My Literature Talk on Click Chemistry for the benefit of chemists around the world.

1. Click Chemistry
Aswinkumar Garimallarprabhakaran
Prof. Michael Harmata Group

2. Outline
 Introduction- Definition
 Classes of click reactions
- Nucleophilic ring opening reactions
-Protecting groups
- Cycloaddtion chemistry
-Huisgen 1,3 dipolar addition.
-Benzyne addition
-Multicomponent reaction
 Clickphines
 Summary
 Acknowledgement

3. IntroductionChemical Philosophy introduced by K. Barry Sharpless in 2001.
Basis
o Nature (Quintessential Chemist) prefers Carbon heteroatom bond (C-X-
C) than C-C-C bond. examples : Nucleic acid, Proteins,
polysaccharides.
Philosophy
“All Searches must be restricted to molecules that are easy to make”.
Prerequisite
o Reactions that are modular, high yielding, wide in scope,
stereospecific, use benign solvent.
Kolb, C. H.; Finn, G. M.; Sharpless, B. K. Angew.Chem.Int.Ed., 2001, 40, 2004-2021.

4. Click Impact
0 3 4 15 52
102
209
362
578
0
100
200
300
400
500
600
700
2000 2001 2002 2003 2004 2005 2006 2007 2008
Number
Year
Number of "Click chemistry" papers
Source : www.chem.wisc.edu/areas/organic/studsemin/mangold/mangold-sem.ppt
Areas of Impact
• Bioconjugation.
• Materials science.
• Drug discovery.

5. Classes of Click Reactions
 C=C additions
 Nucleophilic opening of
highly strained rings
 Protecting groups
 Cycloaddition Reactions

6. Relative Energies of Click
Components

7. C=C addition
 Olefins are primary organic
starting materials.
 Creation of modules by oxidative
addition of heteroatom to olefins.
 Primary oxidation of olefins gives
epoxides, aziridines, diols and
hydroxyl amines.

8. Nucleophilic Opening of Spring
Loaded Rings
 A distinct exothermic reaction –release of strain energy by ring opening ,
makes the reactants “spring loaded”.
 SN2 ring opening of epoxides, aziridines, cyclic sulfates , episulfonium
ions, cyclic sulfamidates, aziridinium ions are
-Reliable
-Stereospecific
-Mostly regioselective
-Quantitative.
 Reactions are frequently performed in alcohol/water mixtures.

10. Click Synthesis from Epoxides
1,3 selectivity is due to
1. Trans diaxial epoxide
opening
2. Intramolecular epoxide
activation
by the hydroxyl group
from the first step.
Polar solvent diminishes
latter effect.
Kolb, C. H.; Finn, G. M.; Sharpless, B. K. Angew.Chem.Int.Ed., 2001, 40, 2004-2021.

11. Click Chemistry Sequences

12. Click synthesis from aziridines
 Regioselective ring
opening of aziridines
are primarly substrate
controlled.
 In first set of example,
Benzyl substitution is
more reactive than 1o
,
2o .
 Substituent on the
nitrogen also influences
the regioselectivity of
aziridine ring opening as
in the second set .
Lin, P. Y.; Bellos, K.; Stamm, H.; Onistschenko, A. Tetrahedron, 1992, 48, 2359-2372

13. Protecting Groups
 Acetals, ketals, and their aza
analogues, have been considered for
long as only protecting groups.
 They can also be considered as
heterocycles with tremendous potential
in medicinal chemistry applications.
 The formation of acetals, ketals and
their aza analogues are part of click
chemistry.

14. Huisgen 1,3-dipolar cycloaddition
 Cycloaddtion of azide and acetylene was first reported by
Dimroth in early 1900s.
 1933- Dipolar nature of azide first recognized by Linus
Pauling
 1960- Mechanism of 1,3-dipolar cycloaddition of azides and
alkynes pioneered by Rolf Huisgen
L. Pauling. Proc. Natl. Acad. Sci. USA 1933, 19, 860-867
Huisgen, R. Angew. Chem. Int. Ed. 1963, 2, 633-696

15. Copper Catalyzed Alkyne Azide
cycloaddition (CuAAC)
• Using copper catalyst and at room temperature.
• Discovered concurrently by K.Barry Sharpless and
Morten Meldal.
 Regiospecific
 Chemoselective
 Concerted reaction: no intermediate
 Cream of the crop
 Perfect click reaction.
Sharpless, K.B. et al. Angew. Chem. Int. Ed 2002, 41, 2596-2599
Meldal,M.J. et al. J. Org. Chem. 2002, 67, 3057-3064

16. CuAAC
 105-106 times rate enhancement.
 Thermodynamic and kinetically favorable (50 and 26
kcal/mol, respectively)
 Terminal alkyne required.
 Triazole stable to oxidation and acid hydrolysis

17. CuAAC Catalytic Cycle
Himo, F. et al. J. Am. Chem. Soc, 2005, 127, 210-216.
Ahlquist, M., Fokin, V.V. Organometallics 2007, 26, 4389-4391

18. Benzyne Click Chemistry
 A variety of substituted benzotriazoles prepared using
[3+2] cyclo addition.
 Fluoride promoted ortho elimination of o-(trimethylsilyl)aryl
triflates results in arynes.
 Such arynes are highly reactive towards nulceophilic
additions and annulations.
Shi, F.; Waldo, P. J.; Chen, Y.; Larock, C. R. Org. Lett. 2008, 10, 2409-2412

19. Benzyne Click Chemistry
 Some Interesting examples

20. Bioconjugation
• Detection of enzyme activities
- Modification of enzyme active site
- Tag may influence properties, e.g. cell permeability.
Speers , Cravatt, Chem. Biol. 2004, 11, 535-46.

21. Imaging using copper free
azide reaction
 Detection by click chemistry
 Copper is toxic to cells
 click chemistry not applicable for imaging in vivo
 Introduction of azido-carbohydrates on cell surface
 Use of copper free 1,3 azide alkyne reaction.
Baskin et al, PNAS 2007, 104, 16793-97

22. Multi Component Reaction
 High degree of atom economy .
 Barbas, demonstrated domino Aldol/Knoevenagel/Michael
reactions using proline/pyrolidine as organo catalysts.
 Incorporation of Diels-Alder and Huisgen cycloaddtion
reaction sequences enable construction of complex
polycycles and thus called Organo-Click Chemistry.
 The reaction sequence and mechanism are shown below.
Ramachary, B. D.; Barbas , F. C. Chem. Eur. J. 2004, 10, 5323-5331.

25. Clickphines
 Novel P, N-type ligand is synthesized using click chemistry.
 First use of triazoles as nitrogen donors in P, N ligands.
 Phosphine is protected to avoid unwanted iminophosphorane
formation.
 These ligands showed excellent regioselectivity in palladium
catalyzed allylic alkylation reaction.
Detz, J. R.; Heras, A. S.; Gelder, D. R.; van Leeuwan, M. N. W. P.; Hiemstra, H.; Reek, H. N. J.;
van Maarseveen, H. J. Org. Lett., 2006, 8, 3227-3230.

26. Clickphines

27. Advantages
• Functional group tolerance
• Aqueous conditions
• Shorter reaction time
• High yield
• High purity
• Regiospecificity

28. Summary
 Click chemistry concept received with bipolar degrees of acceptance.
 Many click type reactions can/must be identified and improved.
 Detractors say that it is just a restatement of common sense concerns of
synthetic chemists who always seek to employ the most efficient reaction for
the task.
 Although considerable number of reactions can be called as “click” type
reactions, Click chemistry lacks broad spectrum of reactions that can be
widely used.
 Process chemists and pharmaceuticals have utilised click chemistry , but
synthetic chemists are yet to embrace click chemistry.

29. Acknowledgements
 Thanks to Dr. Harmata and group members
 Thanks to Dr. Glaser.
 Thanks to audience for the patient attention and
attendance.

30. Questions ? Eh?

31. Material Sciences
 Polymers
 Dendrimers
 Modified biomolecules

32. Drug Discovery
 Target guided synthesis
 Lead compound:
– Chemical with desired biological activity
– Starting point for modifications
 Synthesis of Lead discovery libraries:
 High diversity of compounds
 Low amount of synthetic steps

33. Pka Tables

34. Bond Dissociation Energies