Probing the Reactivity of Solid Supports via Hammett Relationships

A high-throughput technique for elucidating Hammett relationships on solid supports and its application to the comparison of various commercially available solid supports is reported. Specifically, we report the use of competition experiments to derive Hammett relationships for the displacement of a solid-supported pentafluorophenyl (pfp) ester with four para-substituted anilines ( p -MeO, p -Me, p -F, p -Cl) and aniline. By taking advantage of the unique physical properties of the solid supports, we were able to conduct competition experiments with seven different solid supports in a single reaction vessel. This enabled us to generate 35 Hammett plots from only 10 reaction vessels. These studies revealed the strong dependence of the Hammett reaction constant ρ on both the solid support and solvent used in the ester displacement reaction. Interestingly, the ρ values obtained for reactions conducted on poly(ethylene glycol)-grafted polystyrene (PS-PEG) resin closely matched the corresponding solution-phase ρ values, a result which supports the supposition that molecules attached to PS-PEG exhibit “solution-like” behavior. Moreover, changing the solvent from DMF to CH 2 Cl 2 greatly reduced the support-to-support variation in ρ, suggesting that the degree of solvation or “swelling” of the solid support greatly influences the chemical environment around the solid-support substrate.