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Related Reactions
Huisgen 1,3-Dipolar Cycloaddition
Synthesis of 1,2,3-Triazoles

Click Chemistry
Azide-Alkyne Cycloaddition

"Click Chemistry" is a term that was introduced by K. B. Sharpless in 2001 to describe reactions that are high yielding, wide in scope, create only byproducts that can be removed without chromatography, are stereospecific, simple to perform, and can be conducted in easily removable or benign solvents. This concept was developed in parallel with the interest within the pharmaceutical, materials, and other industries in capabilities for generating large libraries of compounds for screening in discovery research. Several types of reaction have been identified that fulfill these criteria, thermodynamically-favored reactions that lead specifically to one product, such as nucleophilic ring opening reactions of epoxides and aziridines, non-aldol type carbonyl reactions, such as formation of hydrazones and heterocycles, additions to carbon-carbon multiple bonds, such as oxidative formation of epoxides and Michael Additions, and cycloaddition reactions.

For example, an examination of the azide-alkyne cycloaddition shows that it fulfills many of the prerequisites. Many of the starting monosubstituted alkynes and organic azides are available commercially, many others can easily be synthesized with a wide range of functional groups, and their cycloaddition reaction selectively gives 1,2,3-triazoles.

Unfortunately, the thermal Huisgen 1,3-Dipolar Cycloaddition of alkynes to azides requires elevated temperatures and often produces mixtures of the two regioisomers when using asymmetric alkynes. In this respect, the classic 1,3-dipolar cycloaddition fails as a true click reaction. A copper-catalyzed variant that follows a different mechanism can be conducted under aqueous conditions, even at room temperature. Additionally, whereas the classic Huisgen 1,3-dipolar cycloaddition often gives mixtures of regioisomers, the copper-catalyzed reaction allows the synthesis of the 1,4-disubstituted regioisomers specifically. By contrast, a later developed ruthenium-catalyzed reaction gives the opposite regioselectivity with the formation of 1,5-disubstituted triazoles. Thus, these catalyzed reactions comply fully with the definition of click chemistry and have put a focus on azide-alkyne cycloaddition as a prototype click reaction.

Mechanism of the Huisgen Azide-Alkyne 1,3-Dipolar Cycloaddition

For the mechanism, please refer to the text on 1,3-dipolar cycloaddition. This reaction is highly exothermic, but the high activation barrier is responsible for a very low reaction rate, even at elevated temperature. Another drawback is the formation of regioisomers, as the two possible HOMO-LUMO interactions of the substrates are closely related in terms of energy. The thermal reaction therefore often gives approximately 1:1 mixtures of both the 1,4-substituted and the 1,5-substituted regioisomers.

V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596-2599.

Mechanism of the Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC)

As one of the best click reactions to date, the copper-catalyzed azide-alkyne cycloaddition features an enormous rate acceleration of 107 to 108 compared to the uncatalyzed 1,3-dipolar cycloaddition. It succeeds over a broad temperature range, is insensitive to aqueous conditions and a pH range over 4 to 12, and tolerates a broad range of functional groups. Pure products can be isolated by simple filtration or extraction without the need for chromatography or recrystallization.

F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210-216.

The active Cu(I) catalyst can be generated from Cu(I) salts or Cu(II) salts using sodium ascorbate as the reducing agent. Addition of a slight excess of sodium ascorbate prevents the formation of oxidative homocoupling products. Disproportionation of a Cu(II) salt in presence of a Cu wire can also be used to form active Cu(I).

DFT calculations have shown that coordination of Cu(I) to the alkyne is slightly endothermic in MeCN, but exothermic in water, which is in agreement with an observed rate acceleration in water. However, coordination of Cu to the acetylene does not accelerate a 1,3-dipolar cycloaddition. Such a process has been calculated to be even less favorable than the uncatalyzed 1,3-dipolar cycloaddition.

Instead, a σ-bound copper acetylide bearing a π-bound copper coordinates the azide. Then, an unusual six-membered copper metallacycle is formed. The 2nd copper atom acts as a stabilizing donor ligand. Ring contraction to a triazolyl-copper derivative is followed by protonolysis that delivers the triazole product and closes the catalytic cycle.

B. T. Worell, J. A. Malik, V. V. Fokin, Science, 2013, 340, 457-460. DOI: 10.1126/science.1229506

Mechanism of the Ruthenium-Catalyzed Azide-Alkyne Cycloaddition (RuAAC)

A search for catalysts revealed that pentamethylcyclopentadienyl ruthenium chloride [Cp*RuCl] complexes are able to catalyze the cycloaddition of azides to terminal alkynes regioselectively leading to 1,5-disubstituted 1,2,3-triazoles. In addition, RuAAC can also be used with internal alkynes, providing fully substituted 1,2,3-triazoles, which contrasts with CuAAC.

B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 8923-8930.

The ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) appears to proceed via oxidative coupling of the azide and the alkyne to give a six-membered ruthenacycle, in which the first new carbon-nitrogen bond is formed between the more electronegative carbon of the alkyne and the terminal, electrophilic nitrogen of the azide. This step is followed by reductive elimination, which forms the triazole product. DFT calculations support this mechanistic proposal and indicate that the reductive elimination step is rate-determining..

B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 8923-8930.

Recent Literature

A Novel Approach to 1-Monosubstituted 1,2,3-Triazoles by a Click Cycloaddition/Decarboxylation Process
M. Xu, C. Kuang, Z. Wang, Q. Yang, Y. Jiang, Synthesis, 2011, 223-228.

The Use of Calcium Carbide in the Synthesis of 1-Monosubstituted Aryl 1,2,3-Triazole via Click Chemistry
Y. Jiang, C. Kuang, Q. Yang, Synlett, 2009, 3163-3166.

Microwave Irradiation as an Effective Means of Synthesizing Unsubstituted N-Linked 1,2,3-Triazoles from Vinyl Acetate and Azides
S. G. Hansen, H. H. Jensen, Synlett, 2009, 3275-3278.

A Convenient Synthesis of 1-Substituted 1,2,3-Triazoles via CuI/Et3N Catalyzed ‘Click Chemistry' from Azides and Acetylene Gas
L.-Y. Wu, Y.-X. Xie, Z.-S. Chen, Y.-N. Niu, Y.-M. Liang, Synlett, 2009, 1453-1456.

2-Ethynylpyridine-Promoted Rapid Copper(I) Chloride Catalyzed Azide-Alkyne Cycloaddition Reaction in Water
H. Hiroki, K. Ogata, S.-i. Fukuzawa, Synlett, 2013, 24, 843-846.

A New Simplified Protocol for Copper(I) Alkyne-Azide Cycloaddition Reactions Using Low Substoichiometric Amounts of Copper(II) Precatalysts in Methanol
B. R. Buckley, M. M. P. Figueres, A. N. Khan, H. Heaney, Synlett, 2016, 27, 51-56.

Tandem Catalysis: From Alkynoic Acids and Aryl Iodides to 1,2,3-Triazoles in One Pot
A. Kolarovič, M. Schnürch, M. D. Mihovilovic, J. Org. Chem., 2011, 76, 2613-2618.

Self-assembly of copper sulfate and a poly(imidazole-acrylamide) amphiphile provides a highly active, reusable, globular, solid-phase catalyst for click chemistry. The insoluble amphiphilic polymeric imidazole Cu catalyst drove the cycloaddition of various of alkynes and organic azides at very low catalyst loadings and can be readily reused without loss of activity to give the corresponding triazoles quantitatively.
Y. M. A. Yamada, S. M. Sarkar, Y. Uozumi, J. Am. Chem. Soc., 2012, 134, 9285-9286.

Copper-Catalyzed Azide-Alkyne Cycloaddition Reaction in Water Using Cyclodextrin as a Phase Transfer Catalyst
J.-A. Shin, Y.-G. Lim, K.-H. Lee, J. Org. Chem., 2012, 77, 4117-4122.

In the presence of a readily accessible nanosized Cu/Fe bimetallic system, Cu-catalyzed azide-alkyne cycloadditions can easily be achieved at ambient temperature with high efficiency. The catalyst produces significantly lower copper contaminants compared to homogeneous copper complexes. Iron not only behaves as support, but also acts as a redox scavenger that reduces the copper contamination of the organic product.
S. Kovács, K. Zih-Peréni, Á. Révész, Z. Novák, Synthesis, 2012, 44, 3722-3730.

CuI/DIPEA/HOAc is as a highly efficient catalytic system for CuAAC. In this novel acid-base jointly promoted formation of 1,2,3-triazoles, HOAc was recognized to accelerate the conversions of the C-Cu bond-containing intermediates and buffer the basicity of DIPEA. As a result, all drawbacks occurring in the popular catalytic system CuI/NR3 were overcome easily.
C. Shao, X. Wang, Q. Zhang, S. Luo, J. Zhao, Y. Hu, J. Org. Chem., 2011, 76, 6832-6836.

[CuBr(PPh3)3] for Azide-Alkyne Cycloaddition Reactions under Strict Click Conditions
S. Lal, S. Díez-González, J. Org. Chem., 2011, 76, 2367-2373.

A Copper(I) Isonitrile Complex as a Heterogeneous Catalyst for Azide-Alkyne Cycloaddition in Water
M. Liu, O. Reiser, Org. Lett., 2011, 13, 1102-1105.

An abnormal NHC complex of copper with 1,4-diphenyl-1,2,3-triazol-5-ylidene [CuCl(TPh)] efficiently catalyzed click reactions of azides with alkynes to give 1,4-substituted 1,2,3-triazoles in excellent yields at room temperature with short reaction times. CuCl(TPh) was particularly effective for the reaction between sterically hindered azides and alkynes.
T. Nakamura, T. Terashima, K. Ogata, S.-i. Fukuzawa, Org. Lett., 2011, 13, 620-623.

Carboxylic Acid-Promoted Copper(I)-Catalyzed Azide-Alkyne Cycloaddition
C. Shao, X. Wang, J. Xu, J. Zhao, Q. Zhang, Y. Hu, J. Org. Chem., 2010, 75, 7002-7005.

A Highly Active Catalyst for Huisgen 1,3-Dipolar Cycloadditions Based on the Tris(triazolyl)methanol-Cu(I) Structure
S. Özçubukçu, E. Ozkal, C. Jimeno, M. A. Pericŕs, Org. Lett., 2009, 11, 4680-4683.

Benzimidazole and Related Ligands for Cu-Catalyzed Azide-Alkyne Cycloaddition
V. O. Rodionov, S. I. Presolski, S. Gardinier, Y.-H. Lim, M. G. Finn, J. Am. Chem. Soc., 2007, 129, 12696-12704.

1,3-Dipolar Cycloaddition of Organic Azides to Alkynes by a Dicopper-Substituted Silicotungstate
K. Kamata, Y. Nakagawa, K. Yamaguchi, N. Mizuno, J. Am. Chem. Soc., 2008, 130, 15304-15310.

Heterogeneous Copper Catalyst for the Cycloaddition of Azides and Alkynes without Additives under Ambient Conditions
I. S. Park, M. S. Kwon, Y. Kim, J. S. Lee, J. Park, Org. Lett., 2008, 10, 497-500.

Heterogeneous Copper-in-Charcoal-Catalyzed Click Chemistry
B. H. Lipshutz, B. R. Taft, Angew. Chem. Int. Ed., 2006, 45, 8235-8238.

A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective Ligation of Azides and Terminal Alkynes
V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596-2599.

Regioselective Synthesis of 1,2,3-Triazoles by Use of a Silica-Supported Copper(I) Catalyst
T. Miaoa, L. Wang, Synthesis, 2008, 363-368.

Efficient Conversion of Aromatic Amines into Azides: A One-Pot Synthesis of Triazole Linkages
K. Barral, A. D. Moorhouse, J. E. Moses, Org. Lett., 2007, 9, 1809-1811.

One-Pot Three-Step Synthesis of 1,2,3-Triazoles by Copper-Catalyzed Cycloaddition of Azides with Alkynes formed by a Sonogashira Cross-Coupling and Desilylation
F. Friscourt, G.-J. Boons, Org. Lett., 2010, 12, 4936-4939.

Copper(II)-Catalyzed Conversion of Aryl/Heteroaryl Boronic Acids, Boronates, and Trifluoroborates into the Corresponding Azides: Substrate Scope and Limitations
K. D. Grimes, A. Gupte, C. C. Aldrich, Synthesis, 2010, 1441-1448.

Ruthenium-Catalyzed Cycloaddition of Aryl Azides and Alkynes
L. K. Rasmussen, B. C. Boren, V. V. Fokin, Org. Lett., 2007, 9, 5337-5339.

Efficient one-pot synthesis of polysubstituted 6-[(1H-1,2,3-triazol-1-yl)methyl]uracils through the "click" protocol
P. Jansa, P. Špaček, I. Votruba, P. Břehová, M. Dračínský, B. Klepetářová, Z. Janeba, Collect. Czech. Chem. Commun., 2011, 13, 1121-1131.