Topochemical Azide–Alkyne Cycloaddition Reaction in Gels: Size-Tunable Synthesis of Triazole-Linked Polypeptides

Abstract

Though topochemical reactions are attractive, the difficulty associated with crystallization such as low yield, unsuitability for large-scale synthesis, etc. warranted the exploitation of other self-assembled media for topochemical reactions. We synthesized a dipeptide gelator decorated with azide and alkyne at its termini, N3-Ala-Val-NHCH2-C≡CH, which is designed to self-assemble through intermolecular hydrogen bonds to β-sheets thereby placing the azide and alkyne motifs in proximity. As anticipated, this peptide forms gels in organic solvents and water via hydrogen-bonded β-sheet assembly as evidenced from IR spectroscopy and PXRD profiling. The microscopic fibers present in organogel and hydrogel have different morphology as was evident from scanning electron microscopy (SEM) imaging of their xerogels, XGh (xerogel made from hydrogel) and XGo (xerogel made from organogel). Heating of xerogels at 80 °C resulted in the topochemical azide–alkyne cycloaddition (TAAC) polymerization to 1,4-triazole-linked oligopeptides. Under identical conditions, XGo produced larger oligopeptides, and XGh produced smaller peptides, as evidenced from MALDI-TOF spectrometry. We have also shown that degree of TAAC polymerization can be controlled by changing gel fiber thickness, which in turn can be controlled by concentration. SEM studies suggested the morphological intactness of the fibers even after the reaction, and their PXRD profiles revealed that both XGh and XGo undergo fiber-to-fiber oligomerization without losing their crystallinity. In contrast to crystals, the xerogels undergo TAAC polymerization in two distinct stages as shown by DSC analyses. Interestingly, XGh and XGo undergo spontaneous TAAC polymerization at room temperature; the latter shows faster kinetics. This is not only the first demonstration of the use of xerogels for thermally induced topochemical polymerization but also the first report on a spontaneous topochemical reaction in xerogels.