable across a wide range of materials, from harder ionic solids to soer organic materials and supramolecular complexes. Levels of mechanical activation and, for example, temperatures of annealing would need to be modied, but I believe the same concepts are valid across diverse chemistries. Elena Boldyreva answered: In my lecture I have given examples of how polymorphic transitions in organic crystals occurring on storage or on heating can be triggered, facilitated by preliminary mechanical treatment. If defects, or a smaller particle size are needed for the start of the transformation, preliminary mechanical activation will work. Lucia Maini replied:Theimportanceoftheprocedureofgrindingandheating is recorded also in the book “Keys of Mercy and Secrets of Wisdom”which is an Arabic translation of texts by Zosimos of Panopolis, a Greco-Egyptian alchemist (third to fourth century CE). One of the text reports: “I told you that the perfection of all the work lies in the cooking and the pounding. Thus if you want the truth, then know that mercury is what transforms natures, they are kneaded in it and with it”. 1 The recent experimental replications of ancient alchemical recipes to extract mercury from cinnabar evidence how the “shake and bake” Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 171 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
procedure was actually a common attempt of the alchemists to manipulate natural substances. 2 1 T. Abt and S. Fuad, The Book of the Keys of the Work by Zosimos of Panopolis, Zurich, 2016, p. 103. 2 M. Marchini, M. Gandol, L. Maini, L. Raggetti and M. Martelli, Exploring the ancient chemistry of mercury, Proc. Natl. Acad. Sci. U. S. A., 2022, 119(24), DOI: 10.1073/ PNAS.2123171119. Lamis El Wenni continued discussion of the paper by Fr´ ed´ eric Lamaty: Have you used anything other than a vibrating ball mill? Does it work well, any preference of 1 ball mill over the other? Fr´ ed´ eric Lamaty responded: In a general sense: (i) We use a vibrating ball-mill (vbm) to explore the initial feasibility of a transformation under mechanochemical conditions, on limited quantities of starting material. (ii) We generally consider that if the conversion of a reaction is not complete aer 2 h of ball-milling in a vbm, it is preferable to switch to a planetary ball-mill (pbm) which is better adapted to longer reaction times. Of note, the temperature inside the milling jar may rise signicantly compared to the vbm. (iii) Another decision factor for using a pbm is the capacity of the jars, larger than for a vbm. A pbm may be needed for the scaling up of a reaction. Tomislav Friˇ sˇ ci´ ccontinued the general discussion: When discussing how reaction kinetics can be affected by experiment design, we noted that reactions would be severely affected during synchrotron studies if the milling jar was not placed perfectly horizontally. That problem was resolved at DESY using custommade jar holders on the mill that prevent non-horizontal positioning of the jar. Cecilia Fiore commented: Vibrating vs. planetary mill: the reaction may not work in one type but can work well in the other. Lucia Maini responded: I do agree. It quite known that the reactions are inuenced by the frequency, as well as the kind of milling. Lars Borchardt remarked: Tilting the vessel (changing its geometry) drastically inuences the movement of the milling ball and thus the mode and number of collisions. This is rarely investigated in the community but has a huge impact. Richard G. Blair added: You are quite correct. The motion of the mills I use (mostly SPEX 8000 series for day to day work) adds a tilt and provides mixing. Discrete element modeling (DEM) can allow this effect to be visualized. We have modeled MM200 and SPEX motion. A useful measure is produced by binning the impact forces predicted, summing the forces above a certain threshold and normalizing by total number of impacts. This produces a value we call the nonzero force collisions (NZF). We used this method to analyze the process with James Mack at the University of Cincinnati. 1 With one 12 mm ball a SPEX mill has 2.60% NZF and a MM200 has 2.95% with two 12 mm balls. However, the smaller volumes of the Retsch vials facilitate the implementation of smaller reactions. Faraday Discussions Discussions 172 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
Interestingly, if a standard Retsch vial is slightly shortened (by 1 cm) the NZF for a two-ball implementation increases to 7.08%. 1 K. S. McKissic, J. T. Caruso, R. G. Blair and J. Mack, Green Chem., 2014, 16, 1628–1632, DOI: 10.1039/c3gc41496e. James Mack continued discussion of the paper by Koji Kubota: In solution people normally stir the ask and start the heating, so the reaction is happening on the way to heating, when you do these reactions do you heat the reaction then mill it or mill it while you start to heating? Koji Kubota responded: This is a very interesting question. Unfortunately we have never tried the mechanochemical reactions via a stepwise method involving heating then milling at room temperature. We guess that heating and milling should apply to amixtureatthesametimetorealizeefficient cross-coupling of insoluble substrates becausetheformationofanamorphousphaseisakeytoachievethehighefficiency. We'll check the suggested procedure to clarify this hypothesis. Stipe Lukin continued the general discussion: Regarding the high-temperature mechanochemical organic reactions, could it be that the inuence of temperature is mainly dominated by the fact that it facilitates melting and that organic reactions preferable occur in melt? Could this explain the increase in the reaction rates in some cases? In the context of milling, if the reaction predominantly happens in a melt, what would be the inuence of milling (for example, changing the frequency of milling)? Could RAM help to resolve the inuence of ball impacts in an example of some organic synthesis in a ball mill vs. RAM, at high temperature, and give additional information on the inuence of melting? Tomislav Friˇ sˇ ci´ creplied: Melting is one form of mobilising molecules or, more generally, reaction substances. Surface amorphisation, surface diffusion (as in the classical work of Rastogi) 1–3 and other effects might be more prominent at high temperatures. Whereas melting can help, we have also seen cases where liquefaction of reaction mixture hinders reactivity. So, melting could be a good guideline, but we do not think it's always the determining factor. I believe RAM is an excellent opportunity to simplify the picture by removing the mental image of a ball impacting a material, in that way enabling us to focus more on the particle– particle interactions. There seems to be a lot of focus on understanding what is the ball actually doing during impact –we are trying to circumvent that question and focus on what happens upon dynamic contact of particles. 1. R. P. Rastogi, P. S. Bassi and S. L. Chadha, J. Phys. Chem., 1963, 67, 2569–2573, DOI: 10.1021/j100806a016. 2. R. P. Rastogi and N. B. Singh, J. Phys. Chem., 1968, 72, 4446–4449, DOI: 10.1021/ j100859a013. 3. R. P. Rastogi and N. B. Singh, J. Phys. Chem., 1966, 70, 3315–3324. DOI: 10.1021/ j100882a047. Elena Boldyreva responded: Temperature can affect mechanochemical reactions if high, and also if low (cryomilling). The effects of heating can be related to melting, sublimation, polymorphic transitions induced by temperature, and also changes in plasticity. High temperature can be also bad for mechanochemistry, if Discussions Faraday Discussions Thisjournalis©TheRoyalSocietyofChemistry2023 Faraday Discuss.,2023,241,150–177 | 173 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online
defects that are needed are annealed, or particles are no longer fragile and their size cannot be reduced so easily. Amorphous state can crystallize on heating, also affecting the reaction. Hydrothermal conditions can be created on milling. 1 The effects of cooling are also very well documented. They can be related to making solids fragile, to glass transitions, 2 to freezing of water/organic solvents, sometimes forming clathrates, to changes in rheology, etc. A possibility that a polymorphic transition induced on cooling makes it possible for another polymorphic transition by mechanical treatment has been also documented. 3 Comparing RAM and ball milling is in fact a very good idea for achieving a better understanding of mechanochemical processes. We tried to move in this direction. 4 In this paper we also discuss the possible role of the frequency of mixing in the RAM-induced processes. 1 V. V. Boldyrev, Hydrothermal reactions under mechanochemical action, Powder Technol., 2002, 122(2–3), 247–254. 2 V. Caron, J. F. Willart, F. Danede and M. Descamps, The implication of the glass transition in the formation of trehalose/mannitol molecular alloys by ball milling, Solid State Commun., 2007, 144(7–8), 288–292. 3 T. N. Drebushchak, A. A. Ogienko and E. V. Boldyreva, “Hedvall effect”in cryogrinding of molecular crystals. A case study of a polymorphic transition in chlorpropamide, CrystEngComm, 2011, 13(13), 4405–4410, DOI: 10.1039/c1ce05189j. 4 A. A. L. Michalchuk, K. S. Hope, S. R. Kennedy, M. V. Blanco, E. V. Boldyreva and C. R. Pulham, Ball-free mechanochemistry: in situ real-time monitoring of pharmaceutical cocrystal formation by resonant acoustic mixing, Chem. Commun., 2018, 54(32), 4033– 4036, DOI: 10.1039/c8cc02187b. Stuart L. James answered: This seems quite possible. Also worth considering is that ball milling can be very effective at mixing, i.e. bringing reactants into contact, but if the reaction itself has an inherently high activation energy then mixing alone will not be enough to cause a reaction. In those cases heating is also needed. Carsten Bolm continued discussion of the paper by Koji Kubota: Besides the uorinated polymer you also added water to the reaction system. What happened to the boronic acid under these conditions in the mill? Koji Kubota replied: Thank you very much for the question. We observed that the reaction without water additive provided signicantly decreased yields. We assume that water can help to improve the mixing efficiency of the inorganic bases under ball-milling conditions. In addition, water may also help to activate the boronic acid, but we did not have experimental evidence. Audrey Moores remarked: B NMR (solid state potentially) could help with the previous question from Carsten Bolm. Koji Kubota responded: Thank you very much for the suggestion. We'll de- nitely check B NMR to understand the role of the water additive. Deniz Karabiyikli asked: Regarding your previous paper in ACS Sustainable Chemistry & Engineering, 1 you have used several sizes of grinding balls in your reactions; 5 mm grinding balls for your “proof of concept”and later 10 mm ones to be precise. Could you please develop the effect of the difference in size of the Faraday Discussions Discussions 174 |Faraday Discuss.,2023,241,150–177 This journal is © The Royal Society of Chemistry 2023 Published on 15 December 2022. Downloaded by Bundesanstalt fuer Materialforschung und -pruefung on 10/31/2025 12:40:16 PM. View Article Online