Click chemistry is a chemical philosophy introduced by K. Barry Sharpless in 2001 ^[1][2] and describes chemistry tailored to generate substances quickly and reliably by joining small units together. This is inspired by the fact that nature also generates substances by joining small modular units.

One of the most popular reactions within the click chemistry philosophy is the azide alkyne Huisgen cycloaddition using a Cu catalyst at room temperature discovered concurrently and independently by the groups of K. Barry Sharpless and Morten Meldal. This was an improvement over the same reaction first popularized by Rolf Huisgen in the 1970s, albeit at elevated temperatures in the absence of water and without a Cu catalyst (it is explained fully in 1,3-Dipolar Cycloaddition Chemistry, published by Wiley and updated in 2002). Copper and Ruthenium are the commonly used catalysts in the reaction. The use of Copper as a catalyst results in the formation of 1,4- regioisomer whereas Ruthenium results in formation of the 1,5- regioisomer.

Contents 1 Explanation 2 How Click Reactions work 3 Mechanism 4 Ligand assistance 5 Ruthenium catalysis 6 Applications 7 References 8 External links

[edit] Explanation

In biochemistry, proteins are made from repeating amino acid units and sugars are made from repeating monosaccharide units. The connecting units are based on carbon - hetero atom bonds C-X-C rather than carbon - carbon bonds. In addition, enzymes ensure that chemical processes can overcome large enthalpy hurdles by division into a series of reactions each with a small energy step. Mimicking nature in organic synthesis of new pharmaceuticals is essential given the large number of possible structures.

In 1996 Guida calculated the size of the pool of drug candidates at 10⁶³, based on the presumption that a candidate consists of less than 30 non-hydrogen atoms, weighs less than 500 daltons, is made up of atoms of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine and bromine, and is stable at room temperature and stable towards oxygen and water ^[3]. Click chemistry in combination with combinatorial chemistry, high-throughput screening and building chemical libraries speeds up new drug discoveries by making each reaction in a multistep synthesis fast, efficient and predictable.

Click chemistry encourages the following criteria:

• application modular and wide in scope
• obtains high chemical yield
• generates inoffensive byproducts
• is stereospecific
• simple reaction conditions
• has readily available starting materials and reagents
• no solvent involved or a benign solvent (preferably water)
• easy product isolation by crystallisation or distillation but not preparative chromatography
• physiologically stable
• large thermodynamic driving force > 84 kJ/mol to favor a reaction with a single reaction product. A distinct exothermic reaction makes a reactant "spring loaded".
• high atom economy

However, the azides and alkynes are both kinetically stable. The reaction is slow and thus requires high temperatures. ^[4]

Another disadvantage of the Cu catalysed click reaction is that it does not work on internal alkynes

Many of the criteria are subjective; and even if measurable and objective criteria could be agreed upon, it's unlikely that any reaction will be perfect for every situation and application. However, several reactions have been identified which fit the bill better than others:

• The Huisgen 1,3-dipolar cycloaddition, in particular the Cu(I)-catalyzed stepwise variant, is often referred to simply as the "click reaction". The Cu(I)-catalyzed variant ^[5] was first reported by Morten Meldal and co-workers from Carlsberg Laboratory, Denmark for the synthesis of peptidotriazoles on solid support. Fokin and Sharpless independently described it as a reliable catalytic process offering "an unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors which depend on the creation of covalent links between diverse building blocks", firmly placing it among the most reliable processes fitting the click criteria.
• Other cycloadditions such as the Diels-Alder reaction
• nucleophilic substitution especially to small strained rings like epoxy and aziridine compounds
• carbonyl-chemistry-like formation of ureas but not reactions of the aldol type due to low thermodynamic driving force.
• addition reactions to carbon-carbon double bonds like dihydroxylation.

[edit] How Click Reactions work

As mentioned above, Copper catalysed click reactions work essentially on terminal alkynes. The Cu species undergo metal insertion rection into the terminal alkynes. These Cu(I) species are typically generated in the reaction pot itself by one of the following ways:

• A Cu compound (in which Copper is present in the +2 oxidation state) is added to the reaction in presence of a reducing agent which reduces the Cu from the (+2) to the (+1) oxidation state. The advantage of generating the Cu(I) species in this manner is it eliminates the need of a base in the reaction. Also the presence of reducing agent makes up for any oxygen which may have gotten into the system. Oxygen oxidises the Cu(I) to Cu(II) which impedes the reaction and results in low yields. One of the more commonly used Cu compounds is CuSO₄
• Oxidation of Cu(0) metal
• Halides of Copper may be used where solubility is an issue. However, the Iodide and Bromide Cu compounds require either the presence of amines or higher temperatures.

Commonly used solvents are polar aprotic solvents such as THF, DMSO, CH₃CN, DMF as well as in non-polar aprotic solvents such as toluene. Neat solvents or a mixture of solvents may be used.

DIPEA (N,N-Diisopropylethylamine) and ET₃N (triethylamine) are commonly used bases. ^[6]

[edit] Mechanism

Copper is a 1^st row transition complex. It has the electronic configuration [Ar] 3d¹⁰ 4s¹. The Copper (I) species generated in situ forms a pi complex with the triple bond of a terminal alkyne. In the presence of a base, the terminal hydrogen, being the most acidic is deprotonated first to give a Cu acetylide intermediate.studies have shown that the reaction is second order with respect to Cu. It has been suggested that the transition state involves two copper atoms. One Copper atom is bonded to the acetylide while the other Cu atom serves to activate the azide. The metal center coordinates with the electrons on the nitrogen atom. The azide and the acetylide are not coordinated to the same Cu atom in this case. The ligands employed are labile and are weakly coordinating. The azide displaces one ligand to generate a copper-azide-acetylide complex . At this point cyclisation takes place. This is followed by protonation; the source of proton being the hydrogen which was pulled off from the terminal acetylene by the base. The product is formed by dissociation and the catalyst ligand complex is regenerated for further reaction cycles.

The reaction is assisted by the copper which when coordinated with the acetylide lowers the pKa of the alkyne C-H by upto 9.8 units. Thus under certain conditions, the reaction may be carried out even in the absence of a base.

In the uncatalysed reaction the alkyne remains a poor electrophile. Thus high energy barriers lead to slow reaction rates. ^[7].

[edit] Ligand assistance

The ligands employed are usually labile i.e they can be displaced easily. Though the ligand plays no direct role in the reaction and click reaction can proceed even in the absence of ligands, the presence of a ligand has its advantages. The ligand protects the Cu ion from interactions leading to degradation and formation of side products and also prevents the oxidation of the Cu(I) species to the Cu(II). Furthermore, the ligand functions as a proton acceptor thus eliminating the need of a base. ^[8]

[edit] Ruthenium catalysis

The Ruthenium catalysed 1,3-dipolar azide-alkyne cycloaddition (RuAAC) gives the 1,5-triazole. Unlike CuAAC in which only terminal alkynes reacted, in RuAAC both, terminal and internal alkynes can participate in the reaction. This suggests that ruthenium acetylides are not involved in the catalytic cycle.

The proposed mechanism suggests that in the first step, the spectator ligands undergo displacement reaction to produce an activated complex which is converted, via oxidative coupling of an alkyne and an azide to the Ruthenium containing metallocyle (Ruthenacycle). The new C-N bond is formed between the more electronegative and less sterically-demanding carbon of the alkyne and the terminal nitrogen of the azide. The metallacycle intermediate then undergoes reductive elimination releasing the aromatic triazole product and regenerating the catalyst or the activated complex for further reaction cycles.

Cp^*RuCl(PPh₃)₂, Cp^*Ru(COD)and Cp^*[RuCl₄] are commonly used Ruthenium catalysts. Catalysts containing cyclopentadienyl(Cp) group are also used. However, better results are observed with pentametylcyclopentadienyl(Cp^*) version. This maybe due to the stearically demanding Cp^* group which facilitates the displacement of the spectator ligands. ^{[9] [10]}

[edit] Applications

Click chemistry has widespread applications. Some of them are Preparative Organic Synthesis of 1,4-Substituted Triazoles; Modification of Peptide Function with Triazoles; Modification of Natural Products and Pharmaceuticals; Drug discovery; Macrocyclizations Using Cu(1) Catalyzed triazole Couplings; Modification of DNA and Nucleotides by triazole Ligation; Supramolecular chemistry: Calixarenes, Rotaxanes, and Catenanes; Dendrimer design; Carbohydrate Clusters and Carbohydrate Conjugation by Cu(1) Catalyzed Triazole Ligation Reactions; Polymers; Material science; Nanotechnology etc. ^[11]

[edit] References

[edit] External links

• Professor Karl Barry Sharpless's Research Website including comprehensive list of click chemistry papers.
• National Science Foundation: Feature "Going Live with Click Chemistry."
• Chemical and Engineering News: Feature "In-Situ Click Chemistry."
• Chemical and Engineering News: Feature "Copper-free Click Chemistry"

v • d • e Chemistry Analytical chemistry · Biochemistry · Bioinorganic chemistry · Bioorganic chemistry · Biophysical chemistry · Chemical biology · Chemistry education · Click chemistry · Cluster chemistry · Computational chemistry · Electrochemistry · Environmental chemistry · Green chemistry · Inorganic chemistry · Materials science · Medicinal chemistry · Nuclear chemistry · Organic chemistry · Organometallic chemistry · Pharmacy · Physical chemistry · Photochemistry · Polymer chemistry · Solid-state chemistry · Supramolecular chemistry · Theoretical chemistry · Thermochemistry · Wet chemistry List of biomolecules · List of inorganic compounds · List of organic compounds · Periodic table