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. 2025 Mar;14(3):e202400289.
doi: 10.1002/open.202400289. Epub 2024 Nov 26.

Toward Polymeric Room Temperature Acid Generators

Joel W Roberts  1 , Amie N Lanzendorf  1 , Jazmin E Aguilar-Romero  1 , Mara L Paterson  1 , Catherine A Jalomo  1 , Ephraim G Morado  1 , Steven C Zimmerman  1
Affiliations

Toward Polymeric Room Temperature Acid Generators

Joel W Roberts et al. ChemistryOpen. 2025 Mar.

Abstract

Although a variety of acid-generating molecules have been developed, the formation of toxic byproducts and the need for light-activation or temperatures that may be incompatible with physiological conditions leave room for the optimization of biocompatible acid-generators. Herein, we report 4-hydroxybenzyl chloride derivatives that generate hydrochloric acid via hydrolysis at the benzylic position at room temperature in the absence of light. Utilizing the acetal protected 4-hydroxybenzyl chloride scaffold, we access a myriad of compounds that generate acid at different rates.

Keywords: Acid amplification; Acid generator; Cancer; Drug delivery; Extra cellular pH.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Ichimura AA 1 and its proposed mechanism of auto‐catalytic acid generation (1→2→3). R=H or NO2 and reaction occurred in acetonitrile at 70 °C. Quinone methide 3 reacts with nucleophiles such as water to produce 4.
Scheme 2
Scheme 2
Mechanism by which 3‐iodopropyl acetal undergoes acid amplified cleavage with liberation of HI and acrolein. Analogous polyacetals underwent acid amplified chain cleavage at elevated temperatures.
Scheme 3
Scheme 3
Acetal 5 studied here and two possible mechanisms for its decomposition to produce HCl.
Scheme 4
Scheme 4
Synthetic route to acetals used in this study.
Figure 1
Figure 1
Representative pH vs time curves of 10 mM solution of 5 in 30 % (v/v) MeCN/H2O PBS buffer. Reported averages are based on 3 independent trials (see Figure S1). Reported error is standard error.
Figure 2
Figure 2
NMR spectra over time of 10 mM 5 in 30 % (v/v) MeCN‐d 3/D2O PBS buffer (initial pD=7.4). The red star indicates the key acetal peak.
Figure 3
Figure 3
Representative pH vs time curves of (a) 8 (b) 9, (c) 10, and (d) 11. All reactions were conducted with an initial concentration of 10 mM compound in 30 % (v/v) MeCN/H2O PBS buffer. Reported averages are based on 3 independent trials (Figures S4, S5, S6, and S7). Reported errors are standard error.
Scheme 5
Scheme 5
Synthesis of acid generating monomer 17.
Scheme 6
Scheme 6
Synthesis of P1 by ROMP using Grubbs catalyst 19.
Figure 4
Figure 4
Plot of pH over time with 5 mg/mL of P1 in deionized water initial pH=5.6 (blue) and 0.1 M acetate buffer initial pH=5.6 (green).
See this image and copyright information in PMC

References

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