Click Chemistry - A Review
Click chemistry refers to a modular chemical approach that utilizes the copper (I) catalyzed 1,2,3-triazole formation from azides and terminal acetylenes as a powerful linking reaction to produce unique useful and versatile new biological compounds. This copper (I) catalyzed coupling of azides to terminal acetylenes is the premier reaction in click chemistry and creates 1,4-disubstitued 1,2,3-triazole linkages. These linkages share useful topological and electronic features with ubiquitous amide connectors that are not susceptible to cleavage.
Figure 1: The copper catalyzed 1,3-dipolar cycloadditon of an azide to an alkyne to create 1,2,3-triazoles is a Huisgen [3 + 2] cycloaddition reaction.
The beauty of click reactions is that click chemistry employs chemical reactions that are high yielding, cover a wide scope of reactions, create only byproducts that can be removed without chromatography, are stereospecific, simple to perform, and can be conducted in easily removable solvents. Since its introduction by K. B. Sharpless in 2001 click chemistry has enabled modular approaches for the generation of novel pharmacophores via a collection of reliable chemical reactions. The power of click chemistry enables the production of stereoselective products in high yields. The resulting products contain inoffensive byproducts, are insensitive to oxygen and water, utilize readily available starting materials, and have a thermodynamic driving force of at least 20 kcal mol-1. According to Rostovtsev et al. (2002) by simply stirring in water, organic azides and terminal alkynes are readily and cleanly converted into 1,4-disubstituted 1,2,3-triazoles through a highly efficient and regioselective copper(I)-catalyzed process.
The dipolar structure of azides was first recognized by Linus Pauling in 1933. Pauling published a paper in 1933 describing the investigation of the structures of methyl azide, CH3-N3, and carbon suboxide, C3O2, by electron-diffraction. The deduced structure for methyl azide as determined by Pauling is illustrated in figure 1.
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Figure 2: The structure for methyl azide as reported by Pauling in 1933 and the structure of the dipolar nature for the resonance hybrids for azides are illustrated.
The copper (I) catalyzed coupling of azides to terminal acetylenes is a Huisgen 1,3-dipolar cycloaddition reaction. Reactions in which azides add to double bonds to give triazolines belong to a large group of 2 + 3 cycloaddition reactions in which five-membered heterocyclic compounds are prepared by the addition of 1,3-dipolar compounds to double bonds. These compounds with the sequence a-b-c contain a sextet of electrons in the outer shell, usually located at a, and an octet with at least one unshared electron pair, located on c. This is a reaction of a 4πe- zwitterionic system with a 2πe- neutral system to form a 5-membered ring. During the reaction the number of σ bonds increase at the expense of the number of π bonds. However, since compounds with six electrons on the outer shell of an atom are usually not stable, the a-b-c system is actually a resonance hybrid as illustrated in figure 2 for the structure of methyl azide.
Carbon-carbon triple bonds can also undergo 1,3-dipolar additions. The Huisgen [3 + 2] cycloaddition between a terminal alkyne and an azide generates substituted 1,2,3-triazoles. This is the premier reaction utilized in click reactions when copper (I) is used for the catalysis of the reaction. Click chemistry is now used for a variety of applications in various facets of drug discovery. Schemes of chemical 1,3-dipolar addition reactions are illustrated in figure 3.
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Figure 3: Reaction schemes of the 1,3-dipolar addition to yield triazolines. A. The addition of molecules with the sequence a-b-c to double bonds is shown. The cycloaddition of phenyl azide is used as an example on the right. B. The addition of molecules with the sequence a-b-c to triple bonds is shown. The reaction of phenyl azide is used as an example on the right. These type of reactions were intensively studied by Rolf Huisgen and are known as 1,3-dipolar Huisgen cycloaddition reaction. C. The copper (I) catalyzed cycloaddition to a triple bond is illustrated here. This chemistry is known as “click chemistry” and yields exclusively the 1,4-disubstituted 1,2,3-triazole.
As pointed out by Barry Sharpless’s group (Kolb et al. 2001), the characteristic of click reactions is the high thermodynamic driving force which is usually greater than 20 kcal per mol. The reactions quickly proceed to completion and tend to be highly selective for a single product. Carbon-heteroatom bond forming reactions are the most common examples.
Click chemistry includes the following classes of chemical transformations:
- Cycloadditions of unsaturated species. Including 1,3-dipolar cycloaddition reactions and Diels-Alder transformations.
- Nucleophilic substitution chemistries. For example, ring-opening reactions of strained heterocyclic electrophiles such as epoxides, aziridines, aziridinium ions, and episulfonium ions.
- Carbonyl chemistry of the “non-aldol” type, such as formation of ureas, thioureas, aromatic heterocycles, oxime ethers, hydrazones, and amides.
- Additions to carbon-carbon multiple bonds. For example, epoxidation, dihydroxylation, azirdination, sulfenyl halide addition and Michael additions of Nu-H reactants.
References
Franck Amblard, Jong Hyun Cho, and Raymond F. Schinazi; The Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in nucleoside, nucleotide and oligonucleotide chemistry. Chem Rev. 2009 September ; 109(9): 4207–4220. doi:10.1021/cr9001462.
Bohm, T.; Webber, A.; Sauer, J. "Nonstereospecific 1,3-Dipolar Cycloadditions of Azomethine Ylides and Enamines." Tetrahedron1999, 55, 9535-9558.
Z. P. Demko and K. B. Sharpless, An Expedient Route to the Tetrazole Analogs of α–Amino Acids, Org. Lett., 4, 2525 (2002).
R. Huisgen, R. Grashey, J. Sauer in Chemistry of Alkenes, Interscience, New York, 1964, 806-877.
IUPAC Nomenclature: http://goldbook.iupac.org/
Hartmuth C. Kolb, M. G. Finn, and K. Barry Sharpless; Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40, 2004 ± 2021.
Jerry March: Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 2nd Edition McGRAW-HILL International Book Company.
March’s: Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 6nd Edition, M.B. Smith and J. March. WILEY-INTERSCIENCE. WILEY.COM.
Sarah A McCarthy, Gemma-Louise Davies & Yurii K Gun'ko; Preparation of multifunctional nanoparticles and their assemblies. Nature Protocols 7, 1677–1693 (2012). doi:10.1038/nprot.2012.082.
Vsevolod V. Rostovtsev, Luke G. Green, Valery V. Fokin and K. Barry Sharpless; A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Article first published online: 15 JUL 2002. DOI: 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4. © 2002 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany. Angewandte Chemie International Edition. Volume 41, Issue 14, pages 2596–2599, July 15, 2002.
Publications of the Sharpless Lab: http://www.scripps.edu/sharpless/pubs.html