Inspired by Jyllian Kemsley's article on mechanochemistry, I decided to take a look at the august pages of Organic Process Research and Development to see if there are any examples of it on industrial scale. From mentor-by-literature Neal Anderson [1] in a review on continuous processing:
Here's an example of a Sukuzi reaction being run in a ball mill by Schneider et al. [2]:
[1] Anderson, N.G. "Practical Use of Continuous Processing in Developing and Scaling Up Laboratory Processes." Org. Process Res. Dev., 2001, 613–621.
[2] Schneider, F.; Stolle, A.; Ondruschka, B.; Hopf, H. "The Suzuki−Miyaura Reaction under Mechanochemical Conditions." Org. Process Res. Dev., 2009, 13, 44–48.
Mechanochemistry has been used for the solvent-free preparation of BH3 for the semiconductor industry. Such ultrahigh-intensity grinding can lead to internal temperatures above 500 °C, and vibratory ball mills were used for the solvent-free preparation of calixarenes.
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| Planetary Micro Mill model “Pulverisette 7” (classic line) (Fritsch GmbH) |
KF-Al2O3 (5 g, 32 wt % of KF), 4-bromoacetophenone (2, 5 mmol, 1.106 g), phenylboronic acid (1, 6.19 mmol, 0.755 g), Pd(OAc)2 (0.18 mmol, 3.56 mol % 0.04 g) were added to the grinding beaker (volume: 45 mL) together with an adequate number of milling balls and placed inside the Planetary Micro Mill model “Pulverisette 7” (Fritsch GmbH). Another grinding beaker filled with a similar batch was mounted on the opposite position of the rotating disc. The mixtures were subsequently milled with the respective rpm and time. The crude product was immediately extracted with 2 mL of deionized water and 3 mL of ethyl acetate.From their conclusions:
When carrying out the Suzuki-Miyaura reaction with high rpm at adequate reaction times and grinding material one can obtain quantitative yields. The following order of the investigated parameters regarding their positive influence on the formation of 3 [CJ: the Suzuki product] can be derived : rpm > milling time > size of milling balls > number of milling balls > grinding material.So it doesn't appear that there are any examples on kilogram-scale as of yet that I've found -- I'm sure I'll find an example soon enough!
[1] Anderson, N.G. "Practical Use of Continuous Processing in Developing and Scaling Up Laboratory Processes." Org. Process Res. Dev., 2001, 613–621.
[2] Schneider, F.; Stolle, A.; Ondruschka, B.; Hopf, H. "The Suzuki−Miyaura Reaction under Mechanochemical Conditions." Org. Process Res. Dev., 2009, 13, 44–48.
Check out the Chemical Society Reviews manuscript referenced in the C&E News article.
ReplyDeleteJames, S.L., C.J. Adams, C. Bolm, D. Braga, P. Collier, T. Friscic, F. Grepioni, K.D.M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L. Maini, A.G. Orpen, I.P. Parkin, W.C. Shearouse, J.W. Steed, and D.C. Waddell, Mechanochemistry: opportunities for new and cleaner synthesis. Chemical Society Reviews, 2012. 41(1).
"Most of the synthesis described in the above sections has been done on laboratory scales ranging from a few hundred milligrams up to a few grams. Whilst milling equipment for much larger scale work is widely available and used in bulk scale materials processing,6a the issue of scalability in mechanosynthesis has not yet been broadly addressed, and indeed a common perception is that there are difficulties in scaling up such mechanochemistry. Therefore, the clear recent demonstration of production-scale (20–50 kg) synthesis of drug/ carrier composites by Vectorpharma Spa described in Section 2, for example, is therefore very noteworthy and encouraging. In addition, the recent report of continuous flow mechanochemistry (a cocrystallization) in a twin-screw extruder points to interesting new directions for scalable approaches, which do not necessarily have to based on ball milling."
As someone keenly interested in performing reactions at increased scale, I am aware of the dearth of publications regarding large (kg+) scale mechanochemical reactions. My group has performed cellulose hydrolysis reactions on the kilogram scale.
http://pubs.rsc.org/en/Content/ArticleLanding/2010/GC/b923079c
Its a fairly simple reaction.
I wonder is some of it might be due to the simplicity of the reaction and protection of intellectual property. A solvent free reaction that produces a valuable product would be useful as a trade secret and kept from the literature. I suspect some companies are performing large scale mechanochemical reactions since Union Process has produced custom mills for reactive milling.
"For this application of dry reactive milling of organic compounds, Union Process modified its typical design to specifically meet the customer's requirements. "
http://www.unionprocess.com/news2007-05b.html