Flavanone-enabled CuAAC Reaction: Noninnocent Reagents Driving a Mononuclear Mechanism Over the Dinuclear Paradigm

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Computational Chemistry

Background:

• Naringenin is a bioactive flavanone with therapeutic potential.
• Triazole moieties are important pharmacophores in drug discovery.
• Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a versatile click chemistry reaction.

Purpose of the Study:

• To synthesize novel triazole derivatives by conjugating a triazole pharmacophore to the naringenin skeleton.
• To investigate the reaction mechanism using computational and experimental methods.
• To explore the catalytic role of copper species in the cycloaddition.

Main Methods:

• Copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction.
• Synthesis of triazole-naringenin conjugates using CuSO4 and sodium ascorbate.
• Density Functional Theory (DFT) calculations.
• High-resolution mass spectrometry (HRMS) for mechanistic studies.

Main Results:

• Moderate to high yields of triazole-naringenin derivatives were achieved using a DMSO-water solvent system.
• Mechanistic investigations suggest a reaction pathway involving a single copper species.
• The cycloaddition step was identified as the rate-determining step in the favored mechanism.

Conclusions:

• The CuAAC reaction provides an efficient route to combine naringenin with triazole pharmacophores.
• The study elucidates the catalytic mechanism, favoring a mononuclear copper species pathway.
• This work contributes to the development of new bioactive compounds with potential pharmaceutical applications.