Indane 2,5-diketopiperazine synthons as probes of solid, solution and gas phase supramolecular non-covalent associations: Synthesis, characterization, and analysis of indane amino acids, unnatural bis-amino esters, indane 2,5-diketopiperazines,

Abstract

Non-covalent interactions influence supramolecular organization in the solid, solution and gaseous state. While intermolecular forces are well understood individually, it is difficult to predict how their interplay will lead to a highly symmetric and low energy crystalline solid. Analysis, design, and prediction of crystalline architecture is a recently popularized sub-field of supramolecular chemistry referred to as 'crystal engineering'. Crystal engineering seeks to fully understand non-bonding intermolecular forces in order to build crystalline solids that serve some designed purpose. Hydrogen bonds are strong and directional intermolecular forces used to build crystalline solids with desirable supramolecular topography. Much focus has been placed on cyclic diamides, such as diureas and dioxamides, as robust structural motifs due to their propensity to form highly rigid hydrogen bonded structures. The diketopiperazine is an exceptional cyclic diamide synthon due to its planar, inflexible, ring structure and predictable solid state organization. Professor E. A. Mash has studied the indane diketopiperazine designed such that hydrogen bonding occurs along one principal axis, while two orthogonal and linearly independent non-covalent interactions occur 90° offset from each other. Substitution changes to the indane ring system can explore a range of non-bonding interactions influencing self-recognition. Several different 1,4-alkyloxy indane 2,5-diketopiperazines were synthesized and studied. The 1,4-dodecyloxy and 1,4-octadecyloxy diketopiperazines are liquid crystalline as observed by differential scanning calorimetry and optical microscopy. The 1,4-dodecyloxy diketopiperazine crystal structure, while exhibiting much alkyl chain disorder, indicated the supramolecular construct remained constant throughout the 1,4-alkyloxy indane diketopiperazine series. In order to better understand non-bonding associations of the indane diketopiperazines in the solid, solution and gas phase, an N-methylated 1,4-methyloxy 2,5-diketopiperazine was synthesized and studied by X-ray crystallography, ESI mass spectrometry, and by UV-VIS and NMR spectroscopy. While the solid state N-Me diketopiperazine is polymorphic, existing as hydrogen bonded dimer and polymer, the gas and solution phase experiments indicated predominant dimeric associations. 1,4-Dialkyloxy indane bis-diketopiperazines were envisioned as the next generation of robust indane targets, and their synthesis required construction of novel unnatural bis-amino esters. All of the bis-diketopiperazines exhibited extremely high melting points and low solubilities. Microcrystalline bis-diketopiperazine material was analyzed by X-ray powder diffraction.