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

Abstract

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 (1)H NMR spectroscopy, isothermal titration calorimetry, and ab initio structure calculations confirm 1 interacts with 2 (K(a) ≈ 33,000 M(-1) in CDCl(3)) 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.

Synthesis of 5‐/8‐Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolec­ular Chemistry

“…[12] A diphenylcarbamoyl protecting group [36] was selected among diverse options, but compound G11 was still unreactive in any Pd-catalyzed Sonogashira or Stille reaction conditions we tried. Therefore, G11 was subjected first to an alkylation reaction either with ethyliodide, 3,4,5-tris(dodecyloxy)benzyl bromide or with tertbutyl bromoacetate.…”

Computational study of the thermodynamic stabilities of hydrogen-bonded complexes in solution

“…Recently, Wilson and coworkers introduced the concept of conformer-independent H-bonding motifs between the novel ureidoimidazole (1, UIM) and amidoisocytosine (2, AIC) H-bonded pairs [42]. The H-bonding of 1-2 was used to form tunable self-assembled elastomers [48].…”

“…In addition, we also thoroughly investigated two newly developed triply H-bonded complexes. One is a well-designed conformer-independent triply H-bonded complex [42], the other was reported to be the most strongly bound neutral H-bonded complex with a DDD-AAA array [43]. In our research, we aim to seek an automated, robust and reliable computational tool to study H-bonding and van der Waals interactions, respectively, for practical chemists and undergraduate students, which can help them to make scientific discoveries and predictions before "setting foot in the laboratory" [31].…”

Strategies for assessing proton linkage to bimolecular interactions by global analysis of isothermal titration calorimetry data

“…It was shown previously by Armstrong et al [3] that fitting a single, unambiguous mathematical binding model to all available experimental data at the different conditions is the most powerful analysis approach. Global analysis has also been found to be a very powerful ITC data analysis concept for the study of two- and three-component complexes with multi-site binding and cooperativity [23; 24; 25; 26; 27; 28; 29]. For the latter purpose we have previously introduced the global modeling capabilities of the software SEDPHAT [26], which is a public domain analysis tool for the global and multi-method modelling of biophysical binding data from various techniques besides ITC, including analytical ultracentrifugation, light scattering, surface plasmon resonance biosensing, and different spectroscopy techniques.…”

“…For the latter purpose we have previously introduced the global modeling capabilities of the software SEDPHAT [26], which is a public domain analysis tool for the global and multi-method modelling of biophysical binding data from various techniques besides ITC, including analytical ultracentrifugation, light scattering, surface plasmon resonance biosensing, and different spectroscopy techniques. It offers many binding models, is flexible and user-friendly in that it has a graphical user interface that does not require any scripting, and has found various applications in ITC to study protein interactions [23; 27; 29; 30; 31; 32; 33; 34]. For the present work we have implemented two protonation models for global analysis of ITC data with multiple buffer ionization enthalpies, temperatures, and/or pH values.…”