（Click Chemistry）是由美国诺贝尔化学奖获得者、史格堡研究院（Skaggs institute）化学生物研究所的研究员贝瑞·夏普利斯（K. Barry Sharpless）提出的一类反应。这类反应一般是高产率，应用范围广，生成单一的不用色谱柱分离的副产物，反应具有立体选择性，易于操作，反应溶剂易于除去。这一概念同样适用于其他领域，如医药，材料，可以合成大量的化合物库用于其他领域的研究。有很多类型的热力动力学只生产一种产物的反应满足点击化学的条件，如环氧乙烷，杂氮环丙烷的亲核开环反应，非醛基羰基化合物反应（制备腙或杂环化合物)，C-C双键三键的反应（如氧化制备环氧化合物，和迈克尔加成和环加成反应等）。

例如，叠氮-炔环加成满足点击化学的条件，单取代的炔和有机叠氮化合物一般比较廉价，另外一些也易于合成，它们的环加成得到1，2，3-三氮唑。

但是，热力学的Huisgen 1,3-偶极环加成需要很高的温度，并且当使用非对称的炔反应时得到是两种异构体的混合物。在这个意义上讲，经典的 1,3-偶极环加成并不属于点击化学的范畴。铜催化的改进方法可以在室温下水溶液中进行，而且与经典的Huisgen 1,3-偶极环加成生成两种异构体的混合物不同，此方法只生成1,4-二取代的的异构体。与之相反，近期发展出一种钌催化的反应可以得到另一种异构体（1,5-二取代三氮唑）。因此，催化的1,3-偶极环加成正好符合点击化学的定义，叠氮-炔环加成是经典的点击化学反应。

Huisgen 叠氮-炔 1,3-偶极环加成的机理

此反应是放热反应，但是很高的反应活化能导致反应速率很慢，甚至很高的温度，速率也很低。另一个缺点就是异构体，由于两种可能HOMO-LUMO在能级上差别不大，因此在热力学反应下得到近乎1:1的1,4-取代和1,5-取代的异构体。

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

铜催化机理 (CuAAC)

作为最经典的点击化学反应，铜催化的叠氮-炔环加成比非催化的1,3-偶极环加成反应速率提高了107 到 108 倍，在很大的温度范围内都能反应，对水不敏感，反应的PH范围4到12都可以发生反应，对很多官能团都有耐受度。纯产品可以通过简单的过滤和萃取得到，而不需要柱层析或重结晶。

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.

活性铜(I)催化剂可以直接用一价铜盐或通过抗败血酸钠还原二价铜得到。反应中会加入稍微过量的抗坏血酸钠防止氧化偶联产物的生成。Cu(II)盐和铜的混合物也可以生成活性铜(I)催化剂。

DFT计算表明Cu(I)与炔偶联在乙腈中是轻微吸热的，但在水中却是放热，这正与此反应在水中反应速率快的现象相符合。然而，铜与乙炔的偶联并没有使1,3-偶极环加成加速，计算表明此过程并不比非催化的1,3-偶极环加成快。金属铜炔化合物形成后，叠氮取代另一个配体与铜键合，进而生成一个独特的六元三价铜金属环，计算表明此过程的活化能比非金属催化的反应低很多。在室温下的计算速率是 1 s-1，此结果还是很合理的。六元环缩环的得到三氮唑-铜衍生物，质子化得到三氮唑产物，完成催化循环。

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.

钌催化的环加成机理 (RuAAC)

一个催化剂的研究表明五甲基环戊二烯氯化钌 [Cp*RuCl] 可以能够催化叠氮对末端炔烃的环加成，得到单一立体选择性的 1,5-二取代 1,2,3-三氮唑。另外RuAAC 可以用于催化非末端炔烃的加成，得到全取代的 1,2,3-三氮唑，这点与 CuAAC不同。

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.

RuAAC机理通过叠氮和炔对钌进行氧化加成得到一个六元有机金属钌中间体，新形成的C-N键在带负电性的炔碳和末端亲电子的叠氮的氮原子间形成。进而发生还原消除，形成三氮唑产物。DFT计算也支持这一机理，而且还表明还原消除是速率决定步骤。

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.

反应实例：

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.

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. Pericàs, 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.

编译自：Organic Chemistry Portal