Nanoconstruction of microspheres and microcapsules using proton-induced phase transitions: Molecular self-recognition by diamide diacids in water

Bis(N-alpha-amido-L-phenylalanine)-1,1-cyclobutane dicarboxylate (5) was st udied by Fourier transform infrared (FTIR) spectroscopy, variable-temperatu re NMR (VT-NMR), transmission electron microscopy, X-ray crystallography, R aman microscopy, and a novel imaging technique known as "soft" X-ray micros copy (XRM). Diamide diacid 5 was shown to self-associate into solid microsp heres during a proton-induced phase transition from the solvated state to t he desolvated assembled state. These diverse techniques allowed for the del ineation of the molecular recognition events involved in the assembly proce ss. X-ray crystallography revealed that 5 packs in a bundled helical array comprised of two types of intermolecular hydrogen bonds (i.e., OC=O . . . H N and COOH . . .O=CN). VT-NMR and IR measurements of 5 (1 mM in CDCl3) reve aled the small temperature dependence of the amide NH chemical shift (Delta delta/DeltaT = -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. Ra man microscopy confirmed that nearly identical bonding patterns are present in the assembled microsphere and the crystal architecture of 5. Collective ly, these observations provide compelling evidence that the assembly of 5 o ccurs via crystalline supramolecular intermediates, which are similar in sh ape and have complementary bonding motifs for proper self-recognition. Comp etition experiments involving varying concentrations of 5 and its microcaps ule-forming cyclopropane analogue 3 revealed that molecular fidelity was le ss important to the microsphere-forming process than the related capsule-fo rming process.