CLICK CHEMISTRY

CLICK CHEMISTRY by VARINDER KHEPAR ( PhD Chemistry), Punjab Agricultural University, Ludhiana, Punjab, INDIA

1. CLICK CHEMISTRY VARINDER KHEPAR PhD Chemistry

2. Concept of Click Chemistry “ Click chemistry” is a chemical philosophy introducded by K.B. S harpless 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 10 7 rate enhancement over noncatalyzed reaction Triazole stable to oxidation and acid hydrolysis

7. Mechanism

8. 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.

9. 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

10. 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

11. 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 .