Conformational Preferences and Self-Template Macrocyclization of Squaramide-Based Foldable Modules

Abstract

Secondary squaramides have considerable potential as hydrogen bond donors and acceptors. In CHCl₃ both, anti- and syn-squaramide rotamers are observed by NMR. The energetic barrier for anti/syn mutual interconversion determined by complete band shape analysis is ∼63 kJ mol^-1. As in proline derivatives, a low rotational barrier is crucial for the design of foldable modules. In this paper, folding based on the low rotational barrier of squaramides is driven by donor atoms (N or O) located in the γ position of an alkyl chain of a secondary squaramide. We demonstrate that the resulting minimal module exists as a folded conformer through the formation of a nine-membered ring stabilized by intramolecular hydrogen bonding. Molecular mechanics calculations and NMR studies support the existence of these folded conformers. The intramolecularly hydrogen bonded conformers are clearly visible even in CHCl₃−EtOH mixtures. Folding occurs even in pure ethanol. As an indirect test, we studied the effectiveness of macrocyclization reactions in pure ethanol that require an effective templating effect to take place. The high yields obtained support the dominant role of a folded conformer even in this solvent.