What are the limitations of click chemistry?

One limitation is that some click chemistry reactions require metal catalysts like copper, which can pose compatibility issues in biological systems. Excess copper can lead to health problems such as hepatitis and neurological diseases. The final product often has poor solubility and removing the catalyst after polymerization can be difficult in reactions that require copper. Additionally, in the Huisgen Cycloaddition reactions, sometimes instead of reacting with the azide, alkynes can end up reacting with each other. To ensure efficient click reactions, both the alkyne and azide need to be positioned at the ends of the alkyl chain. Also, getting the necessary reagents commercially available can still be a challenge for researchers. In Staudinger ligation reactions, phosphine reagents are prone to air oxidation, affecting reaction kinetics and efficiency.