==== Front Nat Commun Nat Commun Nature Communications 2041-1723 Nature Publishing Group UK London 20081 10.1038/s41467-020-20081-8 Article Xenon binding by a tight yet adaptive chiral soft capsule Nie Shi-Xin 12 Guo Hao 12 Huang Teng-Yu 12 Ao Yu-Fei 1 http://orcid.org/0000-0002-9059-5022Wang De-Xian 12 http://orcid.org/0000-0001-5988-1293Wang Qi-Qiang qiqiangw@iccas.ac.cn 12 1 grid.418929.f0000 0004 0596 3295Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, 100190 Beijing, China 2 grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, 100049 Beijing, China 7 12 2020 7 12 2020 2020 11 625711 6 2020 11 11 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Xenon binding has attracted interest due to the potential for xenon separation and emerging applications in magnetic resonance imaging. Compared to their covalent counterparts, assembled hosts that are able to effectively bind xenon are rare. Here, we report a tight yet soft chiral macrocycle dimeric capsule for efficient and adaptive xenon binding in both crystal form and solution. The chiral bisurea-bisthiourea macrocycle can be easily synthesized in multi-gram scale. Through assembly, the flexible macrocycles are locked in a bowl-shaped conformation and buckled to each other, wrapping up a tight, completely sealed yet adjustable cavity suitable for xenon, with a very high affinity for an assembled host. A slow-exchange process and drastic spectral changes are observed in both 1H and 129Xe NMR. With the easy synthesis, modification and reversible characteristics, we believe the robust yet adaptive assembly system may find applications in xenon sequestration and magnetic resonance imaging-based biosensing. Xenon binding carries potential for xenon separation and emerging applications in magnetic resonance imaging. Here, the authors report a rare example of a tight yet soft capsule, assembled from two chiral bisurea-bisthiourea macrocycle components, that can efficiently and adaptively bind xenon in both the solid state and solution. Subject terms Organic chemistryMolecular capsuleshttps://doi.org/10.13039/501100001809National Natural Science Foundation of China (National Science Foundation of China)2187127621521002Wang Qi-Qiang Funder: Chinese Academy of Sciences Number: QYZDJ-SSW-SLH023issue-copyright-statement© The Author(s) 2020 ==== Body Introduction Xenon is a hydrophobic, highly polarizable but rather inert gas. The 129Xe isotope (natural abundance of 26.4%) has a spin of I = 1/2 and its NMR parameters including chemical shift and exchange kinetics are very sensitive to surrounding environments. Meanwhile, application of hyperpolarization (hp) technique can increase the signal by more than 104-fold, thus allowing for very sensitive detection1,2. Consequently, xenon has long been used as an inert probe to determine cavity environments of porous materials and organisms such as proteins3–6. Promise has also been shown for xenon-based magnetic resonance imaging (MRI)7 and target-specific biosensing when a suitable xenon-trapping host is applied8–13. Even with the important applications, especially recent exciting biosensing applications, our understanding of the host-guest chemistry of xenon is limited and development of efficient xenon receptors is highly desirable. As an inert spherical monoatomic gas, xenon lacks an apparent binding site; van der Waals interaction, specifically London dispersion force, is thought to be the main driving force. This makes xenon binding very challenging. Several macrocycle and cage compounds, including hemicarcerands14,15, cyclodextrins16,17, calixarenes18–21, cryptophanes22–30, cucurbiturils31–37, and recent porous imine cages38–40 have been explored for xenon binding, in solution or solid state. Cryptophanes are shown to be outstanding in terms of high affinity and competence for biosensing applications8,9,13,41,42, though, tedious synthesis and sometimes chiral resolution of the intrinsic enantiomers are required for chirality-sensitive detection43–45. On the other hand, assembled hosts have the advantages of reversible formation and easy modular accessibility, however, they are barely explored for xenon binding. In the only few reported examples, earlier Rebek’s rigid, hydrogen-bonded “tennis ball” was found to include xenon on 1H NMR observation46. Recently a cyclic peptide-based columnar assembly was shown able to confine xenon in crystalline form47. Meanwhile, metal-assembled Fe4L648 and Co4L649 cages were recently shown able to encapsulate xenon, with a binding constant of 16 M−1 determined for the former. Herein we report a stable dimeric assembly of a chiral bisurea-bisthiourea macrocycle and its favorable, adaptive-binding ability toward xenon. The assembly represents a tight, completely sealed yet rather soft capsule and encapsulates xenon with a very high affinity for an assembled host. The adaptive-binding dynamics due to induced fit of the surrounding macrocyclic skeletons is revealed not only in crystal form, but also in solution through the unique spectral features of the dimeric assembly. Results Design and synthesis Recently we have developed a set of chiral tetraamino-bisthiourea macrocycles for substrate-induced assembly asymmetric catalysis50. We envisioned that introducing additional carbonyl groups to the diamine moieties on both sides will lead to a type of bisurea-bisthiourea chiral macrocycle M which incorporates multiple hydrogen bond donors (NH) and acceptors (C=S, C=O) simultaneously, and would favor intra- or intermolecular assembly (Fig. 1). The synthesis of the macrocycle is straightforward. After several simple transformations, the 1 + 1 condensation between bis-amine 1 and bis-isothiocyanate 2 furnished multi-grams of the chiral macrocycle in one batch with an excellent yield of 71% (Fig. 1 and Supplementary Methods).Fig. 1 Synthesis of the chiral bisurea-bisthiourea macrocycle M. The structures of the macrocycle and its hydrogen-bonded dimeric form are drawn in the bottom. Structures of the dimeric capsule High-quality crystals of the dimeric capsule M2 were reproducibly obtained by diffusion of n-hexane to a macrocycle toluene solution. Two forms of crystallographically independent dimeric capsules were observed. As shown by the first form in Fig. 2, the two macrocycles adopt a bowl-shaped conformation and crossly overlay to each other through fourfold intermolecular C=O∙∙∙H–N hydrogen bonds (2.81–2.83 Å). The thiourea moieties lie in the bottom and adopt an unusual syn-anti configuration. The forming of two pairs of parallel intramolecular C=S∙∙∙H–N hydrogen bonds (3.39–3.40 Å) in the meantime helps lock the bowl-shaped macrocyclic conformation, leaving four exo NH sites for intermolecular hydrogen bonding. All the phenyl rings from different macrocycles stack onto each other, which may provide further stabilization.Fig. 2 Crystal structure of the dimeric capsule M2. a Top view. b Side view. c Space filling view. Only the first form (Form 1) of the two crystallographically independent dimeric capsules is shown. H-bonding distances (given by the heavy atom distances): C=O∙∙∙H–N 2.808, 2.832, 2.808, and 2.832 Å; C=S∙∙∙H–N 3.393, 3.399, 3.393, and 3.399 Å. The buckling of the two bowl-shaped macrocycles produces a completely sealed dimeric capsule (Fig. 2c). The cavity volume was detected to be 72 Å3 for the first form (Fig. 3a). Surprisingly, while the overall interacting motif holds, the second form shows a much smaller cavity (36 Å3; Fig. 3b and Supplementary Table 4). The cavity reduction is due to flattening of the bowl-shaped macrocyclic conformation as reflected by shortened (S=)C---C(=S) and lengthened (C=)O---O(=C) dimensions (Fig. 3b vs 3a), suggesting considerable flexibility of the macrocyclic skeleton. The inter- and intramolecular hydrogen bonding, however, is not significantly affected. The existence of the two forms of dimeric capsules is probably caused by crystal packing effect, as the macrocyclic component has a rather flexible skeleton. In both forms, the solvent molecules were found too large to occupy the cavity.Fig. 3 Cavity volume of the dimeric capsule M2. a Form 1 (72 Å3). b Form 2 (36 Å3). The cavity volume is determined by a spherical probe of 1.4 Å using SwissPdbViewer54 and depicted in red. Dimeric assembly in solution The formation of dimeric assembly in solution was further studied. 1H NMR in (CDCl2)2/DMSO-d6 (5:1) shows a set of simple signals, consistent with an overall D2-symmetric free macrocycle structure in this competitive solvent system (Fig. 4b). In contrast, in pure (CDCl2)2, the spectrum totally changed to two sets of signals at equal intensity, in line with a reduced C2 macrocycle symmetry (Fig. 4c). The NH signals moved largely to downfield direction, suggesting favorable hydrogen bonding formation. By a combination of 1H, 13C and various 2D NMR (Supplementary Figs. 7–14), a dimeric capsular structure similar to that in crystal can be elucidated with all signals well assigned. The two sets of protons (in blue and purple) can exchange their positions through overturn of the syn-anti thiourea configuration as shown by 2D EXSY NMR (Supplementary Fig. 14; vide infra). As the solvent molecule is too large to fit, most capsules are likely to be empty except those occupied by N2 as indicated by the set of minor N2 inclusion peaks (Fig. 4c). High stability of the assembly was demonstrated by concentration-variable NMR as no essential spectral changes observed until dilution to 0.05 mM (Supplementary Fig. 23). A large dimerization constant of (1.9 ± 0.3) × 104 M−1 was further determined by isothermal titration calorimetry (ITC; Supplementary Fig. 26). The dimeric assembly was also confirmed with high-resolution CSI-MS where a peak at m/z = 2111.5522 corresponding to [M2−H]− dominated (Supplementary Fig. 27).Fig. 4 1H NMR (298 K, 500 M) of the macrocycle M in different solvent systems with or without xenon. a The chemical structures of the macrocycle and dimeric capsule with related protons labeled. b 1H NMR in (CDCl2)2/DMSO-d6 (5:1). The macrocycle exists as monomeric form. c 1H NMR in (CDCl2)2. The macrocycle exists as dimeric capsule form. Asterisk denotes the minor N2 inclusion peaks (for details see Supplementary Fig. 7). d 1H NMR in (CDCl2)2 after bubbling of xenon. The major peaks correspond to Xe ⊂  M2. In all cases, the initial concentration of the macrocycle ([M]initial) for preparing each solution is 10 mM. Xenon binding The macrocycle can congruously form a stable, sealed dimeric capsule in both solid state and solution with a cavity possibly suited for xenon (dw = 4.3 Å, V = 42 Å3). To our delight, through bubbling xenon gas, the original 1H NMR signals of the free dimeric capsule almost disappeared, instead a new group of sharp and well-resolved signals dominated, which can correspond to Xe ⊂ M2 (Fig. 4d). All signals were clearly assigned by a combination of 1H, 13C, and various 2D NMR (Supplementary Figs. 15–22). The upfield shift of NH signals and drastic changes of other proton signals may reflect a shielding effect of large electron cloud of xenon and an induced structural change due to tight inclusion (vide infra). The remarkable spectral difference is distinguished from the usually reported, relatively rigid hosts, suggesting the dimeric capsule is rather soft (as also shown in crystal) and can adaptively include the incoming xenon guest. The 129Xe NMR showed a similar slow exchange process and the signal of the bound xenon appeared at 169.6 ppm, largely upfield-shifted comparing to the free xenon in solution (Δδ = −53.4 ppm; Fig. 5). A binding constant of 99 ± 4 M−1 was determined for xenon by 1H NMR integration (see Supplementary Methods and Supplementary Fig. 15). To the best of our knowledge, this is the highest xenon affinity reported to date for assembled hosts. As compared, a previous only known binding constant of 16 M−1 was reported for a metal-assembled Fe4L6 host48.Fig. 5 129Xe NMR (298 K, 138 MHz) of xenon saturated in (CDCl2)2 without or with the dimeric capsule. a The blank xenon solution. b In the presence of the dimeric capsule M2 (20 mM). The chemical shift of the free xenon was referenced according to the literature22. The existence of two sets of position-exchangeable protons in the macrocyclic skeleton provides a unique probe for exploring the adaptive xenon binding dynamics. As intracapsular, simultaneous overturn of the many locked syn-anti configurated thiourea motifs seems unlikely, the position exchange is probably accomplished through a disassembly-reassembly pathway, i.e., once disassembled the conformation of the free macrocycle can be readily converted (Fig. 6a). Accordingly, the position-exchange rate can reflect the assembly-disassembly dynamics. The influence of xenon binding can thus be probed by comparing the temperature-variable 1H NMR before and after xenon inclusion (Fig. 6b, c). Upon temperature increasing, the two sets of signals started to coalesce and Xe ⊂ M2 showed an obviously higher coalescence temperature Tc and accordingly a higher activation energy ΔG‡ than M2 (17.4 ± 0.1 vs 16.4 ± 0.2 kcal mol−1; Supplementary Figs. 24 and 25 and Supplementary Table 6). This suggests upon xenon inclusion, the dimeric assembly becomes more kinetically stable; in other words, xenon binding could have induced a tighter capsular structure by fitting the soft macrocyclic skeletons. It is worth noting that even at elevated temperatures (up to 373 K), the assembly was still kept intact, once again showing its high thermodynamic stability.Fig. 6 Determination of the xenon binding dynamics. a Proposed exchange mechanism of the two sets of macrocycle protons (depicted in blue and purple) in the dimeric capsule. b, c Partial temperature-variable 1H NMR (500 MHz, (CDCl2)2) of M2 and Xe ⊂ M2 respectively. Asterisk denotes the emerging peaks of free M2. In both cases, [M]initial = 10 mM. For a complete set of spectra, see Supplementary Figs. 24 and 25. Structures of Xe ⊂ M2 Two different high-quality crystals of Xe ⊂ M2 were independently obtained by diffusion of n-hexane to a macrocycle solution in chloroform or toluene saturated with xenon (Supplementary Tables 2–5). The first crystal crystallized in orthorhombic system as the free dimeric capsule with similar cell parameters (vide supra). As shown by the first form of the two crystallographically independent complexes (Fig. 7), the xenon was completely sealed in the cavity with a perfect packing coefficient of 52%51. In order to fit xenon, the cavity volume was expanded to 81 Å3. The xenon atom shows multiple contacts with the surrounding macrocyclic skeletons, including with the four endo nitrogen (3.83–3.87 Å; the sum of van der Waals radii of nitrogen and xenon is 3.71 Å52) and four carbon atoms (3.98–4.01 Å; the sum of van der Waals radii of carbon and xenon is 3.86 Å52) from the thiourea groups, and with the interior carbon (3.86–4.02 Å) and hydrogen atoms (3.23–3.42 Å; the sum of van der Waals radii of hydrogen and xenon is 3.36 Å52) from four diagonal phenyl rings (Fig. 7a). These contacts, especially that with polar nitrogen atoms, are different to those rigid aromatic faces or sole C–H sites in the usually reported xenon hosts. The second form showed an overall similar structure with a cavity of 69 Å3 and xenon packing coefficient of 61% (Supplementary Tables 4 and 5). The cavity size is largely expanded comparing to that free form of 36 Å3 (vide supra), reflecting the adaptive ability of this tight yet soft capsule. Again, the adaptation is accomplished through the adjust of the bowl-shaped macrocyclic conformation, rather than the change of hydrogen bonding distances.Fig. 7 Crystal structure of Xe ⊂ M2. a Top view with the atoms contacting to xenon labeled (only the upside is labeled). b Side view with the front urea moiety cut off for clarity. c Side view with the macrocycle molecular surfaces shown. d Space filling view. The second crystal crystallized in a different monoclinic system, but exhibited a similar capsular structure and xenon binding motif (Supplementary Tables 4 and 5). The contacts of xenon to the relevant thiourea nitrogen atoms are even shorter (3.69–3.82 Å). It is worth noting that, even both crystals were grown under 1 atm xenon pressure, the averaged xenon occupancy in the cavity reaches 0.85 and 0.94 respectively, suggesting favored binding53. The sealed but reversible assembly capsule system could thus have potentials for sequestration and separation of xenon (see Supplementary Note 1 for detailed discussion). In conclusion, a chiral bisurea-bisthiourea macrocycle was efficiently synthesized. This macrocycle can form stable dimeric capsular assembly in both solid state and solution. The capsule possesses a tight, sealed cavity, and effectively binds xenon. Different from other rigid hosts, the capsule is rather soft and can adaptively include xenon through induced fit of the surrounding macrocyclic skeletons. Multiple contacts including several unusual contacts to polar nitrogen atoms are engaged. The adaptive binding dynamic was demonstrated not only in crystal, but also in solution by taking the unique spectral features of the dimeric assembly. These knowledges should have advanced our current understanding on the host–guest chemistry of xenon. The sealed but reversible assembly could also have potentials for developing host materials toward xenon sequestration and separation. With the easy synthesis, modification, robust yet adjustable assembly features, further optimization of the xenon affinity, and 129Xe NMR related parameters should be feasible toward biosensing applications. The enantiopure form of the chiral assembly could also have advantages on chirality-sensitive detection. Supplementary information Supplementary Information Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. These authors contributed equally: Shi-Xin Nie, Hao Guo. Supplementary information Supplementary information is available for this paper at 10.1038/s41467-020-20081-8. Acknowledgements Financial supports from National Natural Science Foundation of China (21871276 and 21521002) and Chinese Academy of Sciences (QYZDJ-SSW-SLH023) are gratefully acknowledged. We thank Dr. Junfeng Xiang (NMR), Dr. Xiang Hao and Mrs. Tongling Liang (crystallography) from ICCAS for helpful discussion. Author contributions Q.Q.W. designed, supervised the project, and wrote the manuscript. S.X.N. and H.G. performed most of the synthesis and characterization experiments. T.Y.H. performed the VT-NMR analysis. Y.F.A. and D.X.W. discussed the results and co-edited the manuscript. Data availability The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2006631-2006633. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary methods for synthesis and characterization, crystallography, NMR, ITC studies, and additional data supporting the findings of this study are available in Supplementary Information file. Competing interests The authors declare no competing interests. ==== Refs References 1. Walker TG Happer W Spin-exchange optical pumping of noble-gas nuclei Rev. Mod. Phys. 1997 69 629 642 10.1103/RevModPhys.69.629 2. Meersmann T Brunner E Hyperpolarized Xenon-129 Magnetic Resonance: Concepts, Production, Techniques and Applications 2015 Cambridge RSC 3. Dybowski C Bansal N NMR spectroscopy of xenon in confined spaces: clathrates, intercalates, and zeolites Annu. Rev. Phys. Chem. 1991 42 433 464 10.1146/annurev.pc.42.100191.002245 4. Goodson BM Nuclear magnetic resonance of laser-polarized noble gases in molecules, materials, and organisms J. Magn. Reson. 2002 155 157 216 10.1006/jmre.2001.2341 12036331 5. Rubin SM Lee SY Ruiz EJ Pines A Wemmer DE Detection and characterization of xenon-binding sites in proteins by Xe-129 NMR spectroscopy J. Mol. Biol. 2002 322 425 440 10.1016/S0022-2836(02)00739-8 12217701 6. Weiland E Springuel-Huet M Nossov A Gédéon A 129 Xenon NMR: review of recent insights into porous materials Micropor. Mesopor. Mater. 2016 225 41 65 10.1016/j.micromeso.2015.11.025 7. Albert MS Biological magnetic resonance imaging using laser-polarized 129 Xe Nature 1994 370 199 201 10.1038/370199a0 8028666 8. Spence MM Functionalized xenon as a biosensor Proc. Natl Acad. Sci. USA 2001 98 10654 10657 10.1073/pnas.191368398 11535830 9. Schröder L Lowery TJ Hilty C Wemmer DE Pines A Molecular imaging using a targeted magnetic resonance hyperpolarized biosensor Science 2006 314 446 449 10.1126/science.1131847 17053143 10. Berthault P Huber G Desvaux H Biosensing using laser-polarized xenon NMR/MRI Prog. Nucl. Magn. Reson. Spectrosc. 2009 55 35 60 10.1016/j.pnmrs.2008.11.003 11. Schröder L Xenon for NMR biosensing – inert but alert Phys. Med. 2013 29 3 16 10.1016/j.ejmp.2011.11.001 22119272 12. Palaniappan KK Francis MB Pines A Wemmer DE Molecular sensing using hyperpolarized xenon NMR spectroscopy Isr. J. Chem. 2014 54 104 112 10.1002/ijch.201300128 13. Wang Y Dmochowski IJ An expanded palette of xenon-129 NMR biosensors Acc. Chem. Res. 2016 49 2179 2187 10.1021/acs.accounts.6b00309 27643815 14. Cram DJ Tanner ME Knobler CB Guest release and capture by hemicarcerands introduces the phenomenon of constrictive binding J. Am. Chem. Soc. 1991 113 7717 7727 10.1021/ja00020a039 15. Robbins TA Knobler CB Bellew DR Cram DJ A highly adaptive and strongly binding hemicarcerand J. Am. Chem. Soc. 1994 116 111 122 10.1021/ja00080a014 16. Bartik K Luhmer M Heyes SJ Ottinger R Reisse J Probing molecular cavities in α -cyclodextrin solutions by xenon NMR J. Magn. Reson. Ser. B 1995 109 164 168 10.1006/jmrb.1995.0005 17. Song Y-Q Selective enhancement of NMR signals for α -cyclodextrin with laser-polarized xenon Angew. Chem. Int. Ed. Engl. 1997 36 2368 2370 10.1002/anie.199723681 18. Brouwer, E. B., Enright, G. D. & Ripmeester, J. A. Solid-state NMR and diffraction studies of p-tert-butylcalix[4]arene·nitrobenzene·xenon. Chem. Commun. 939–940 (1997). 19. Enright GD Udachin KA Moudrakovski IL Ripmeester JA Thermally programmable gas storage and release in single crystals of an organic van der waals host J. Am. Chem. Soc. 2003 125 9896 9897 10.1021/ja0351701 12914432 20. Fukutomi J Adachi Y Kaneko A Kimura A Fujiwara H Inclusion complex formation of thiacalix[4]arene and Xe in aqueous solution studied by hyperpolarized 129 Xe NMR J. Incl. Phenom. Macrocycl. Chem. 2007 58 115 122 10.1007/s10847-006-9130-1 21. Ananchenko GS Moudrakovski IL Coleman AW Ripmeester JA A channel-free soft-walled capsular calixarene solid for gas adsorption Angew. Chem. Int. Ed. 2008 47 5616 5618 10.1002/anie.200800071 22. Bartik K Luhmer M Dutasta J-P Collet A Reisse J 129 Xe and 1 H NMR study of the reversible trapping of xenon by cryptophane-A in organic solution J. Am. Chem. Soc. 1998 120 784 791 10.1021/ja972377j 23. Luhmer M Study of xenon binding in cryptophane-A using laser-induced NMR polarization enhancement J. Am. Chem. Soc. 1999 121 3502 3512 10.1021/ja9841916 24. Brotin T Lesage A Emsley L Collet A 129 Xe NMR spectroscopy of deuterium-labeled cryptophane-A xenon complexes: investigation of host-guest complexation dynamics J. Am. Chem. Soc. 2000 122 1171 1174 10.1021/ja993053t 25. Huber G Water soluble cryptophanes showing unprecedented affinity for xenon: candidates as NMR-based biosensors J. Am. Chem. Soc. 2006 128 6239 6246 10.1021/ja060266r 16669694 26. Hill PA Wei Q Eckenhoff RG Dmochowski IJ Thermodynamics of xenon binding to cryptophane in water and human plasma J. Am. Chem. Soc. 2007 129 9262 9263 10.1021/ja072965p 17616197 27. Fogarty HA A cryptophane core optimized for xenon encapsulation J. Am. Chem. Soc. 2007 129 10332 10333 10.1021/ja073771c 17676741 28. Fairchild RM A water-soluble Xe@cryptophane-111 complex exhibits very high thermodynamic stability and a peculiar 129 Xe NMR chemical shift J. Am. Chem. Soc. 2010 132 15505 15507 10.1021/ja1071515 20958059 29. Taratula O Hill PA Khan NS Carroll PJ Dmochowski IJ Crystallographic observation of ‘induced fit’ in a cryptophane host–guest model system Nat. Commun. 2010 1 148 10.1038/ncomms1151 21266998 30. Joseph AI Lapidus SH Kane CM Holman KT Extreme confinement of xenon by cryptophane-111 in the solid state Angew. Chem. Int. Ed. 2015 54 1471 1475 10.1002/anie.201409415 31. Haouaj ME Luhmer M Ko YH Kim K Bartik K NMR study of the reversible complexation of xenon by cucurbituril J. Chem. Soc. Perkin Trans. 2001 2 804 807 10.1039/b008623l 32. Miyahara Y Abe K Inazu T “Molecular” molecular sieves: lid-free decamethylcucurbit[5]uril absorbs and desorbs gases selectively Angew. Chem. Int. Ed. 2002 41 3020 3023 10.1002/1521-3773(20020816)41:16<3020::AID-ANIE3020>3.0.CO;2-4 33. Kim, B. S. et al. Water soluble cucurbit[6]uril derivative as a potential Xe carrier for 129Xe NMR-based biosensors. Chem. Commun. 2756–2758 (2008). 34. Huber G Interaction of xenon with cucurbit[5]uril in water ChemPhysChem 2011 12 1053 1055 10.1002/cphc.201100068 21404420 35. Wang Y Dmochowski IJ Cucurbit[6]uril is an ultrasensitive 129 Xe NMR contrast agent Chem. Commun. 2015 51 8982 8985 10.1039/C5CC01826A 36. He S Cavitation energies can outperform dispersion interactions Nat. Chem. 2018 10 1252 1257 10.1038/s41557-018-0146-0 30297753 37. Truxal AE Cao L Isaacs L Wemmer DE Pines A Directly functionalized cucurbit[7]uril as a biosensor for the selective detection of protein interactions by 129 Xe HyperCEST NMR Chem. Eur. J. 2019 25 6108 6112 10.1002/chem.201900610 30868660 38. Chen L Separation of rare gases and chiral molecules by selective binding in porous organic cages Nat. Mater. 2014 13 954 960 10.1038/nmat4035 25038731 39. Komulainen S Inside information on xenon adsorption in porous organic cages by NMR Chem. Sci. 2017 8 5721 5727 10.1039/C7SC01990D 28989612 40. Egleston BD Controlling gas selectivity in molecular porous liquids by tuning the cage window size Angew. Chem. Int. Ed. 2020 59 7362 7366 10.1002/anie.201914037 41. Brotin T Dutasta J-P Cryptophanes and their complexes – present and future Chem. Rev. 2009 109 88 130 10.1021/cr0680437 19086781 42. El-Ayle, G. & Holman, K. T. in Comprehensive Supramolecular Chemistry II (ed. Atwood, J. L.) (Elsevier Ltd: Amsterdam, Netherlands, 2017). 43. Huber JG NMR study of optically active monosubstituted cryptophanes and their interaction with xenon J. Phys. Chem. A 2004 108 9608 9615 10.1021/jp0472055 44. Ruiz EJ Sears DN Pines A Jameson CJ Diastereomeric Xe chemical shifts in tethered cryptophane cages J. Am. Chem. Soc. 2006 128 16980 16988 10.1021/ja066661z 17177449 45. Taratula O Synthesis of enantiopure, trisubstituted cryptophane-A derivatives Org. Lett. 2012 14 3580 3583 10.1021/ol300943w 22783828 46. Branda N Grotzfeld RM Valdés C Rebek J Jr. Control of self-assembly and reversible encapsulation of xenon in a self-assembling dimer by acid–base chemistry J. Am. Chem. Soc. 1995 117 85 88 10.1021/ja00106a010 47. Pizzi A Tight xenon confinement in a crystalline sandwich-like hydrogen bonded dimeric capsule of a cyclic peptide Angew. Chem. Int. Ed. 2019 58 14472 14476 10.1002/anie.201906599 48. Roukala J Encapsulation of xenon by a self-assembled Fe4 L6 metallosupramolecular cage J. Am. Chem. Soc. 2015 137 2464 2467 10.1021/ja5130176 25671394 49. Du, K., Zemerov, S. D., Parra, S. H., Kikkawa, J. M. & Dmochowski, I. J. Paramagnetic organocobalt capsule revealing xenon host-guest chemistry. Inorg. Chem. 59, 13831–13844 (2020). 50. Guo H Substrate-induced dimerization assembly of chiral macrocycle catalysts toward cooperative asymmetric catalysis Angew. Chem. Int. Ed. 2020 59 2623 2627 10.1002/anie.201910399 51. Mecozzi S Rebek J Jr. The 55% solution: a formula for molecular recognition in the liquid state Chem. Eur. J. 1998 4 1016 1022 10.1002/(SICI)1521-3765(19980615)4:6<1016::AID-CHEM1016>3.0.CO;2-B 52. Bondi A van der Waals Volumes and Radii J. Phys. Chem. 1964 68 441 451 10.1021/j100785a001 53. Kane CM Banisafar A Dougherty TP Barbour LJ Holman KT Enclathration and confinement of small gases by the intrinsically 0D porous molecular solid, Me,H,SiMe2 J. Am. Chem. Soc. 2016 138 4377 4392 10.1021/jacs.5b11395 26954555 54. Guex N Peitsch MC SWISS-MODEL and the Swiss-Pdb viewer: an environment for comparative protein modeling Electrophoresis 1997 18 2714 2723 10.1002/elps.1150181505 9504803