CHAPTER 5: Nucleophilic Thiol‐alkene Michael Addition for the Functionalization of Polymers and for Bioconjugation

Thiol‐ene reactions can be efficiently catalysed by appropriate bases and nucleophiles. The most efficient catalysts are usually primary amines or certain phosphines which preclude the need for light and offer an attractive alternative to radical thiol‐ene reactions, which generally use thermal free radical generators such as azo compounds or light. The base catalysed thiol‐ene lends itself to polymer modification reactions and bioconjugation. Perhaps one of the most utilised thiol‐alkene reactions is the Michael addition at maleimides, which has been used effectively for pegylation and bioconjugation at cysteines. This effective reaction is excellent for site‐specific conjugation at either naturally occurring thiols or where the cysteine has been introduced by chemical or biological manipulation. The Michael addition to maleimides has been extended to substitution reactions at dibromo‐ and dithio‐functional maleimides leading to very efficient reactions. Polymer modification via thiol‐ene Michael addition can occur with either thiol or vinyl functional polymers. Polymeric acrylates can be used as effective bioconjugation agents to cysteine, and polymers containing disulphides or free thiols can be readily modified by reaction with acrylates, methacrylates and related small molecules.