Past exam of the MPhil in micro- and nanotechnology enterprise course of the University of Cambridge / 2021 / Paper 1 / 10 / ii

The end groups associate reversibly through a complementary hydrogen-bond array. At low concentration, bringing the two ends of the same molecule together avoids the concentration-dependent cost of finding another molecule, so an intramolecular ring is favored.

For A, increasing concentration permits end-to-end intermolecular association to compete successfully with ring closure. It produces long, reversible supramolecular chains. Increasing chain length and entanglement account for the highly viscous solution without requiring covalent polymerization.

B has more favorably positioned attachment points on its rigid aromatic core. Its arms can close a less strained ring, so intramolecular association remains strongly competitive over the stated range. Predominantly discrete rings do not form the same extended chain network, explaining the retained fluidity. Both compounds can make the same local hydrogen bonds; their different balance of ring strain, preorganization and intermolecular association explains the macroscopic difference.

The terminal ureidopyrimidinone groups supply the association sites. Their urea/pyrimidinone NH donors and carbonyl/ring-nitrogen acceptors can form a self-complementary array of four hydrogen bonds between two UPy units. Joining the two terminal units of one molecule by this noncovalent association closes the ring.

The ether-containing arms provide flexibility and spacing; they are not covalently joined together during ring formation. The ring is therefore a supramolecular conformation of the existing molecule, rather than a new covalent ether macrocycle.

DMSO is a strong hydrogen-bond acceptor. It competes for the NH donors of the UPy units and solvates the association sites, weakening their mutual hydrogen bonding.

For A, the intermolecular chains should shorten or dissociate, reducing the association-driven viscosity. For B, the intramolecular ring should become less populated, increasing the fraction of open conformations. Sufficient DMSO also weakens rings of A and any intermolecular associations of B. The covalent molecular skeletons remain intact.

The extent depends on DMSO fraction and the association free energies in the mixed solvent. solvent viscosity itself also changes, so the prediction concerns the supramolecular contribution rather than an unconditional numerical value for total solution viscosity.

Use two-dimensional NOESY, or ROESY where molecular tumbling makes NOESY less favorable, to look for through-space correlations between proton sites on the two ends that are brought together in the closed conformation. Assign resonances first and compare predicted ring contacts with an open reference or model.

The nuclear Overhauser effect involves NMR cross-relaxation through magnetic dipole–dipole coupling. Its strong approximate $r^{-6}$ dependence makes it sensitive to short interproton distances. A NOESY cross-peak therefore reports spatial proximity, including between sites far apart along the covalent skeleton; it is not a NMR scalar coupling transmitted along that skeleton.

Run a dilution series: end-to-end contacts that persist at concentrations where intermolecular association is negligible support intramolecular ring closure. Hydrogen-bonded NH chemical shifts and diffusion measurements can support the assignment, but neither alone proves ring topology. A flexible open chain can transiently bring ends together, and intermolecular contacts can also give NOEs. Several geometry-consistent cross-peaks, concentration behavior and controlled mixing times make the case much stronger than one peak.

The rigid naphthalene core fixes the separation and directions of the two arm attachment points. In A they point from more separated regions of the core, so closure requires the flexible arms to span the core and adopt less favorable torsional arrangements. In B the closer, more convergent attachment geometry permits the UPy ends to meet with less conformational strain and better preorganization.

Both rings gain similar local UPy hydrogen-bonding interactions, but A pays a larger deformation cost in its linkers and overall geometry. That can rationalize its higher calculated total energy and its greater tendency to open into intermolecular chains.

The quoted $50\mathrm{kJ}\mathrm{mo}{\mathrm{l}}^{-1}$ is large compared with $RT\simeq 2.48\mathrm{kJ}\mathrm{mo}{\mathrm{l}}^{-1}$. Nevertheless a total-energy difference is not automatically a solution Gibbs free-energy difference: solvent and entropy contributions would be needed before converting it into an equilibrium population ratio.