<i>α</i> ‐Functionalization of Polyethers With <scp>NHS</scp> Ester for Orthogonal Conjugation

ABSTRACT Poly(ethylene glycol) (PEG) derivatives (polyethers) with functional groups attached as pendants and at the chain ends (hetero‐multifunctional polymers) provide numerous opportunities for synthetic modification. Exploiting these functionalities to conjugate polyethers to proteins, nanoparticles, other polymers, and low molecular weight drugs/molecules has prompted innovations in a vast range of applications, including drug delivery, sensors, coatings, and energy storage. The coupling of PEG or PEG derivatives to a target moiety often requires postmodification of the chain termini in order to introduce functional groups selective to the available reactive groups on the target moiety, one of the most common being succinimidyl esters that readily react with lysine residues on proteins. Thus, an NHS dimethyl aluminum initiator (NHS‐SAl) was synthesized and used to directly incorporate an NHS terminus with a functional initiator ( α ‐functionalization) in multifunctional PEG derivatives, poly(propylene oxide), poly(epichlorohydrin), and poly(allyl glycidyl ether), for facile conjugation to primary amines. NHS‐SAl can be easily synthesized from the reaction of an N ‐hydroxy succinimide ester and trimethylaluminum. The structure and kinetics of polymerizations initiated from NHS‐ SAl were investigated to gain an understanding of the synthetic methodology, as well as structural and composition capabilities. Polymer end group reactivity was confirmed by coupling to amine‐modified silica nanoparticles, poly(ethyleneimine), bovine serum albumin, and other small amine‐containing molecules. Overall, a novel synthetic route for multifunctional PEG derivates with direct incorporation of a terminal NHS group by α ‐functionalization was established, further augmenting polymer conjugation methods.