Dynamic Phosphorus: Thiolate Exchange Cascades with Higher Phosphorothioates

Area of Science:

• Chemical Synthesis
• Supramolecular Chemistry
• Materials Science

Background:

• Dynamic covalent chemistry (DCvC) relies on reversible bond-forming reactions.
• Pnictogens, like phosphorus, are underexplored as core components in DCvC systems.
• Developing new DCvC platforms is crucial for advanced materials and biological applications.

Purpose of the Study:

• To introduce phosphorus-based compounds as versatile exchange centers for DCvC.
• To demonstrate the cascade exchange of phosphorotrithioates and phosphorotetrathioates with thiolates.
• To investigate the factors influencing exchange rates and the behavior of these systems in biological contexts.

Main Methods:

• Synthesis and characterization of neutral phosphorotri- and -tetrathioates.
• Demonstration of cascade exchange reactions in organic solvents, aqueous micellar systems, and live cells.
• Kinetic studies to determine the influence of pH, electrophilicity, and nucleophilicity on exchange rates.
• Computational simulations of molecular walking along Hammett gradients.
• Cytotoxicity assays using HeLa Kyoto cells.

Main Results:

• Phosphorus compounds function effectively as exchange centers in DCvC.
• Cascade exchange reactions were successfully achieved with thiolates under various conditions.
• Exchange rates are pH-dependent and influenced by the electrophilicity of the phosphorus center and nucleophilicity of thiolates.
• Phosphorotetrathioates exhibit higher exchange rates than phosphorotrithioates.
• Dynamic phosphorus compounds are non-toxic and facilitate thiol-mediated cellular uptake.

Conclusions:

• Neutral phosphorotri- and -tetrathioates represent a novel class of building blocks for dynamic covalent chemistry.
• The demonstrated exchange reactions are efficient, tunable, and applicable in biologically relevant media.
• These findings open new avenues for designing dynamic materials and developing targeted drug delivery systems.