A fast and versatile cross-linking strategy via o-phthalaldehyde condensation for mechanically strengthened and functional hydrogels

Fast and catalyst-free cross-linking strategy is of great significance for construction of covalently cross-linked hydrogels. Here, we report the condensation reaction between o-phthalaldehyde (OPA) and N-nucleophiles (primary amine, hydrazide and aminooxy) for hydrogel formation for the first time. When four-arm poly(ethylene glycol) (4aPEG) capped with OPA was mixed with various N-nucleophile-terminated 4aPEG as building blocks, hydrogels were formed with superfast gelation rate, higher mechanical strength and markedly lower critical gelation concentrations, compared to benzaldehyde-based counterparts. Small molecule model reactions indicate the key to these cross-links is the fast formation of heterocycle phthalimidine product or isoindole (bis)hemiaminal intermediates, depending on the N-nucleophiles. The second-order rate constant for the formation of phthalimidine linkage (4.3 M-1 s(-1)) is over 3000 times and 200 times higher than those for acylhydrazone and oxime formation from benzaldehyde, respectively, and comparable to many cycloaddition click reactions. Based on the versatile OPA chemistry, various hydrogels can be readily prepared from naturally derived polysaccharides, proteins or synthetic polymers without complicated chemical modification. Moreover, biofunctionality is facilely imparted to the hydrogels by introducing amine-bearing peptides via the reaction between OPA and amino group.

Automated summary

A fast and catalyst-free cross-linking strategy using o-phthalaldehyde (OPA) and N-nucleophiles was reported for constructing covalently cross-linked hydrogels. The hydrogels formed have superfast gelation rate, higher mechanical strength, and lower critical gelation concentrations compared to benzaldehyde-based counterparts. The versatile OPA chemistry allows for facile preparation of various hydrogels from naturally derived polysaccharides, proteins, or synthetic polymers, with the ability to introduce biofunctionality by reacting with amine-bearing peptides.