Substituent Effects on the pH Sensitivity of Acetals and Ketals and Their Correlation with Encapsulation Stability in Polymeric Nanogels

摘要

Effect of structural variations in acetal- and ketal- based linkers upon their degradation kinetics is studied through the design, synthesis and study of six series of molecules, comprising a total of eighteen different molecules. Through this systematic study, we show that the structural fine-tuning of the linkers allow access to variations in kinetics of degradation of more than six orders of magnitude. Hammett correlations show that the ρ value for the hydrolysis of benzylidene acetals is about −4.06, which is comparable to an SN1-like process. This shows that there is a strong, developing positive charge at the benzylic position in the transition state during the degradation of acetals. This positively charged transition state is consistent with the relative degradation rates of acetals vs. ketals (correlated to stabilities of 1°, 2°, and 3° carboxonium ion type intermediates) and the observed effect of proximal electron-withdrawing groups upon the degradation rates. Following this, we studied whether the degradation kinetics study correlates with pH-sensitive variations in the host-guest characteristics of polymeric nanogels that contains these acetal or ketal moieties as crosslinking functionalities. Indeed, the trends observed in the small molecule degradation have clear correlations with the encapsulation stability of guest molecules within these polymeric nanogels. The implications of this fundamental study extend to a broad range of applications, well beyond the polymeric nanogel examples studied here.