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

Abstract

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.

Design Strategies for Functionalized Poly(2-oxazoline)s and Derived Materials

“…Hoogenboom, Schubert and co-workers investigated these thermoresponsive copolymers and found a linear correlation between the cloud point temperatures and the content of sugar groups; consequently the cloud points can be tuned as requested. Telechelic pEtOx-stat-p n Dec = Ox, end-functionalized with an azide and an anthracene functionality, respectively, in addition enabled for triple post-modification due to the three different orthogonal click-able functional groups: azide alkyne cycloaddition (azide), Diels-Alder cycloaddition (anthracene), and thiol-ene click chemistry (p n Dec = Ox) [187]. In this context, the reader's attention is brought to the work of Böhme and co-workers who synthesized multifunctional coupling agents bearing a 2-oxazoline, an azinone, and an allyl ether group [188].…”

Poly(2-oxazoline)s and click chemistry: A versatile toolbox toward multi-functional polymers

“…68 Here, three different clickable groups were incorporated into the PAOx structure, namely anthracene (initiation), alkene (side-chain) and azide (termination). Three Cu-free reactions, namely the Diels-Alder, thiol-ene and SPAAC reaction with maleimide, a thiolfunctionalized sugar and cyclootyne, respectively, could be performed in a one-pot synthesis, emphasizing the orthogonality of the different reactions.…”

Synthesis and gelation properties of poly(2-alkyl-2-oxazoline) based thermo-gels

“…These are synthesized via a cationic ring opening polymerization which allows polymers with a narrow polydispersity index (PDI) to be prepared. In addition, it provides a convenient route for controlling end-group functionality through careful design of the initiator and terminator 13 , see Figure 2. One poly(2-oxazoline) of considerable interest is poly(2-isopropyl-2-oxazoline) (PiPrOx), which has an LCST of 36°C 14 , similar to that of PNiPAAM.…”