Nanoconstruction of Microspheres and Microcapsules Using Proton-Induced Phase Transitions: Molecular Self-Recognition by Diamide Diacids in Water

Bis( N α -amido- l -phenylalanine)-1,1-cyclobutane dicarboxylate ( 5 ) was studied by Fourier transform infrared (FTIR) spectroscopy, variable-temperature NMR (VT-NMR), transmission electron microscopy, X-ray crystallography, Raman microscopy, and a novel imaging technique known as “soft” X-ray microscopy (XRM). Diamide diacid 5 was shown to self-associate into solid microspheres during a proton-induced phase transition from the solvated state to the desolvated assembled state. These diverse techniques allowed for the delineation of the molecular recognition events involved in the assembly process. X-ray crystallography revealed that 5 packs in a bundled helical array comprised of two types of intermolecular hydrogen bonds (i.e., OC O···HN and COOH···O CN). VT-NMR and IR measurements of 5 (1 mM in CDCl 3 ) revealed the small temperature dependence of the amide NH chemical shift (Δδ/Δ T = −1.1 ppb/K) and the availability of the “free” amide NH of 5 to form intermolecular hydrogen bonds. Supramolecular rodlike structures were observed during the aqueous assembly of 5 into microspheres by XRM. Raman microscopy confirmed that nearly identical bonding patterns are present in the assembled microsphere and the crystal architecture of 5 . Collectively, these observations provide compelling evidence that the assembly of 5 occurs via crystalline supramolecular intermediates, which are similar in shape and have complementary bonding motifs for proper self-recognition. Competition experiments involving varying concentrations of 5 and its microcapsule-forming cyclopropane analogue 3 revealed that molecular fidelity was less important to the microsphere-forming process than the related capsule-forming process.