A Thermally Stable SO2-Releasing Mechanophore: Facile Activation, Single-Event Spectroscopy, and Molecular Dynamic Simulations

Yunyan Sun; William J Neary; Xiao Huang; Tatiana B Kouznetsova; Tetsu Ouchi; Ilia Kevlishvili; Kecheng Wang; Yingying Chen; Heather J Kulik; Stephen L Craig; Jeffrey S Moore

doi:10.1021/jacs.4c02139

A Thermally Stable SO₂-Releasing Mechanophore: Facile Activation, Single-Event Spectroscopy, and Molecular Dynamic Simulations

J Am Chem Soc. 2024 Apr 17;146(15):10943-10952. doi: 10.1021/jacs.4c02139. Epub 2024 Apr 6.

Authors

Yunyan Sun^{1

2}, William J Neary^{1

2}, Xiao Huang³, Tatiana B Kouznetsova⁴, Tetsu Ouchi⁴, Ilia Kevlishvili⁵, Kecheng Wang¹, Yingying Chen^{2

6}, Heather J Kulik^{3

5}, Stephen L Craig⁴, Jeffrey S Moore^{1

2}

Affiliations

¹ Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
² Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
³ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
⁴ Department of Chemistry, Duke University, Durham, North Carolina 27708, United States.
⁵ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
⁶ Department of Material Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.

PMID: 38581383
DOI: 10.1021/jacs.4c02139

Abstract

Polymers that release small molecules in response to mechanical force are promising candidates as next-generation on-demand delivery systems. Despite advancements in the development of mechanophores for releasing diverse payloads through careful molecular design, the availability of scaffolds capable of discharging biomedically significant cargos in substantial quantities remains scarce. In this report, we detail a nonscissile mechanophore built from an 8-thiabicyclo[3.2.1]octane 8,8-dioxide (TBO) motif that releases one equivalent of sulfur dioxide (SO₂) from each repeat unit. The TBO mechanophore exhibits high thermal stability but is activated mechanochemically using solution ultrasonication in either organic solvent or aqueous media with up to 63% efficiency, equating to 206 molecules of SO₂ released per 143.3 kDa chain. We quantified the mechanochemical reactivity of TBO by single-molecule force spectroscopy and resolved its single-event activation. The force-coupled rate constant for TBO opening reaches ∼9.0 s^-1 at ∼1520 pN, and each reaction of a single TBO domain releases a stored length of ∼0.68 nm. We investigated the mechanism of TBO activation using ab initio steered molecular dynamic simulations and rationalized the observed stereoselectivity. These comprehensive studies of the TBO mechanophore provide a mechanically coupled mechanism of multi-SO₂ release from one polymer chain, facilitating the translation of polymer mechanochemistry to potential biomedical applications.