Click Chemistry Reagents

Nature has ability to generate an unending array of molecules from very small number of building blocks, even simple microbes such as E. coli have synthetic chemical prowess that can bring the most sophisticated organic chemistry labs to their shame. Inspired by the nature’s ability to knit complex molecules from a small number of building blocks, using simple modular reactions, Berry Sharpless, and his coworkers, defined and invented the area of ‘click chemistry’. Together, Berry Sharpless and Carolyn Bertozzi redefined the use of simple modular reactions that had already existed to modify biomolecules in situ using chemistry that did not interfere with their native biological reactions and functions, known as Bioorthogonal Chemistry. 

What is click chemistry?

Click Chemistry is defined by several essential features;

1.  Reaction should go to completion without side products. 
   The key fact is ‘Click’ reactions do have a high thermodynamic driving force. There is just one predominant outcome of reaction, like fitting blocks together in a LEGO with a “click” you get two simple molecules combine.
2. Should be easily performed in benign solvents like water.
   Click chemistry is green in its approach
3. Tolerant of other side groups. No protection and deprotection is required.
   Simple, hassle free organic synthesis is the aim.
4. The product should be easily isolated; no complicated and costly purification steps are required.

The most popular and widely used click  reaction is Cu(I)- catalysed Huisgen, 1,3-dipolar cycloaddition reaction of terminal alkynes and azides to generate 1,2,3-triazoles (See Figure 1A). Copper catalysed Huisgen reaction can happen in aqueous medium, can tolerate a wide range of pH from 5 to 12, it does not require any thermal activation (can occur between 0 to 160°C). The most interesting part about this click reaction is its orthogonal character, which has made it so popular amongst biochemists, chemical biologists and protein chemists. The term orthogonal nature or bio-orthogonal character implies that the participating reactants, a terminal alkyne and an azide moiety, can combine with each other, driven by a high thermodynamic force but they don’t react with other molecules in the cell, which according to Barry Sharpless is “is to create highly reactive ‘sticky spots’ with the right target groups while having them remain invisible to most other types of molecule”. This character is called bio-orthogonal and enables chemical biologists and protein scientists to apply this reaction to a range of applications for chemical proteomics.