A New Methodology for Assessing Macromolecular Click Reactions and Its Application to Amine-Tertiary Isocyanate Coupling for Polymer Ligation

Click reactions have provided access to an array of remarkably complex polymer architectures. However, the term click is often applied inaccurately to polymer ligation reactions that fail to respect the criteria that typify a true click reaction. With the purpose of providing a universal way to benchmark polymer polymer coupling efficiency at equimolarity and thus evaluate the fulfilment of click criteria, we report a simple one-pot methodology involving the homodicoupling of alpha-end-functionalized polymers using a small-molecule bifunctional linker. A combination of SEC analysis and chromatogram deconvolution enables straightforward quantification of the coupling efficiency. We subsequently employ this methodology to evaluate an overlooked candidate for the click reaction family: the addition of primary amines to alpha-tertiary isocyanates (alpha-(NCO)-N-t). Using our bifunctional linker coupling strategy, we show that the amine-(NCO)-N-t reaction fulfills the criteria for a polymer polymer click reaction, achieving rapid, chemoselective, and quantitative coupling at room temperature without generating any byproducts. We demonstrate that amine-(NCO)-N-t coupling is faster and more efficient than the more common amine tertiary active ester coupling under equivalent conditions. Additionally, we show that the alpha-(NCO)-N-t end group is unprecedentedly stable in aqueous media. Thus, we propose that the amine-(NCO)-N-t ligation is a powerful new click reaction for efficient macromolecular coupling.