Real-time and in situ monitoring of mechanochemical milling reactions

  • A Corrigendum to this article was published on 24 January 2013


Chemical and structural transformations have long been carried out by milling. Such mechanochemical steps are now ubiquitous in a number of industries (such as the pharmaceutical, chemical and metallurgical industries), and are emerging as excellent environmentally friendly alternatives to solution-based syntheses. However, mechanochemical transformations are typically difficult to monitor in real time, which leaves a large gap in the mechanistic understanding required for their development. We now report the real-time study of mechanochemical transformations in a ball mill by means of in situ diffraction of high-energy synchrotron X-rays. Focusing on the mechanosynthesis of metal–organic frameworks, we have directly monitored reaction profiles, the formation of intermediates, and interconversions of framework topologies. Our results reveal that mechanochemistry is highly dynamic, with reaction rates comparable to or greater than those in solution. The technique also enabled us to probe directly how catalytic additives recently introduced in the mechanosynthesis of metal–organic frameworks, such as organic liquids or ionic species, change the reactivity pathways and kinetics.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The chemical reaction and participating species.
Figure 2: Time-resolved monitoring of mechanochemical synthesis of the ZIF-8 framework from a mixture of ZnO and HMeIm ligand.
Figure 3: Mechanochemical conversions involving the HEtIm ligand depending on the amount of added liquid.
Figure 4: Mechanochemical reactions of ZnO and HIm in the presence of ethanol.
Figure 5: Mechanochemical reactions of ZnO and HIm in the presence of DMF.

Change history

  • 08 January 2013

    In the version of this Article originally published, EPSRC and J. K. M. Sanders should have been included in the Acknowledgements section; this has now been corrected in the HTML and PDF versions of this Article.


  1. 1

    Takacs, L. Quicksilver from cinnabar: the first documented mechanochemical reaction? J. Minerals Metals Mater. Soc. 52, 12–13 (2000).

    CAS  Article  Google Scholar 

  2. 2

    James, S. L. et al. Mechanochemistry: opportunities for new and cleaner synthesis. Chem. Soc. Rev. 41, 413–447 (2012).

    CAS  Article  Google Scholar 

  3. 3

    Baláž, P. & Dutková, E. Fine milling in applied mechanochemistry. Miner. Eng. 22, 681–694 (2009).

    Article  Google Scholar 

  4. 4

    Janot, R. & Guérard, D. Ball-milling in liquid media: applications to the preparation of anodic materials for lithium-ion batteries. Prog. Mater. Sci. 50, 1–92 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Bruckmann, A., Krebs, A. & Bolm, C. Organocatalytic reactions: effects of ball milling, microwave and ultrasound irradiation. Green Chem. 10, 1131–1141 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Stolle, A., Szuppa, T., Leonhardt, S. E. S. & Ondruschka, B. Ball milling in organic synthesis: solutions and challenges. Chem. Soc. Rev. 40, 2317–2329 (2011).

    CAS  Article  Google Scholar 

  7. 7

    Lazuen-Garay, A., Pichon, A. & James, S. L. Solvent-free synthesis of metal complexes. Chem. Soc. Rev. 36, 846–855 (2007).

    Article  Google Scholar 

  8. 8

    Adams, C. J., Haddow, M. F., Lusi, M. & Orpen, A. G. Crystal engineering of lattice metrics of perhalometallate salts and MOFs. Proc. Natl Acad. Sci. USA 107, 16033–16038 (2010).

    CAS  Article  Google Scholar 

  9. 9

    Beldon, P. J. et al. Rapid room-temperature synthesis of zeolitic imidazolate frameworks by using mechanochemistry. Angew. Chem. Int. Ed. 49, 9640–9643 (2010).

    CAS  Article  Google Scholar 

  10. 10

    André, V. M. et al. Mechanosynthesis of the metallodrug bismuth subsalicylate from Bi2O3 and structure of bismuth salicylate without auxiliary organic ligands. Angew. Chem. Int. Ed. 50, 7858–7861 (2011).

    Article  Google Scholar 

  11. 11

    Baláž, P. & Dutková, E. Mechanochemistry of sulphides, from minerals to advanced nanocrystalline materials. J. Therm. Anal. Cal. 90, 85–92 (2007).

    Article  Google Scholar 

  12. 12

    Rodríguez, B., Bruckmann, A., Rantanen, T. & Bolm, C. Solvent-free carbon–carbon bond formations in ball mills. Adv. Synth. Catal. 349, 2213–2233 (2007).

    Article  Google Scholar 

  13. 13

    Delori, A., Friščić, T. & Jones, W. The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials. CrystEngComm 14, 2350–2362 (2012).

    CAS  Article  Google Scholar 

  14. 14

    Daurio, D., Medina, C., Saw, R., Nagapudi, K. & Alvarez-Núñez, F. Application of twin screw extrusion in the manufacture of cocrystals, part I: four case studies. Pharmaceutics 3, 582–600 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Nguyen, K. L., Friščić, T., Day, G. M., Gladden, L. F. & Jones, W. Nature Mater. 6, 206–209 (2007).

    CAS  Article  Google Scholar 

  16. 16

    Friščić, T. et al. Ion- and liquid-assisted grinding: improved mechanochemical synthesis of metal–organic frameworks reveals salt inclusion and anion templating. Angew. Chem. Int. Ed. 49, 712–715 (2010).

    Article  Google Scholar 

  17. 17

    Friščić, T. & Jones, W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst. Growth Des. 9, 1621–1637 (2009).

    Article  Google Scholar 

  18. 18

    Urakaev, F. Kh. & Boldyrev, V. V. Mechanism and kinetics of mechanochemical processes in comminuting devices 1. Theory. Powder Technol. 107, 93–107 (2000).

    CAS  Article  Google Scholar 

  19. 19

    Gutman, E. M. Mechanochemistry of Materials (Cambridge International Science, 1998).

    Google Scholar 

  20. 20

    Kaupp, G. Solid-state molecular syntheses: complete reactions without auxiliaries based on the new solid-state mechanism. CrystEngComm 5, 117–133 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Rastogi, R. P. & Singh, N. B. Solid-state reactivity of picric acid and substituted hydrocarbons. J. Phys. Chem. 72, 4446–4449 (1968).

    CAS  Article  Google Scholar 

  22. 22

    Rothenberg, G., Downie, A. P., Raston, C. L. & Scott, J. L. Understanding solid/solid organic reactions. J. Am. Chem. Soc. 123, 8701–8708 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Tumanov, I. A., Achkasov, A. F., Boldyreva, E. V. & Boldyrev, V. V. Following the products of mechanochemical synthesis step by step. CrystEngComm 13, 2213 (2011).

    CAS  Article  Google Scholar 

  24. 24

    Takacs, L. Self-sustaining reactions induced by ball milling. Prog. Mater. Sci. 47, 355–414 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Cinčić, D., Friščić, T. & Jones, W. Stepwise mechanism for the mechanochemical synthesis of halogen-bonded cocrystal architectures. J. Am. Chem. Soc. 130, 7524–7525 (2008).

    Article  Google Scholar 

  26. 26

    Štrukil, V. et al. Towards an environmentally-friendly laboratory: dimensionality and reactivity in the mechanosynthesis of metal–organic compounds. Chem. Commun. 46, 9191–9193 (2010).

    Article  Google Scholar 

  27. 27

    Braga, D. et al. Mechanochemical preparation of molecular and supramolecular organometallic materials and coordination networks. J. Chem. Soc. Dalton Trans. 1249–1263 (2006).

  28. 28

    Braga, D., Grepioni, F. & Lampronti, G. I. Supramolecular metathesis: co-former exchange in co-crystals of pyrazine with (R,R)-, (S,S)-, (R,S)- and (S,S/R,R)-tartaric acid. CrystEngComm 13, 3122–3124 (2011).

    CAS  Article  Google Scholar 

  29. 29

    Bowmaker, G. A. et al. Solution and mechanochemical syntheses, and spectroscopic and structural studies in the silver(I) (bi-)carbonate: triphenylphosphine system. J. Chem. Soc. Dalton Trans. 40, 7210–7218 (2011).

    CAS  Article  Google Scholar 

  30. 30

    Ibrahim, A. Y., Forbes, R. T. & Blagden, N. Spontaneous crystal growth of co-crystals: the contribution of particle size reduction and convection mixing of the co-formers. CrystEngComm 13, 1141–1152 (2011).

    CAS  Article  Google Scholar 

  31. 31

    Fujii, K. et al. Direct structure elucidation by powder X-ray diffraction of a metal–organic framework material prepared by solvent-free grinding. Chem. Commun. 46, 7572–7574 (2010).

    CAS  Article  Google Scholar 

  32. 32

    Adams, C. J., Haddow, M. F. & Orpen, A. G. Crystal synthesis of 1,4-phenylenediamine salts and coordination networks. CrystEngComm 13, 4324–4331 (2011).

    CAS  Article  Google Scholar 

  33. 33

    Zhang, J-P., Zhang, Y-B., Lin, J-B. & Chen, X-M. Metal azolate frameworks: from crystal engineering to functional materials. Chem. Rev. 112, 1001–1033 (2012).

    CAS  Article  Google Scholar 

  34. 34

    Friščić, T., Childs, S. L., Rizvi, S. A. A. & Jones, W. Qualitative view of the role of solvent in mechanochemical and sonochemical cocrystal formation: a solubility-based approach for predicting cocrystallisation outcome. CrystEngComm 11, 418–426 (2009).

    Article  Google Scholar 

  35. 35

    Pawley, G. S. Unit-cell refinement from powder diffraction scans. J. Appl. Crystallogr. 14, 357–361 (1981).

    CAS  Article  Google Scholar 

  36. 36

    Venna, S. R., Jasinski, J. B. & Carreon, M. A. Structural evolution of zeolitic imidazolate framework–8. J. Am. Chem. Soc. 132, 18030–18033 (2010).

    CAS  Article  Google Scholar 

  37. 37

    Cravillon, J. et al. Fast nucleation and growth of ZIF-8 nanocrystals monitored by time-resolved in situ small-angle and wide-angle X-ray scattering. Angew. Chem. Int. Ed. 50, 8067–8081 (2011).

    CAS  Article  Google Scholar 

  38. 38

    Huang, X-C., Lin, Y-Y., Zhang, J-P. & Chen, X-M. Ligand-directed strategy for zeolite-type metal–organic frameworks: zinc(II) imidazolates with unusual zeolitic topologies. Angew. Chem. Int. Ed. 45, 1557–1559 (2006).

    CAS  Article  Google Scholar 

  39. 39

    Fernández-Bertrán, J., Castellanos-Serra, L., Yee-Madeira, H. & Reguera, E. Proton transfer in solid state: mechanochemical reactions of imidazole with metallic oxides. J. Solid State Chem. 147, 561–564 (1999).

    Article  Google Scholar 

  40. 40

    Spencer, E. C., Angel, R. J., Ross, N. L., Hanson, B. E. & Howard, J. A. K. Pressure-induced cooperative bond rearrangement in a zinc imidazolate framework: a high-pressure single-crystal X-ray diffraction study. J. Am. Chem. Soc. 131, 4022–4026 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Park, K. S. et al. Exceptional chemical and thermal stability of zeolitic imidazolate frameworks. Proc. Natl Acad. Sci. USA 103, 10186–10191 (2006).

    CAS  Article  Google Scholar 

  42. 42

    Martins, G. A. V. et al. The use of ionic liquids in the synthesis of zinc imidazolate frameworks. J. Chem. Soc. Dalton Trans. 39, 1758–1762 (2010).

    CAS  Article  Google Scholar 

  43. 43

    Bowmaker, G. A., Hanna, J. V., Skelton, B. W. & White, A. H. Solvent-assisted solid-state synthesis: separating the chemical from the mechanical in mechanochemical synthesis. Chem. Commun. 2168–2170 (2009).

  44. 44

    Cumbrera, F. L. & Sánchez-Bajo, F. The use of JMAYK kinetic equation for the analysis of solid-state reactions: critical considerations and recent interpretations. Thermochim. Acta 266, 315–330 (1995).

    CAS  Article  Google Scholar 

  45. 45

    Khawam, A. & Flanagan, D. R. Solid-state kinetic models: basics and mathematical fundamentals. J. Phys. Chem. B 110, 17315–17328 (2006).

    CAS  Article  Google Scholar 

  46. 46

    Williams, G. R. & O'Hare D. O. J. Phys. Chem. B 110, 10619–10629 (2006).

    CAS  Article  Google Scholar 

  47. 47

    Baláž, P. Mechanochemistry in Nanoscience and Minerals Engineering (Springer-Verlag, 2010).

    Google Scholar 

  48. 48

    Wilmer, C. E. et al. Large-scale screening of hypothetical metal–organic frameworks. Nature Chem. 4, 83–89 (2012).

    CAS  Article  Google Scholar 

  49. 49

    Sonneveld, E. J. & Visser, J. W. Automatic collection of powder data from photographs. J. Appl. Crystallogr. 8, 1–7 (1975).

    Article  Google Scholar 

  50. 50

    Hinrichsen, B. Dinnebier, R. E. & Jansen, M. Powder3D: an easy to use program for data reduction and graphical presentation of large numbers of powder diffraction patterns. Z. Kristallogr. 23 (Suppl), 231–236 (2006).

    Article  Google Scholar 

  51. 51

    Rietveld, H. M. A profile refinement for nuclear and magnetic structures. J. Appl. Crystallogr. 2, 65–71 (1969).

    CAS  Article  Google Scholar 

Download references


The authors acknowledge financial support from the Herchel Smith Fund, the British Council/DAAD (grant no. 1377), ESRF Grenoble, NanoDTC, the University of Cambridge, the Ministry of Science, Education and Sports of the Republic of Croatia and EPSRC, as well as a research fellowship (T.F.) and a doctoral fellowship (P.J.B.). McGill University and FQRNT Centre for Green Chemistry and Catalysis are acknowledged for support. The authors thank A.K. Cheetham for comments, W. Jones for support in acquiring the instrumentation and R.C. Nightingale for equipment design and manufacture and J. K. M. Sanders for support. The assistance of A. Kovač and V. Dunjko with graphics preparation is acknowledged.

Author information




The research was organized by T.F., I.H. and R.E.D. Experiments were performed by T.F., I.H., P.J.B., A.M.B., F.A., S.A.J.K. and V.H. Data analysis was performed by I.H., S.A.J.K., T.F., P.J.B. and R.E.D. The manuscript was written by T.F. and I.H., and graphical materials were prepared by I.H., T.F. and P.J.B.

Corresponding author

Correspondence to Tomislav Friščić.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 4570 kb)

Supplementary Movie 1

Supplementary Movie 1 (AVI 19406 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Friščić, T., Halasz, I., Beldon, P. et al. Real-time and in situ monitoring of mechanochemical milling reactions. Nature Chem 5, 66–73 (2013).

Download citation

Further reading