Control of Structural Isomerism in Noncovalent Hydrogen-Bonded Assemblies Using Peripheral Chiral Information

Abstract

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 D3, C3h, or Cs symmetry. The isomeric distribution can be readily determined via a combination of 1H NMR and 13C 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 D3 and C3h isomeric forms of the assembly. For the D3 isomer the RCM results in the formation of a cyclic trimer, comprising three dimelamines, whereas for the C3h 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 D3 isomer, because steric hindrance between the barbiturate substituents prevents formation of the C3h and Cs isomers. In contrast, assemblies with isocyanuric acid derivatives exhibit increased stability of the C3h and Cs 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.