Controlling Rates and Reversibilities of Elimination Reactions of Hydroxybenzylammoniums by Tuning Dearomatization Energies

Hydroxybenzylammonium compounds can undergo a reversible 1,4- or 1,6-elimination to afford quinone methide intermediates after release of the amine. These molecules are useful for the reversible conjugation of payloads to amines in proteins and peptides. We hypothesized that aromaticity could be used to alter the rate of reversibility as a distinct driving force. We describe the use of density functional theory (DFT) calculations to determine the effect of aromaticity on the rate of release of the amine from hydroxybenzylammonium compounds. Namely, altering the aromatic scaffold to lower the energy of dearomatization reduces the kinetic barrier and prevents the reversibility of the amine elimination. We consequently synthesized a small library of polycyclic hydroxybenzylammoniums, which resulted in a range of release half-lives from 18 minutes to 350 hours. The novel mechanistic insight provided in this study significantly expands the range of release rates amenable to hydroxybenzylammonium-containing compounds. This work is useful for the field of traceless, self-immolative linkers as it provides another way to affect the rate of payload release.