Control of structural isomerism in noncovalent hydrogen-bonded assemblies using peripheral chiral information

The results of a systematic study of the structural isomerism in more than 30 noncovalent hydrogen-bonded assemblies are described. These dynamic assemblies, composed of three calix[4]arene dimelamines and six barbiturates/cyanurates, can be present in three isomeric forms with either D-3, C-3h, or C-s symmetry. The isomeric distribution can be readily determined via a combination of H-1 NMR and C-13 NMR spectroscopy. In one case it is shown that the covalent capture of the dynamic assemblies via a ring-closing metathesis (RCM) reaction provides a novel analytical tool to distinguish between the D-3 and C-3h isomeric forms of the assembly. For the D-3 isomer the RCM results in the formation of a cyclic trimer, comprising three dimelamines, whereas for the C-3h isomer a cyclic monomer is formed. Molecular dynamics simulations in chloroform are qualitatively in agreement with the experimental data and reveal that the isomeric distribution is determined by a combination of steric, electronic, and solvation effects. A wide range of isomeric distributions covering all extremes has been found for the studied assemblies. Those with 5,5-disubstituted barbituric acid derivatives exclusively form the D-3 isomer, because steric hindrance between the barbiturate substituents prevents formation of the C-3h and C-s isomers. In contrast, assemblies with isocyanuric acid derivatives exhibit increased stability of the C-3h and C-s isomers upon increasing the size of the isocyanurate substituent. The outcome of the assembly process can be controlled to a large extent via chiral substituents in the calix[4]arene dimelamines, due to the preferred orientation of the chiral centers.