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

Nature Protocols volume 16, pages 3492–3521 (2021)Cite this article

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Abstract

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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Fig. 1: 2D time-resolved Raman spectra of NG cocrystals formation between na and sal.
Fig. 2: Schematic representation of the protocol’s flow.
Fig. 3: Reaction profile obtained by plotting intensities at the peak maximum versus time for NG of na and sal.
Fig. 4: Equipment setup.
Fig. 5: Equipment setup.
Fig. 6: Equipment settings.
Fig. 7: Understanding the results window.
Fig. 8: Subtracting background.
Fig. 9: Equipment setup.
Fig. 10: Changing parameters.
Fig. 11: Used icons on the secondary toolbar highlighted in the OceanView software window.
Fig. 12: Raman spectrum of silicon.
Fig. 13: Adjusting the x-axis.
Fig. 14: Reaction setup.
Fig. 15: Results from an optimization experiment.
Fig. 16: Screenshot—how to use the software.
Fig. 17: Annotation of the GUI for GNU Octave.

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Data availability

The dataset generated during the current study is available in the Supplementary Information and at the GitHub repository (https://github.com/stipe-lukin/Nat_Prot).

Code availability

All the in-house written scripts used for analysis are available in the Supplementary Information and at the GitHub repository (https://github.com/stipe-lukin/Nat_Prot).

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Acknowledgements

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).

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  1. Ruđer Bošković Institute, Zagreb, Croatia

    Stipe Lukin, Krunoslav Užarević & Ivan Halasz

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  1. Stipe Lukin
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  3. Ivan Halasz
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Contributions

The methodology was originally designed and adapted by I.H. and K.U. and further developed by S.L. S.L. performed experiments and script preparation. S.L. wrote and prepared the manuscript with input from I.H. and K.U.

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Correspondence to Stipe Lukin.

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Competing interests

I.H. and K.U. are shareholders in InSolido Technologies (Croatia).

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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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Lukin, S. et al. Chem. Eur. J. 23, 13941–13949 (2017): https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/chem.201702489

Lukin, S. et al. J. Am. Chem. Soc. 141, 1212–1216 (2019): https://pubs.acs.org/doi/10.1021/jacs.8b12149

Gracin, D., Štrukil, V., Friščić, T., Halasz, I. & Užarević, K. Angew. Chem. Int. Ed. 53, 6193-6197 (2014): https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201402334

Lukin, S. et al. Chem. Commun. 54, 13216–13219 (2018): https://pubs.rsc.org/en/content/articlelanding/2018/cc/c8cc07853j#!divAbstract

Bjelopetrović, A. et al. Chem. Eur. J. 24, 10672–10682 (2018): https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/chem.201802403

Extended data

Extended Data Fig. 1

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.

Extended Data Fig. 3 Selected Raman spectra from the monitoring experiment.

Lines indicate the Raman bands of interest for qualitative monitoring of the reaction progress.

Extended Data Fig. 4

The plot of in situ collected Raman spectra stored in variable SpectraAll before spike corrections.

Extended Data Fig. 5

The plot of in situ collected Raman spectra stored in variable SpectraAll after spike corrections.

Extended Data Fig. 6

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.

Extended Data Fig. 8

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.

Extended Data Fig. 9

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.

Supplementary information

Supplementary Information

Supplementary Figs. 1–3.

Reporting Summary

Supplementary Data 1

Experimental Raman spectra and GNU Octave scripts.

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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

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