Sequential Topochemical Reactions Through an Evolving Reaction Lattice

ABSTRACT Difficult peptides, particularly those enriched in β ‐branched hydrophobic residues, readily aggregate but often resist crystallization, limiting their use as substrates for topochemical synthesis. Here, we show that a β ‐sheet xerogel (XG) derived from a homochiral valine dipeptide provides a highly ordered supramolecular framework that supports an unprecedented two‐stage topochemical azide–alkyne cycloaddition. Mild heating (70°C) induces quantitative, regiospecific monomer‐to‐dimer conversion with sigmoidal kinetics while preserving the cross‐ β architecture. This first topochemical reaction generates an ordered dimer phase that, upon further heating (160°C), undergoes a second sigmoidal topochemical reaction in which the dimer becomes the operative reactive repeat unit, affording a regiospecific 1,4‐triazole‐linked pseudopolypeptide. Differential scanning calorimetry (DSC) reveals two discrete exotherms that are consumed sequentially, while time‐resolved PXRD shows evolution of the reaction lattice with retention of the characteristic cross‐ β reflections, albeit with changes in the longer‐range diffraction features. Fourier transform infrared (FT‐IR) spectroscopy further supports preservation of the hydrogen‐bonded β ‐sheet framework throughout both transformations. Together, these observations reveal a mechanism in which the β ‐sheet framework persists while the supramolecular structure reorganizes, redefining the reactive periodicity from monomer to dimer.