Three-Fold Metal-Free Efficient (“Click”) Reactions onto a Multifunctional Poly(2-oxazoline) Designer Scaffold

The synthesis of a new multifunctional copoly(2-oxazoline) scaffold containing a-anthracene and ω-azide termini as well as pendant alkene groups in the side chain is described. With its three different functionalities this system represents the first polymer scaffold that can be applied in triple orthogonal (“click”) post-modification reactions. Thus, the functional groups were exploited for sequential 3-fold metal-free efficient reactions encompassing Diels–Alder cycloaddition (DA), thiol–ene coupling (TE) and strain-promoted azide alkyne cycloaddition (SPAAC) reactions. Each reaction was optimized individually to determine the preferential reaction order for the sequential three-step functionalization of the polymer scaffold: SPAAC–DA–TE. The successful progress of the successive reactions was confirmed by 1H NMR spectroscopy, MALDI–TOF MS spectrometry, (online) infrared spectroscopy and UV–Vis spectroscopy, respectively. Furthermore, a one-pot three-step reaction for the 3-fold modification of the polymer scaffold is reported. Finally, the potential of the triple post-modifications for the preparation of functional nanoparticles by nanoprecipitation is presented using various functional groups to tune the overall solubility of the copolymer, to attach cell penetrating or targeting groups and to prepare labeled systems demonstrating the versatility of this approach for the preparation of multifunctional nanoparticles.