Conformer-Independent Ureidoimidazole Motifs—Tools to Probe Conformational and Tautomeric Effects on the Molecular Recognition of Triply Hydrogen-Bonded Heterodimers



Linear arrays of hydrogen bonds are useful for the reversible assembly of “stimuli-responsive” supramolecular materials. There is thus an ongoing requirement for easy-to-synthesise motifs that are capable of presenting hydrogen-bonding functionality in a predictable manner, such that high-affinity and high-fidelity recognition occurs. The design of linear arrays is made challenging as a consequence of their ability to adopt multiple conformational and tautomeric configurations; with each additional hydrogen-bonding heteroatom added to an array, the available tautomeric and conformational space increases and it can be difficult to anticipate where unproductive conformers/tautomers will arise. This paper describes a detailed study on the complementary ureidoimidazole donor–donor–acceptor (DDA) array (1) and amidoisocytosine donor–acceptor–acceptor (DAA) array (2). A specific feature of 1 is that two degenerate, intramolecular hydrogen-bonded conformations are postulated, both of which present a DDA array that is complementary to appropriate DAA partners. 1D and 2D 1H NMR spectroscopy, isothermal titration calorimetry, and ab initio structure calculations confirm 1 interacts with 2 (Ka≈33000 M−1 in CDCl3) in a conformer-independent fashion driven by enthalpy. Comparison of the binding behaviour of 1 with hexylamidocytosine (4) and amidonaphthyridine (5) provides insight on the role that intramolecular hydrogen-bonding plays in mediating affinity towards DAA partners.