Click processes orthogonal to CuAAC and SuFEx forge selectively modifiable fluorescent linkers

Area of Science:

• Organic Chemistry
• Catalysis
• Polymer Chemistry
• Medicinal Chemistry

Background:

• Copper-catalyzed azide-alkyne cycloaddition (CuAAC) and sulfur-fluoride exchange (SuFEx) are key click chemistry reactions.
• CuAAC yields non-modifiable triazole rings, and SuFEx connectors lack selective functionalization.
• There is a need for click chemistry methods that provide modifiable and functionalizable linkages.

Purpose of the Study:

• To introduce novel click chemistry reactions that overcome limitations of existing methods.
• To develop reactions yielding robust, alterable, and tunable fluorescent molecular hubs.
• To demonstrate the utility of these new methods in complex molecular synthesis.

Main Methods:

• Bisphosphine-copper-catalyzed phenoxydiazaborinine formation (CuPDF) for linking nitriles, allenes, diboranes, and hydrazines.
• Copper- and palladium-catalyzed quinoline formation (Cu/PdQNF) in aqueous media using anilines as modifiers.
• Orthogonal application of CuPDF and Cu/PdQNF with CuAAC and SuFEx.

Main Results:

• CuPDF and Cu/PdQNF reactions are easily performed, yielding robust, alterable, and tunable fluorescent hubs.
• Both new methods are orthogonal to CuAAC and SuFEx, expanding click chemistry compatibility.
• Successful application in protecting group-free synthesis of branched oligomers, a modifiable polymer, and drug conjugates.

Conclusions:

• CuPDF and Cu/PdQNF represent significant advancements in click chemistry, offering enhanced modularity and functionality.
• These methods provide versatile platforms for constructing complex molecular architectures, including polymers and drug delivery systems.
• The developed reactions broaden the scope of click chemistry for applications in materials science and medicinal chemistry.