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Complex structures arising from the self-assembly of a simple organic salt


Molecular self-assembly is the spontaneous association of simple molecules into larger and ordered structures1. It is the basis of several natural processes, such as the formation of colloids, crystals, proteins, viruses and double-helical DNA2. Molecular self-assembly has inspired strategies for the rational design of materials with specific chemical and physical properties3, and is one of the most important concepts in supramolecular chemistry. Although molecular self-assembly has been extensively investigated, understanding the rules governing this phenomenon remains challenging. Here we report on a simple hydrochloride salt of fampridine that crystallizes as four different structures, two of which adopt unusual self-assemblies consisting of polyhedral clusters of chloride and pyridinium ions. These two structures represent Frank–Kasper (FK) phases of a small and rigid organic molecule. Although discovered in metal alloys4,5 more than 60 years ago, FK phases have recently been observed in several classes of supramolecular soft matter6,7,8,9,10,11 and in gold nanocrystal superlattices12 and remain the object of recent discoveries13. In these systems, atoms or spherical assemblies of molecules are packed to form polyhedra with coordination numbers 12, 14, 15 or 16. The two FK structures reported here crystallize from a dense liquid phase and show a complexity that is generally not observed in small rigid organic molecules. Investigation of the precursor dense liquid phase by cryogenic electron microscopy reveals the presence of spherical aggregates with sizes ranging between 1.5 and 4.6 nanometres. These structures, together with the experimental procedure used for their preparation, invite interesting speculation about their formation and open different perspectives for the design of organic crystalline materials.

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Fig. 1: Crystal packing and self-assembly of phases 1 and 2.
Fig. 2: Self-assembly in the solid state.
Fig. 3: Self-assembly in the liquid state.

Data availability

Full crystallographic details in CIF format have been deposited in the Cambridge Crystallographic Data Centre database (deposition numbers: phase 1, CCDC 1540139 (unconstrained) and 1540140 (constrained); phase 2, CCDC 1897427; phase 3, CCDC 1540141; phase 4, 1897428). Copies of this information may be obtained free of charge from or Raw single-crystal diffraction data corresponding to the structures of phases 14 have been deposited in the Zenodo repository at the following locations: phase 1,; phase 2,; phase 3,; phase 4, The CCD images (in either Rigaku IMG or Bruker KCD format) have been deposited, along with instrument parameters and all files associated with image processing. This will enable the reader to fully validate these structural models and, for those who wish to investigate alternative approaches to modelling these results or develop them further, it will be possible to do so without having to synthesize the materials and collect diffraction data. NMR results are extensively described in Supplementary Information (section 5), and data are available on request. A selection of relevant cryo-EM images is included in the manuscript (Fig. 3, Extended Data Fig. 6). Further data are available on request.


  1. 1.

    Lehn, J.-M. Supramolecular chemistry—scope and perspectives molecules, supermolecules, and molecular devices (Nobel lecture). Angew. Chem. Int. Ed. 27, 89–112 (1988).

    Article  Google Scholar 

  2. 2.

    Whitesides, G. M., Mathias, J. P. & Seto, C. T. Molecular self-assembly and nanochemistry: a chemical strategy for the synthesis of nanostructures. Science 254, 1312–1319 (1991).

    CAS  Article  ADS  Google Scholar 

  3. 3.

    Lehn, J.-M. Perspectives in supramolecular chemistry—from molecular recognition towards molecular information processing and self-organization. Angew. Chem. Int. Ed. 29, 1304–1319 (1990).

    Article  Google Scholar 

  4. 4.

    Frank, F. C. & Kasper, J. S. Complex alloy structures regarded as sphere packings. I. Definitions and basic principles. Acta Crystallogr. 11, 184–190 (1958).

    CAS  Article  Google Scholar 

  5. 5.

    Frank, F. C. & Kasper, J. S. Complex alloy structures regarded as sphere packings. II. Analysis and classification of representative structures. Acta Crystallogr. 12, 483–499 (1959).

    CAS  Article  Google Scholar 

  6. 6.

    Ungar, G. & Zeng, X. Frank–Kasper, quasicrystalline and related phases in liquid crystals. Soft Matter 1, 95–106 (2005).

    CAS  Article  ADS  Google Scholar 

  7. 7.

    Huang, M. et al. Selective assemblies of giant tetrahedra via precisely controlled positional interactions. Science 348, 424–428 (2015).

    CAS  Article  ADS  Google Scholar 

  8. 8.

    Zhang, J. & Bates, F. S. Dodecagonal quasicrystalline morphology in a poly(styrene-b- isoprene-b-styrene-b-ethylene oxide) tetrablock terpolymer. J. Am. Chem. Soc. 134, 7636–7639 (2012).

    CAS  Article  Google Scholar 

  9. 9.

    Reddy, A. et al. Stable Frank–Kasper phases of self-assembled, soft matter spheres. Proc. Natl Acad. Sci. USA 115, 10233–10238 (2018).

    CAS  Article  ADS  Google Scholar 

  10. 10.

    Lee, S., Bluemle, M. J. & Bates, F. S. Discovery of a Frank–Kasper σ phase in sphere-forming block copolymer melts. Science 330, 349–353 (2010).

    CAS  Article  ADS  Google Scholar 

  11. 11.

    Kim, S. A., Jeong, K.-J., Yethiraj, A. & Mahanthappa, M. K. Low-symmetry sphere packings of simple surfactant micelles induced by ionic sphericity. Proc. Natl Acad. Sci. USA 114, 4072–4077 (2017).

    CAS  Article  Google Scholar 

  12. 12.

    Goodfellow, B. W. et al. Ordered structure rearrangements in heated gold nanocrystal superlattices. Nano Lett. 13, 5710–5714 (2013).

    CAS  Article  ADS  Google Scholar 

  13. 13.

    Su, Z. et al. Identification of a Frank–Kasper Z phase from shape amphiphile self-assembly. Nat. Chem. 11, 899–905 (2019).

    CAS  Article  Google Scholar 

  14. 14.

    Macksasitorn, S., Hu, Y. & Stork, J. R. Homoconjugated 4-aminopyridine salts: influence of anions on network topology. CrystEngComm 15, 1698–1705 (2013).

    CAS  Article  Google Scholar 

  15. 15.

    Montis, R. & Hursthouse, M. B. Crystalline adducts of some substituted salicylic acids with 4-aminopyridine, including hydrates and solvates: contact and separated ionic complexes with diverse supramolecular synthons. CrystEngComm 14, 7466–7478 (2012).

    CAS  Article  Google Scholar 

  16. 16.

    Hursthouse, M. B. et al. Anhydrates and/or hydrates in nitrate, sulphate and phosphate salts of 4-aminopyridine, (4-AP) and 3,4-diaminopyridine (3,4-DAP): the role of the water molecules in the hydrates. CrystEngComm 16, 2205–2219 (2014).

    CAS  Article  Google Scholar 

  17. 17.

    Kukkonen, E., Malinen, H., Haukka, M. & Konu, J. Reactivity of 4-aminopyridine with halogens and interhalogens: weak interactions supported networks of 4-aminopyridine and 4-aminopyridinium. Cryst. Growth Des. 19, 2434–2445 (2019).

    CAS  Article  Google Scholar 

  18. 18.

    Nguyen, A. H. & Molinero, V. Stability and metastability of bromine clathrate polymorphs. J. Phys. Chem. B 117, 6330–6338 (2013).

    CAS  Article  Google Scholar 

  19. 19.

    Taratuta, V. G., Holschbach, A., Thurston, G. M., Blankschtein, D. & Benedek, G. B. Liquid–liquid phase separation of aqueous lysozyme solutions: effects of pH and salt identity. J. Phys. Chem. 94, 2140–2144 (1990).

    CAS  Article  Google Scholar 

  20. 20.

    Deneau, E. & Steele, G. An in-line study of oiling out and crystallization. Org. Process Res. Dev. 9, 943–950 (2005).

    CAS  Article  Google Scholar 

  21. 21.

    Veesler, S., Revalor, E., Bottini, O. & Hoff, C. Crystallization in the presence of a liquid−liquid phase separation. Org. Process Res. Dev. 10, 841–845 (2006).

    CAS  Article  Google Scholar 

  22. 22.

    Bonnett P. E., Carpenter K. J. Dawson S. and Davey R. Solution crystallisation via a submerged liquid–liquid phase boundary: oiling out. Chem. Comm. 6, 698–699 (2003)

    Article  Google Scholar 

  23. 23.

    Ilevbare, G. A. & Taylor, L. S. Liquid–liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: implications for solubility enhancing formulations. Cryst. Growth Des. 13, 1497–1509 (2013).

    CAS  Article  Google Scholar 

  24. 24.

    ten Wolde, P. R. & Frenkel, D. Enhancement of protein crystal nucleation by critical density fluctuations. Science 277, 1975–1978 (1997).

    Article  Google Scholar 

  25. 25.

    Pan, W., Kolomeisky, A. B. & Vekilov, P. G. Nucleation of ordered solid phases of proteins via a disordered high-density state: phenomenological approach. J. Chem. Phys. 122, 174905 (2005).

    Article  ADS  Google Scholar 

  26. 26.

    Gebauer, D. Volkel, A. & Cölfen, H. Stable prenucleation calcium carbonate clusters. Science 322, 1819–1822 (2008).

    CAS  Article  ADS  Google Scholar 

  27. 27.

    Wiedenbeck, E., Kovermann, M., Gebauer, D. & Colfen, H. Liquid metastable precursors of ibuprofen as aqueous nucleation intermediates. Angew. Chem. Int. Ed. 58, 19103 (2019).

    CAS  Article  Google Scholar 

  28. 28.

    Zaccaro, J., Matic, J., Myerson, A. S. & Garetz, B. A. Nonphotochemical, laser-induced nucleation of supersaturated aqueous glycine produces unexpected γ-polymorph. Cryst. Growth Des. 1, 5–8 (2001).

    CAS  Article  Google Scholar 

  29. 29.

    Tsarfati, Y. et al. Crystallization of organic molecules: nonclassical mechanism revealed by direct imaging. ACS Cent. Sci. 4, 1031–1036 (2018).

    CAS  Article  Google Scholar 

  30. 30.

    Ecija, D. et al. Five-vertex Archimedean surface tessellation bylanthanide-directed molecular self-assembly. Proc. Natl Acad. Sci. USA 110, 6678–6681 (2013).

    CAS  Article  ADS  Google Scholar 

  31. 31.

    Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Crystallogr. C 71, 3–8 (2015).

    Article  Google Scholar 

  32. 32.

    Sheldrick, G. M. SHELXT – Integrated space-group and crystal-structure determination. Acta Crystallogr. A 71, 3–8 (2015).

    Article  Google Scholar 

  33. 33.

    Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).

    Article  Google Scholar 

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We thank the UK Engineering and Physical Sciences Research Council for financial support for single-crystal diffraction facilities through funding of the UK National Crystallography Service. R.M. thanks R. Davey (The University of Manchester) for comments and discussions. We thank M. Sanselme (Université de Rouen Normandie) for help with in situ X-ray diffraction measurements. We thank the technological platform “Physico-Chemical Characterization” – PC2 (University of Namur) for providing resources used for this research.

Author information




R.M. defined the protocol for the crystallization of phases 1-4 and performed the initial preparations and crystallizations. R.M., M.B.H. and P.N.H. performed the single-crystal data collections and crystal structure refinements. R.M. and A.D.R. analysed the crystal structures. R.M. and L.F. described structures 1 and 2 as FK phases and produced all the relevant images. L.F. performed the NMR characterization and independently carried out reproducibility crystallization experiments. N.T. characterized phases 1–4 using powder X-ray diffraction. G.C. and A.L. independently performed reproducibility crystallization experiments and PXRD characterization of phases 1 and 3 and conducted the humidity measurements. Thermal analysis was performed independently by the University of Namur (N.T. and L.F.), Université de Rouen Normandie (G.C. and A.L.) and University of Southampton (R.M. and P.N.H.). A.F. and R.S. performed the cryo-EM measurements and the analysis of the results. R.M., L.F., A.D.R., T.L.T., M.B.H., N.T. and S.J.C. undertook the extensive analysis of the results and wrote the manuscript.

Corresponding author

Correspondence to Riccardo Montis.

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The authors declare no competing interests.

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Peer review information Nature thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 LLPS in 4-APH+Cl.

a, Starting solution and LLPS upon addition of various amounts of acetone. b, Droplet formation upon addition of acetone. c, Evolution of droplet formation as a function of time and separation of the DLP at the bottom of the vial. d, The starting solution (left), after the separation of droplets (middle) and after crystal separation from the DLP (right). A sample showing persistent cloudiness is indicated with a red circle.

Extended Data Fig. 2 Examples of crystals in phases 1–4.

a, Phase 1; b, phase 2; c, phase 3; d, phase 4. Crystals for phases 2 and 4 were obtained by slow-cooling crystallization from the melt of phase 1.

Extended Data Fig. 3 Crystal packing of phases 1–4, viewed along the three axes of the unit cell.

a, Phase 1; b, phase 2; c, phase 3; d, phase 4.

Extended Data Fig. 4 Main self-assemblies in phases 1–4.

a, Phase 1: hexagonal and pentagonal tiles and polyhedral assemblies. b, Phase 2: hexagonal and pentagonal tiles and polyhedral assemblies. c, Phase 3: 4-APH+–H2O and 4-APH+–Cl interactions, H2O–Cl rhombohedral clusters and simple π–π stacking arrangements. d, Phase 4: hexagonal tiles and two-dimensional tiling. In the polyhedra, pentagonal and hexagonal tiles are capped by a further Cl anion that in some cases interacts with the 4-APH+ via π–Cl interactions (Cl–centroid distance in the range 3.4–3.7 Å).

Extended Data Fig. 5 Fullerene-like polyhedra.

ac, Representative spherical polyhedra for phase 1 are shown around clusters A1 (a), A2 (b) and B (c). d, e, Packing of fullerene-like spheres in phase 1 (d) and phase 2 (e).

Extended Data Fig. 6 Cryo-EM images of small objects embedded in the frozen DLP sample that obtained LLPS, promoted by the antisolvent acetone.

Zones 1 and 2 in the two top images containing the small objects are magnified in the bottom panels, which show the same zones after further image processing (fast Fourier transform bandpass filter, filtering features smaller than 5 Å, followed by a further autoscaling of contrast and brightness) to improve the low signal-to-noise ratio of the images and enhance the contrast of the imaged objects. In panel 1, the white arrow indicates a spherical object of diameter 1.5 ± 0.5 nm, and in panel 2 it indicates a further isolated spherical object of diameter 2.8 ± 0.5 nm. The scale bars in the bottom panels correspond to 10 nm.

Extended Data Table 1 Crystal data for phases 1–4

Supplementary information

Supplementary Information

This file contains Supplementary sections 1–7, including Supplementary Figs 1–24 and Supplementary references.

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Montis, R., Fusaro, L., Falqui, A. et al. Complex structures arising from the self-assembly of a simple organic salt. Nature 590, 275–278 (2021).

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