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Diversity in supramolecular chemistry can showcase itself in many ways. This includes the diversity of thought and topics covered in research (from fundamental science to applications in biology and materials), as well as the diversity of people (e.g., diversity in race, gender, sexual orientation, country of origin, type of higher education institute, career stage,…). At the North American Supramolecular Chemistry (NASC) meetings, we aim to bring together the best that supramolecular chemistry has to offer in North America, create a sense of community and provide a platform for researchers at any stage of their career to present their work. NASC 2023 was the successful second edition of the NASC meeting series, and this proceedings article highlights the research and impressions of some of the speakers at NASC 2023.

We report the design and synthesis of the acyclic cucurbit[n]uril-β-cyclodextrin chimeric host H1 . The goal of the study is to deepen the cavity of the receptor to allow β-CD complexation of moieties on the guest (especially fentanyl) that protrude from the cavity of the primary acyclic CB[n] binding site to enhance binding affinity and deliver new supramolecular antidotes for fentanyl intoxication. 1 H NMR spectroscopy was used to deduce the geometry of the complexes between H1 and H2 and the guest panel ( G1 - G8 and fentanyl) whereas isothermal titration calorimetry was used to determine the thermodynamic parameters of complexation. Hosts H1 and H2 retain the essential molecular recognition features of CB[n] receptors, but chimeric host H1 binds slightly stronger toward the guest panel than H2 for reasons that remain unclear. Compared to tetraanionic hosts M1 and M2 , the dianionic hosts H1 and H2 are less potent receptors which reflects the importance of electrostatic (ion-ion and ion-dipole) interactions in this series of hosts. The work highlights the challenges inherent in the optimization of binding affinity of hosts as potential supramolecular antidotes.

We report preparation of (bis)aniline ligand 4 which contains a central viologen binding domain and its subcomponent self-assembly with aldehyde 5 and Fe(OTf) 2 in CH 3 CN to yield tetrahedral assembly 6 . Complexation of ligand 4 with CB[7] in the form of CB[7]• 4 •2PF 6 allows the preparation of assembly 7 which contains an average of 1.95 (range 1-3) mechanically interlocked CB[7] units. Assemblies 6 and 7 are hydrolytically unstable in water due to their imine linkages. Redesign of our system with water stable 2,2'-bipyridine end groups was realized in the form of ligands 11 and 16 which also contain a central viologen binding domain. Self-assembly of 11 with Fe(NTf 2 ) 2 gave tetrahedral MOP 12 as evidenced by 1 H NMR, DOSY, and mass spectrometric analysis. In contrast, isomeric ligand 16 underwent self-assembly with Fe(OTf) 2 to give cubic assembly 17 . Precomplexation of ligands 11 and 16 with CB[7] gave the acetonitrile soluble CB[7]• 11 •2PF 6 and CB[7]• 16 •2PF 6 complexes. Self-assembly of CB[7]• 11 •2PF 6 with Fe(OTf) 2 gave tetrahedron 13 which contains on average 1.8 mechanically interlocked CB[7] units as determined by 1 H NMR, DOSY, and ESI-MS analysis. Self-assembly of CB[7]• 16 •2PF 6 with Fe(OTf) 2 gave cube 13 which contains 6.59 mechanically interlocked CB[7] units as determined by 1 H NMR and DOSY measurements., Competing Interests: Disclosure Statement. The authors have no competing interests to declare.

We report the synthesis of the conformationally mobile S-shaped glycoluril pentamer building block 3a and two new acyclic CB[n]-type receptors P1 and P2 . P1 (9 mM) and P2 (11 mM) have moderate aqueous solubility but their host•guest complexes are poorly soluble. Host P1 does not undergo intermolecular self-association whereas P2 does (K s = 189±27 M -1 ). 1 H NMR titrations show that P1 and P2 are poor hosts toward hydrophobic (di)cations 6 - 11 ( P1 : K a = 375-1400 M -1 ; P2 : K a = 1950-19800 M -1 ) compared to Tet1 and Tet2 ( Tet1 : K a = 3.09 × 10 6 to 4.69 × 10 8 M -1 ; Tet2 : K a = 4.59 × 10 8 to 1.30 × 10 10 M -1 ). Molecular modelling shows that P1 and P2 exist as a mixture of three different conformers due to the two S-shaped methylene bridged glycoluril dimer subunits that each possess two different conformations. The lowest energy conformers of P1 and P2 do not feature a well-defined central cavity. In the presence of guests, P2 adapts its conformation to form 1:1 P2 •guest complexes; the binding free energy pays the energetic price of conformer selection. This energetically unfavorable conformer selection results in significantly decreased K a values of P1 and P2 compared to Tet1 and Tet2 .

Two acyclic CB[ n ]-type hosts ( 1 and 2 ) which possess four 2° or 3° amide arms are reported; 1 and 2 are slightly soluble in water and do not self-associate. Host 2 has four 3° amide arms that exist as a mixture of E- and Z-isomers. 1 H NMR was used to qualitatively investigate the binding properties of 1 and 2 which indicates they retain the essential binding features of macrocyclic CB[ n ] hosts (e.g. cavity binding of hydrophobic residues and portal binding of cationic groups). We measured the K a values of 1 and 2 toward guests 6 - 12 , methamphetamine, and fentanyl by ITC to evaluate their potential as in vivo sequestration agents. Neutral hosts 1 and 2 bind less tightly than tetraanionic hosts M1 , ACB1 , and ACB2 . We attribute the lower K a values to the absence of secondary ion-ion (ammonium•••sulfonate or ammonium•••carboxylate) electrostatic interactions for host•guest complexes of 1 and 2 . The secondary amide functionality on 1 decreases affinity by formation of intramolecular NH•••O=C H-bonds. Tertiary amide host 2 binds even more weakly than 1 due to backfolding of the amide N-CH 3 -groups of 2 into its own cavity. The x-ray crystal structure of 2 supports this conclusion.

We report the synthesis of M2NH3 which is a tetracationic analogue of our prototypical acyclic CB[n]-type molecular container M2 . Both M1NH3 and M2NH3 possess excellent solubility in D 2 O and do not undergo intermolecular self-association processes that would impinge on their molecular recognition properties. Compounds M1NH3 and M2NH3 do, however, undergo an intramolecular self-complexation process driven by ion-dipole interactions between the ureidyl C=O portals and the OCH 2 CH 2 NH 3 arms along with inclusion of one aromatic wall in its own hydrophobic cavity. The K a values for M1NH3 and M2NH3 toward seven nucleotides were determined by 1 H NMR titration and found to be quite modest (K a in the 10 2 - 10 3 M -1 range) although M2NH3 is slightly more potent. The more highly charged guests (e.g. ATP) form stronger complexes with M1NH3 and M2NH3 than the less highly charged guest (e.g. ADP, AMP). The work highlights the dominant influence of the ureidyl C=O portals on the molecular recognition behavior of acyclic CB[n]-type receptors and suggests routes (e.g. more highly charged arms) to enhance their recognition behavior toward anions.

Cucurbit[7]uril (CB[7]) is currently being investigated as a solubilizing agent for insoluble drugs. We recently found that acyclic CB[n]-type receptors that bear sulfonate solubilizing groups are well suited for this application. Herein, we report cucurbit[7]uril derivative ( 1 ) that bears two sulfonate groups on its convex face that we hypothesized would be a superior solubilizing excipient for insoluble drugs. Before using 1 for drug solubilization experiments we showed that 1 does not self-associate and that it retained its ability to bind to diammonium compounds as common guests for CB[7] sized cavities. X-ray crystallography shows that 1 maintains the key structural features of CB[7] with only minor ellipsoidal deformations at the equator and carbonyl portals of 1 . Unfortunately, the aqueous solubility of 1 (20 mM) is slightly lower than CB[7] (20-30 mM) which limits its potential as a solubilizing excipient for insoluble drugs. We created phase solubility diagrams for the solubilization of three drugs (camptothecin, albendazole, cinnarizine) with two different containers ( 1 and CB[7]). CB[7] and 1 exhibit comparable solubilization abilities (e.g. K a and maximum solubility) toward camptothecin and albendazole but 1 is an inferior solubilizing agent for cinnarizine because of the low solubility exhibited by the 1 •cinnarizine complex.