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 3 h, or C s symmetry. The isomeric distribution can be readily determined via a combination of 1 H NMR and 13 C 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 3 h 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 3 h 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 3 h and C s isomers. In contrast, assemblies with isocyanuric acid derivatives exhibit increased stability of the C 3 h 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.