Click chemistry, introduced by K.B. Sharpless in 2001, is a chemical approach that emphasizes rapid and reliable creation of substances through modular reactions with high yields and benign by-products. Key reactions in this field include the copper(I)-catalyzed azide-alkyne cycloaddition and strain-promoted azide-alkyne cycloaddition, which are applied in various areas such as drug discovery, material science, and modification of natural products. The methodology is characterized by simplicity, insensitivity to reaction conditions, and high atom economy.

1. CLICK
CHEMISTRY
VARINDER KHEPAR
PhD Chemistry

2. Concept of Click Chemistry
“Click chemistry” is a chemical
philosophy introducded by K.B.
Sharpless in 2001, which describes the
chemistry that can generate substances
quickly and reliably by joining small units
together with high thermodynamic force.

3. “ A click reaction must be
modular, wide in scope, high
yielding, create only
inoffensive by-products (that
can be removed without
chromatography), are stereo
specific, simple to perform
and that require benign or
easily removed solvent.”–
K.Barry Sharpless
K B Sharpless
Nobel prize winner
(2001)

4. Characteristics of click reaction
• Modularity
• Insensitivity to solvent parameters
• High chemical yields
• Insensitivity towards oxygen and water
• Regiospecificity and stereospecificity
• Require a large thermodynamic driving force
to favor a reaction
• Single reaction product or no byproducts

5. Conditions for click process
• Have simple reaction conditions
• Use readily available starting materials and
reagents
• Use no solvent or use a solvent that is easily
removed (preferably water)
• Provide simple product isolation by non-
chromatographic methods
(crystallisation or distillation)
• Have high atom economy

6. Copper(I)-catalyzed azide-alkyne
cycloaddition (CuAAC)
• It is the copper-catalyzed reaction of an azide
with an alkyne to form a 5-
membered heteroatom ring
• Thermodynamic and kinetically favorable (50 and
26 kcal/mol, respectively)
• Regiospecific and chemoselective
• 107 rate enhancement over noncatalyzed
reaction
• Triazole stable to oxidation and acid hydrolysis

8. Mechanism

9. Strain-promoted azide-alkyne
cycloaddition (SPAAC)
• Instead of using Cu(I) to activate the alkyne,
the alkyne is introduced in a strained
difluorooctyne (DIFO), having electron-with
• This reaction proceeds as a concerted [3+2]
cycloaddition drawing fluorines destabilize
the alkyne.
• The reaction rate is slower than CuAAC.
Moreover, because the synthesis of
cyclooctynes often gives low yield.

11. Strain-promoted alkyne-nitrone
cycloaddition (SPANC)
• Diaryl-strained-cyclooctynes including
dibenzylcyclooctyne (DIBO) have also been
used to react with 1,3-nitrones yield N-
alkylated isoxazolines
• faster than both the CuAAC or the SPAAC

13. APPLICATIONS OF CLICK CHEMISTRY
• 2-D gel electrophoresis separation
• Preparative organic synthesis of 1,4-substituted triazoles
• Modification of natural products and pharmaceuticals
• Natural product discovery
• Drug discovery
• Macrocyclizations using Cu(I) catalyzed triazole couplings
• Modification of DNA and nucleotides by triazole ligation
• Dendrimer design
• Polymers and biopolymers
• Material science
• Nanotechnology

14. REFERENCES
• Liang L and Astruc D (2011) The copper(I)-catalyzed
alkyne-azide cycloaddition (CuAAC) “click” reaction
and its applications. An overview. Coordination
Chemistry Reviews. 255 (23): 2933-45.
• https://en.wikipedia.org/wiki/Click_chemistry
• Cox, Courtney L, Tietz, Jonathan I, Sokolowski, Karol,
Melby, Joel O, Doroghazi, James R, Mitchell and
Douglas (2014) Nucleophilic 1,4-Additions for Natural
Product Discovery. ACS Chemi. Bio. 9(9):2014-22.