Molecular Modeling of the 1,1-Cyclopropane- and 1,1-Cyclobutanedicarboxamide Systems. Insights into the Self-Assembly of Diamide Diacids in Water

Modeling of the following compounds bis-(N--amido-L-phenylalaninyl)-1,1-cyclopropane dicarboxylate, 3, and bis-(N--amido-L-phenylalaninyl)-1,1-cyclobutane dicarboxylate, 4, were undertaken. The study involved construction and optimization of the precursory 1,1-dicarboxaldehydes and continued stepwise via the 1,1-dicarboxamides, the bis-N-(methyl)dicarboxamides, the bis(N--amidoglycinyl) dicarboxylates, the bis(N--amido-L-alaninyl) dicarboxylates and onto the targeted bis(N--amido-L-phenylalaninyl) dicarboxylates. Using the X-ray crystal structure of 4 (i.e., 4X) as a guide, we found that our approach was not able to reproduce the packable conformer of 4, via the computational methods employed. Nevertheless, an enhanced understanding of the intramolecular hydrogen bonding patterns available to these systems was obtained from IR and VT-NMR studies. In summary, the conformational preferences found in the 1,1-disubstituted cycloalkanes (3 and 4) direct their respective self-assembly processes by controlling the orientation of their amide NH populations.