What is Click Chemistry?

By Devansh Jhawar | 29 September 2024

The ‘click’ in click chemistry is intended to convey that sense of satisfaction you receive when you put Lego pieces together. In fact, the story goes that the term was coined by Jan Dueser, the wife of K. Barry Sharpless, the American chemist who was recently awarded the Nobel Prize for his work in click reactions. Jan found the simplicity of click reactions similar to clicking Lego blocks together.

Click reactions:

  1. Have high yield and purity.
  2. Produce minimal waste/toxic products and next to no byproducts.
  3. Have elementary/mild reaction conditions and are simple to perform.
  4. Have fast kinetics.
  5. Are highly selective and specific, i.e. are mutually orthogonal (specific components of the reactants react in the presence of many other functional groups without affecting them).

The ‘cream and the crop of click chemistry’ is undoubtedly the Copper(I)-catalysed azide-alkyne cycloaddition (CuAAC). For this, we will first need to understand cycloaddition reactions.

A cycloaddition reaction is the formation of cyclic compounds (a cyclic adduct - a direct combination of molecular species without any loss of atoms) when multiple unsaturated molecules (having double or triple bonds) come together and are joined by sigma-bonds (single bonds). Linearly connected multiple-bonded molecules form sigma bonds at the terminals to form cyclic compounds. A cycloaddition generally results in a decrease in bond multiplicity - that is, the overall number of electron pairs shared between two atoms.In simple words, the double/triple bonds ‘convert’ into single bonds at the terminals to form a ring. The illustration given below should provide a fair idea.

To get to know click reactions better, let us look at the gold standard of click reactions - CuAAC and then compare it with its contemporary Huisgen 1,3-Dipolar Cycloaddition (non-catalysed) to understand what qualifies as a click reaction, and what does not.

The CuACC reaction transforms an organic azide and a terminal alkyne exclusively into a triazole. A triazole consists of a five-membered ring with two carbon atoms and three nitrogen atoms.

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More specifically, the product is a 1,4-disubstituted 1,2,3-triazole.

Let’s compare the non-catalysed Huisgen 1,3-dipolar cycloaddition (henceforth referred to as HDC) with the copper-catalyzed variant, CuAAC - to understand why one is a click reaction and the other isn’t.

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  1. Right off the bat, HDC forms two isomers, whereas CuACC yields a single product. A click reaction is highly specific and yields a high-purity product with no other byproducts. The formation of a single product eliminates the need for further purification in the case of CuACC.
  2. HDC requires high temperatures (sometimes above 100°C) to proceed. These conditions limit the reaction’s applicability with heat-sensitive substrates. CuACC occurs under mild conditions like room temperature, which increases the sensitivity of the reaction to certain other molecules.
  3. Talking about sensitivity, the CuACC has a wide range of tolerance for functional groups. For example, the presence of carboxyl, amino, hydroxyl, etc. functional groups does not interfere with the reaction, making it a lot more versatile than HDC.
  4. The uncatalysed reaction is slow, often taking hours or even days to achieve completion, whereas CuACC is extremely fast and essentially irreversible, and is usually complete within minutes.

Basically, click reactions are just better, and all other reactions have a skill issue when compared with click reactions.

References:

  1. Zihau Xu, Kaitlin M. Bratlie. (2018, May 26). Click Chemistry and Material Selection for in Situ Fabrication of Hydrogels in Tissue Engineering Applications. ACS Publications.
  2. Lisa M. Gaetke, Ching Kuang Chow Copper toxicity, oxidative stress, and antioxidant nutrients
  3. Jeremy M. Baskin; Jennifer A. Prescher; Scott T. Laughlin; Nicholas J. Agard; Pamela V. Chang; Isaac A. Miller; Anderson Lo; Julian A. Codelli; Carolyn R. Bertozzi (2007). "Copper-free click chemistry for dynamic in vivo imaging". Proceedings of the National Academy of Sciences.
  4. Rostovtsev, VV, Green, LG, Fokin, VV, Sharpless, KB. (2002) Angew. Chem.. 114, 2596.
  5. Olof Ramstrom. (2022, October 5). Scientific Background on the Nobel Prize in Chemistry 2022, CLICK CHEMISTRY AND BIOORTHOGONAL CHEMISTRY. The Nobel Committee for Chemistry
  6. Images: Future Journal of Pharmaceutical Sciences

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