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

Abstract

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 deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk. 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, https://doi.org/10.5281/zenodo.2595089; phase 2, https://doi.org/10.5281/zenodo.2585776; phase 3, https://doi.org/10.5281/zenodo.2593670; phase 4, https://doi.org/10.5281/zenodo.2593677. 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.

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Acknowledgements

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

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Authors

Contributions

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). https://doi.org/10.1038/s41586-021-03194-y

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