Evaluating Nucleophile Byproduct Formation during Phosphine- and Amine-Promoted Thiol–Methyl Acrylate Reactions

The commonly accepted mechanism of nucleophile-initiated thiol–acrylate reactions requires the formation of undesired nucleophile byproducts. A systematic evaluation of the formation of such nucleophile byproducts has been carried out to understand the relationships between byproduct formation and nucleophile structure, stoichiometry, solvent, and reaction type. Three common nucleophiles for thiol-Michael reactions were investigated: dimethylphenylphosphine (DMPP), diethylamine (DEA), and hexylamine (HA). The formation of phosphonium ester and aza-Michael byproducts upon initiating a representative thiol–acrylate reaction between 1-hexanethiol and methyl acrylate at a range of initiator loading (0.01–10.0 equiv) and in different solvents (neat, DMSO, THF, and CHCl3) was determined by 1H NMR spectroscopy. The influence of reaction type was investigated by expanding from small molecule reactions to end group thiol–acrylate functionalization of PEG-diacrylate polymers and through investigations of polymer–polymer coupling reactions. Results indicate that the propensity of forming nucleophile byproducts varies with nucleophile type, solvent, and reaction type. Interestingly, for all but polymer–polymer ligation reactions, nucleophile byproduct formation is largely unobserved for nitrogen-centered nucleophiles DEA and HA and essentially nonexistent for the phorphorous-centered nucleophile DMPP. A rationale for the differences in nucleophile byproduct formation for DMPP, DEA, and HA is proposed and supported by experimental and computational analysis