Raman spectroscopy for real-time and in situ monitoring of mechanochemical milling reactions

Raman spectroscopy is an essential technique of process analytical technologies used in the chemical and biopharmaceutical industry for uninterrupted monitoring of manufacturing processes. Now, it is also a powerful tool for monitoring solid-state milling reactions on vibratory ball mills.

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I remember the first in situ Raman spectroscopy experiment performed by dr. Ivan Halasz, dr. Krunoslav Užarević and dr. Davor Gracin with me, an undergraduate student at the time as a witness. It did not proceed as they wish. There were many issues in collecting the data and adjusting the probe attached to the first thing they found in a small basement laboratory on Ruđer Bošković Insitute. For me, it was pretty fun, although I didn't understand much what is going on and what they were expecting to see.

Fast forward a year or so, and I was in my graduate studies, preparing to start working on my master thesis. Ivan showed me how to start a laser, collect the data and adjust the probe to see the signals from a reaction mixture. We used the old software where if we wanted to collect in situ data, we had to wait until the end of the reaction and then run a Mathematica script wrote by Ivan to plot the data. This took way more time than I am willing to tolerate today. Needless to say, I spent months doing experiments (ball milling and various other stuff like drop crystallization) and constantly thinking about how to improve the current setup. On several occasions, I took the whole instrument with me in my room under the staircases (I heard some people call it a Harry Potter room) where Tomislav Stolar and I proudly reside. The result was that after some programming and googling we could now collect and preprocess the collected spectra in situ, and plotting the data took seconds instead of minutes. I like developing a new technique like this because it forces you to learn stuff that you, as a chemist, were not supposed to primarily learn - programming, computer issues solving skills, etc.

During my PhD, I was lucky enough to try Raman spectroscopy monitoring on various solid-state model systems. There were cocrystallization reactions, synthesis of metal-organic frameworks, organometallic reactions, and purely organic synthesis reactions. I can tell you right now, once you hook on being able to see what's going on during the entire reaction, performing regular ones without monitoring feels like you are missing something important. While I do not know the best way to learn something, I can tell you that learning by making (a lot) mistakes is probably the slowest but the most effective. Because of these mistakes, we learned the best way to collect the data, how to process it, and explained the best practices in the Protocol. Hopefully, it will speed up your learning process when implementing Raman spectroscopy monitoring for your milling reactions.

In the Protocol, you can find out more about milling reactions and in situ monitoring in general, but also what is important to consider when you decide to buy essential equipment. This equipment is made of three main things – a laser, spectrometer, and a Raman probe. You can read more on where to position your probe depending on which mill you have in the laboratory. Lastly, there is a detailed procedure of how to collect the data and process it. We included Octave/MATLAB scripts that are a great starting point for beginners to get themselves acquainted with scripting and matrix data analysis.        

I believe the future will see more and more mechanochemical milling research using Raman spectroscopy monitoring because it is easy to use and can provide valuable insight into milling dynamics. It is not just possible to identify intermediates and reaction pathways qualitatively, but it enables the quantitative assessment and extraction of reaction profiles, kinetic modeling, and thereafter tentative mechanistic modeling. The more of these observations we have, we will gain a deeper understanding of how milling reactions proceed and how to control them. For detailed explanations, I point you to the Protocol, and for any questions, get in touch.

Stipe Lukin

Postdoctoral researcher, Ruđer Bošković Insitute

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