Solid-state milling has emerged as an alternative, sustainable approach for preparing virtually all classes of compounds and materials. In situ reaction monitoring is essential to understanding the kinetics and mechanisms of these reactions, but it has proved difficult to use standard analytical techniques to analyze the contents of the closed, rapidly moving reaction chamber (jar). Monitoring by Raman spectroscopy is an attractive choice, because it allows uninterrupted data collection from the outside of a translucent milling jar. It complements the already established in situ monitoring based on powder X-ray diffraction, which has limited accessibility to the wider research community, because it requires a synchrotron X-ray source. The Raman spectroscopy monitoring setup used in this protocol consists of an affordable, small portable spectrometer, a laser source and a Raman probe. Translucent reaction jars, most commonly made from a plastic material, enable interaction of the laser beam with the solid sample residing inside the closed reaction jar and collection of Raman-scattered photons while the ball mill is in operation. Acquired Raman spectra are analyzed using commercial or open-source software for data analysis (e.g., MATLAB, Octave, Python, R). Plotting the Raman spectra versus time enables qualitative analysis of reaction paths. This is demonstrated for an example reaction: the formation in the solid state of a cocrystal between nicotinamide and salicylic acid. A more rigorous data analysis can be achieved using multivariate analysis.
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We thank the Ruđer Bošković Institute for financial support and our colleagues at the fine-mechanics workshop for their continuous help. The Croatian Science Foundation supports S.L. We thank the reviewers for their constructive critiques and suggestions to improve our manuscript. Part of this work was supported by the COST Action CA18112—Mechanochemistry for Sustainable Industry and by the Croatian Science Foundation (IP-2020-02-1419).
I.H. and K.U. are shareholders in InSolido Technologies (Croatia).
Peer review information Nature Protocols thanks Ana Belenguer, Nicholas Leadbeater and Adam Michalchuk for their contribution to the peer review of this work.
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Key references using this protocol
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ATR-IR of reactants na, sal and resulting na:sal cocrystal.
Extended Data Fig. 2 Rietveld refinement of PXRD pattern (X-ray source: CuKα) of the resulting na:sal cocrystal after 60 min milling.
CSD code of the used structural model: SODDOF. Color scheme: blue—experimental PXRD pattern, red—refinement, gray—difference.
Lines indicate the Raman bands of interest for qualitative monitoring of the reaction progress.
The plot of in situ collected Raman spectra stored in variable SpectraAll before spike corrections.
The plot of in situ collected Raman spectra stored in variable SpectraAll after spike corrections.
The plot of in situ collected Raman spectra stored in variable Spectra after the subtraction of the PMMA contribution.
Extended Data Fig. 7 The plot of in situ collected Raman spectra stored in variable sp after defining spectral and temporal range.
Note that spectral range is now in the range from first_wnmb up to last_wnmb.
a,b, Examples of the baseline correction of selected in situ Raman spectra at 1 min (a) and 50 min (b) into milling experiment. Color code: blue—experimental Raman spectrum, orange—baseline estimation.
The plot of in situ collected Raman spectra stored in variable Nsp after the baseline correction.
Extended Data Fig. 10 The plot of in situ collected Raman spectra stored in variable N1sp after normalization.
Note the different scale on y-axis when compared with the nonnormalized spectra in Extended Data Fig. 9.
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Lukin, S., Užarević, K. & Halasz, I. Raman spectroscopy for real-time and in situ monitoring of mechanochemical milling reactions. Nat Protoc 16, 3492–3521 (2021). https://doi.org/10.1038/s41596-021-00545-x