The copper(I)-catalyzed 1,2,3-triazole forming reaction between azides and terminal alkynes (also known as Copper Catalyzed Azide-Alkyne Cycloaddition (CuAAC)) and the ruthenium catalyzed 1,2,3-triazole forming reaction between azides and terminal or internal alkynes (also known as Ruthenium Catalyzed Azide-Alkyne Cycloaddition (RuAAC), both developed at The Scripps Research Institute (TSRI), are leading examples of the click chemistry approach. The use of CuAAC results in the formation of a 1,4-regioisomer whereas RuAAC results in the formation of the 1,5-regioisomer.
Click chemistry is a modular synthetic approach towards the assembly of new molecular entities by efficiently and reliably joining small units together. By applying this concept, it becomes possible to produce manmade compounds of vastly greater diversity than what is currently known or available. The copper-catalyzed cycloaddition of azides and alkynes (CuAAC) developed for click chemistry by Professors Valery V. Fokin and Nobel Laureate K. Barry Sharpless at TSRI has become emblematic of the click chemistry philosophy.
The traditional Huisgen cycloaddition reaction joins an organic azide and alkyne together by heating, often to more than 100 °C for a least several hours that produces a mixture of 1,4- and 1,5-triazoles (Scheme 1). Copper catalysts discovered by Fokin and Sharpless accelerate the reaction to minutes and at much lower temperatures. The result of this copper catalyzed reaction is mostly, if not completely, a 1,4-triazole product (Scheme 2). The copper catalyzed reaction proceeds well in both aqueous and organic solvents under very simple experimental conditions. This characteristic along with the unnecessary requirement of high temperatures radically improves the utility of this reaction. In addition, the improved reaction is so thermodynamically favorable as to be irreversible.
The use of copper led the investigators to successfully use other metals as catalyst, like Ruthenium, in the Huisgen cycloaddition. In contrast to copper catalysts, ruthenium-catalyzed reactions proceed both with internal and terminal alkynes, and produces a 1,5-regioisomers.
Publications citing click chemistry has seen explosive growth in recent years with a number of applications being described. Of the click chemistry reactions, the CuAAC reaction currently has the greatest potential for commercial application across a number of different industries. For simplicity, these applications can be categorized into two major categories: (i) life sciences and (ii) materials science.
In the Life Sciences category, bioconjugation is one of the most commonly cited uses of click chemistry and is a term generally used to describe a technique in which a synthetic label (e.g. fluorophores, ligands, chelates, or radioisotopes) is covalently linked to a biomolecule (e.g. proteins and nucleic acids). However, bioconjugation can also include the fusing of biomolecules with other biomolecules. The research/life sciences market and diagnostic markets are most interested in this application of click chemistry. In the life sciences market, click chemistry allows researchers to label and detect biomolecules in a live cell or a complex cell lysate with greater selectivity and specificity. In the diagnostic market, it allows a physician or a radiologist to label biomarkers to detect the progression of a disease in a patient or the effectiveness of a treatment to treat a disease. Other published literature have described using click chemistry to design and make new compounds or help modify existing compounds to change their biochemistry.
Material science is the creation of new materials with specific desired properties. For example, coatings for glass, metals, plastics and other surfaces that could be impact and corrosion resistant, responsiveness to light, or controlled permeability to liquids and gas. Specific applications include the making of antibacterial, anti-immunogenic coatings for medical implants or metal coatings for semiconductors.