80 81 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 2 1 / 2 2 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 2 1 / 2 2 Weaving amolecular knot Related publication: Leigh, D. A., Danon, J. J., Fielden, S. D. P., Lemonnier, J.-F.,Whitehead, G. F. S., &Woltering, S. L. Amolecular endless (7 4 ) knot. Nature Chemistry , 13 117–122 (2021). DOI: 10.1038/s41557-020-00594-x Publication keywords: Supramolecular chemistry; Interwoven grids; Molecular knots K nots have been used for thousands of years to create tools and materials. The ability to knot molecular-sized threads, approximately 100,000 times thinner than a human hair, should allow us to make incredibly strong novel materials. However, methods of knotting such small threads are lacking, so researchers have developed a new technique for weaving at the molecular scale. They investigated differentmolecular strand designs to ensure theywere the correct shape to bewoven together into a grid. They had tofind a suitable template, a metal compound that could control the weaving process by guiding the strands into a grid structure. Thewovengrid is far too small tobe seenby thenakedeye, so theyhad touse X-raydiffractionon the SmallMolecule Single Crystal Diffraction beamline (I19) to probe the relative positions of molecular strands. Their experiment revealed that the molecular strands had indeed woven together to give a grid structure. It allowed them to determine the distances and angles between the strands and templates and show how the weaving process was controlled. They also showed that the strands were of the correct length so their ends could be connected to give a molecular knot. Molecular knots have unique molecular structures that have been shown to catalyse chemical reactions, act as sequestering agents and kill cancer cells. Interwoven molecular grids can be connected to each other to give extended 2D materials with high stiffness that can act as molecular-sized nets. Knots play an important role at the nanoscale. Knots are found in DNA and proteins, where they profoundly impact the stability and biological activity of these macromolecules. Synthetic polymer chains also spontaneously tie into knots; the resulting entanglements determine macroscopic material properties such as stiffness and viscosity. The ways that a strand can be tied into a knot are practically limitless; there are billions of tabulated knot types. However, it remains extremely difficult to tie a molecular strand precisely into a specific type of knot 1 . This means systematic studies into the implications and applications of tying a molecule into a knot are currently scarce. For this study, inspiration was taken from the macroscopic weaving of threads to develop a new strategy to access molecular knots. This approach involves the self-assembly of organic polytopic ligands and metal salts into an interwoven grid 2 . If the ends of the ligands are connected to each other, a molecular knot is obtained. Specifically, a 3×3 interwoven grid was targeted in order to obtain a molecular ‘endless knot’ (7 4 by Alexander Briggs notation) 3 . Such a structure would result from the self-assembly of six ligands around an array of nine co-planar metal ions. The crossing points (entanglements) of the knot are generated using the thiazolo[5,4–d]thiazole unit to ensure the ligand adopts a zig-zag conformation when coordinating to metals in the grid architecture. After several design iterations, a suitable ligand containing three binding pockets with the correct spacing, geometry and electron donating ability was found. Combining this ligand with Fe(II)(BF 4 ) 2 or Zn(II)(BF 4 ) 2 in organic solvent leads to the near-quantitative formation of a molecular 3×3 interwoven Figure 1: Synthesis of a molecular endless knot via a 3×3 interwoven grid. Reagents and conditions: (i) 1.5 equivalents M(BF 4 )2∙6H 2 O (M= Fe(II) or Zn(II)), CH 3 CN:/CHCl 3 1:1, room temperature, 5 minutes for M= Zn(II); CH 3 CN/toluene 5:3, 100 °C, 72 hours for Fe(II); (ii) Second generation Hoveyda–Grubbs catalyst, 0.1 equivalents per olefin, CH 2 Cl 2 /CH 3 NO 2 3:1, 110 °C (microwave irradiation), 1.5 hours; (iii) Li 2 S(aq.) for M= Zn(II), Na 4 EDTA(aq.) for M= Fe(II). grid (Fig. 1). Whilst these assemblies could be studied using 1 H/ 13 C nuclear magnetic resonance and electrospray ionisation mass spectrometry, the most compelling proof of the interwoven nature of the grid was provided by single crystal X-ray diffraction. The data for this experiment were obtained at the I19 beamline at Diamond Light Source. The X-ray structure (Fig. 2) shows the desired interwoven arrangement of ligands around an array of metal ions was indeed present. Unexpectedly, it was found in preliminary studies that the counter anions of the templating metal cations also played a role in the self-assembly process. The use of tetrafluoroborate salts was necessary to produce a 3×3 grid; other salts gave simpler complexes such as squares and dimers. The unanticipated role played by tetrafluoroborate ions was revealed in the X-ray structure. A BF 4 − ion is found bound within each of the four-square cavities formed between ligands placed at right angles. The B–F bonds of these anions point towards the templating metal ions situated at the corners of the square, whilst the fluorine atoms are in close contact with the centres of the thiazole rings. This suggests the driving force for grid self-assembly is partially derived from a combination of charge-dipole and anion-π interactions. Adjacent ligands of the grid were connected using olefin metathesis. After the metal ions were removed a wholly organic endless knot, containing seven crossings in a loop 258 atoms long, was isolated. It was found that the sequence of ligand closures dictated the product outcome – if olefins were not connected in a perfect alternating pattern other cyclic species are formed: either a Solomon link (doubly interlocked rings) or unknot (non-entangled macrocycle). The endless knot could be remetallated with Zn(II)BF 4 to again form the planar grid complex. The endless knot has significant symbolic relevance in several ancient and modern civilisations: it is the smallest Chinese knot, one of the eight auspicious symbols of Buddhismand Hinduismand is often found in Celtic knotwork. From a chemist’s perspective, the ability to precisely synthesise hitherto inaccessible knots opens the door for studies that give deeper understanding to the role of knotting at the molecular scale. Whilst it has been known for at least 50 years that molecular entanglement has profound impact on material properties, explanations to the molecular origins for such effects remain elusive. Routine access to a variety of molecular topologies will provide themissing link to allow the specific molecular entanglement sequences to be exploited. In addition, tessellation of molecular grids provides a new strategy to access 2D interwoven materials 4 . References: 1. Fielden, S. D. P. et al . Molecular knots. Angewandte Chemie International Edition 56 , 11166–11194 (2017). DOI: 10.1002/anie.201702531 2. Hubin, T. J. et al. Template routes to interlocked molecular structures and orderly molecular entanglements. Coordination Chemistry Reviews 200–202 , 5–52 (2000). DOI: 10.1016/S0010-8545(99)00242-8 3. Alexander, J. W. et al . On types of knotted curves. Annals of Mathematics 28 , 562-586 (1926). DOI: 10.2307/1968399 4. August, D. P. et al . Self-assembly of a layered two-dimensional molecularly woven fabric. Nature 588 , 429–435 (2020). DOI: 10.1038/ s41586-020-3019-9 Funding acknowledgement: We thank the Engineering and Physical Sciences Research Council (EPSRC; EP/P027067/1), the European Research Council (ERC; Advanced Grant no. 786630), and East China Normal University for funding; the EPSRC National Mass Spectrometry Service Centre for high-resolution mass spectrometry; the Diamond Light Source for synchrotron beam time on Beamline I19 (XR029); networking contributions from the COST Action CA17139. David Leigh is a Royal Society Research Professor. Corresponding author: Dr Stephen Fielden, University of Birmingham,
[email protected] Crystallography Group Beamline I19 Figure 2: X-ray crystal structure of 3×3 interwoven grid containing Fe(II), in which the disordered olefin-terminated chains are replaced by cyclised end groups modelled by a Merck molecular force field; a) Viewed orthogonally to the plane of the nine Fe(II) ions. b) Angled view showing the planarity of the weft and warp strands and the directionality of the anion–π and anion– Fe(II)interactions of the BF 4 − templates; c) Viewed along the plane of the Fe(II) ions. d) One of the square cavities formed between the criss-crossed strands. Distances in Å.