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

Abstract

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.

Facile approach to prepare pH and redox-responsive nanogels via Diels-Alder click reaction

“…Drug molecules can be efficiently loaded in nanogels before or after crosslinking process [13][14][15]. Cleavable crosslinks (e.g., ester, acetal, ketal, disulfide, hydrazine, amide, and anhydride bonds) are inserted either in cross-linkers or polymeric chains for allowing degradation of the nanogels network [16][17][18]. Recently, the Diels-Alder (DA) click reaction between maleimide and furan has attracted much attention for the design of crosslinked nanogels, since they can be efficiently carried out in water at low temperature without any catalyst and side-products [19][20][21][22].…”

A new design of cleavable acetal‐containing amphiphilic block copolymers triggered by light

“…Acetals are commonly used protecting groups for carbonyls or diols. They can be hydrolyzed under acidic condition (pH < 7) but they are very stable with respect to hydrolysis at pH > 7 . There are examples showing acetals of salicylaldehyde and coumarin derivatives to be excellent photolabile protection groups, comparable to benzyl‐based esters .…”

“…They can be hydrolyzed under acidic condition (pH < 7) but they are very stable with respect to hydrolysis at pH > 7. [23][24][25][26][27] There are examples showing acetals of salicylaldehyde and coumarin derivatives to be excellent photolabile protection groups, comparable to benzyl-based esters. 28,29 Therefore, those acetals are ideal chromophores to combine dual responsiveness, that is, light and pH, to a homopolymer.…”

Altering the Peptide Binding Selectivity of Polymeric Reverse Micelle Assemblies via Metal Ion Loading

“…18−28 As an example, polymeric nanogels with acetal- and ketal-based linkers show a variable encapsulation/release ability for guest molecules via pH-dependent cross-linker degradation. 21 …”