Controlling rates and reversibilities of elimination reactions of hydroxybenzylammoniums by tuning dearomatization energies

• Published in: Chemical science (Cambridge) 2024-07, Vol.15 (27), p.1448-1454
• Main Authors: Fu, Zihuan, Treacy, Joseph W, Hosier, Brock M, Houk, K. N, Maynard, Heather D
• Format: Article
• Language: English
• Subjects: Amines; Aromatic compounds; Aromaticity; Chemical synthesis; Chemistry; Conjugation; Density functional theory; Payloads; Quinones
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d4sc02985b

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. We hypothesized that aromaticity could be used to alter the rate of reversibility as a distinct thermodynamic 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, the aromatic scaffold affects the dearomatization reaction to reduce the kinetic barrier and prevent 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 herein significantly expands the range of release rates amenable to hydroxybenzylammonium-containing compounds. This work provides another way to affect the rate of payload release in hydroxybenzylammoniums. The factors that govern hydroxybenzylammonium-mediated amine releasing reactions have been computationally examined. This mechanistic insight led to subsequent experimental validation and generation of release half-lives as fast as 18 minutes.