Efficient DNA–Polymer Coupling in Organic Solvents: A Survey of Amide Coupling, Thiol-Ene and Tetrazine–Norbornene Chemistries Applied to Conjugation of Poly(N-Isopropylacrylamide)

Abstract

A range of chemistries were explored for the efficient covalent conjugation of DNA to poly(N-isopropylacrylamide) (poly(NIPAM)) in organic solvents. Amide coupling and thiol–ene Michael addition were found to be ineffective for the synthesis of the desired products. However, the inverse electron-demand Diels–Alder (DAinv) reaction between tetrazine (Tz) and norbornene (Nb) was found to give DNA–polymer conjugates in good yields (up to 40%) in organic solvents (N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone), and without the need for a catalyst. Methods for the synthesis of Tz-and Nb- functionalised DNA were developed, along with a post-polymerisation functionalisation strategy for the production of Tz-functionalised polymers.