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Click chemistry is a term applied to chemical synthesis tailored to generate substances quickly

and reliably by joining small units together. Click chemistry is not a single specific reaction, but
describes a way of generating products that follows examples in nature, which also generates
substances by joining small modular units. The term was coined by K. Barry Sharpless in 1998,
and was first fully described by Sharpless, Hartmuth Kolb, and M.G. Finn of The Scripps
Research Institute in 2001.[1][2]
A desirable click chemistry reaction would:[1]

be modular

be wide in scope

give very high chemical yields

generate only inoffensive byproducts

be stereospecific

be physiologically stable

exhibit a 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".

have high atom economy.

The process would preferably:

have simple reaction conditions

use readily available starting materials and reagents

use no solvent or use a solvent that is benign or easily removed (preferably water)

provide simple product isolation by non-chromatographic methods

(crystallisation or distillation)

Proteins are made from repeating amino acid units, and sugars are made from
repeating monosaccharide units. The connections are carbonhetero atom bonds C-X-C, rather
than carboncarbon bonds. In addition, enzymes ensure that chemical processes can overcome
large enthalpy hurdles by a series of reactions each requiring only a small energy step. Mimicking

nature in organic synthesis may facilitate the discovery of new pharmaceuticals given the large
number of possible structures.
In 1996, Guida calculated the size of the pool of drug candidates at 10 63, based on the
presumption that a candidate consists of fewer 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, is stable
at room temperature, and does not react with 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
Many of the Click chemistry criteria are subjective, and even if measurable and objective criteria
could be agreed upon, it is unlikely that any reaction will be perfect for every situation and
application. However, several reactions have been identified that fit the concept better than
others:[clarification needed]

[3+2] cycloadditions, such as the Huisgen 1,3-dipolar cycloaddition, in particular the Cu(I)catalyzed stepwise variant,[4] are often referred to simply as Click reactions

thiol-ene click reactions[5]

Diels-Alder reaction and inverse electron demand Diels-Alder reaction[6]

[4+1] cycloadditions between isonitriles (isocyanides) and tetrazines[7]

nucleophilic substitution especially to small strained rings

like epoxy [8] 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 or the alkynes in

the thiol-yne reaction.

Azide alkyne Huisgen cycloaddition

Main article: Azide alkyne Huisgen cycloaddition
One of the most popular[9][10] reactions within the Click chemistry concept is the azide alkyne
Huisgen cycloaddition using a Copper (Cu) catalyst at room temperature. It was discovered
concurrently and independently by the groups of Valery V. Fokin and K. Barry Sharpless at
the Scripps Research Institute in California[11] and Morten Meldal in theCarlsberg Laboratory,
Denmark.[12] Although the Cu(I)-catalyzed variant was first reported by Meldal and co-workers for
the synthesis of peptidotriazoles on solid support, these authors did not recognize the potential of

the reaction and did not make a connection with the click chemistry concept. Sharpless and Fokin
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."

Click chemistry has widespread applications. Some of them are:

Two-dimensional gel electrophoresis separation[13]

preparative organic synthesis of 1,4-substituted triazoles

modification of peptide function with triazoles

modification of natural products and pharmaceuticals

natural product discovery [14]

drug discovery

macrocyclizations using Cu(I) 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


Polymers and Biopolymers [15]


material science

nanotechnology,[17] and

Bioconjugation, for example, azidocoumarin.


Click chemistry has also been used for selectively labeling biomolecules within biological
systems. A Click reaction that is to be performed in a living system must meet an even more
rigorous set of criteria than in an in vitro reaction. It must be bioorthogonal, meaning the reagents
used may not interact with the biological system in any way, nor may they be toxic. The reaction
must also occur at neutral pH and at or around body temperature. Most Click reactions have a
high energy content. The reactions are irreversible and involve carbon-hetero atom bonding
processes. An example is the Staudinger ligation of azides.

Technology license
The Scripps Research Institute has a portfolio of click chemistry patents. [19] Licensees
include Invitrogen,[20] Allozyne,[21] Aileron,[22] Integrated Diagnostics,[23] and the biotech
company baseclick, a BASF spin-off created to sell products made using click chemistry.

Moreover, baseclick holds a worldwide exclusive license for the research and diagnostic

market for the nucleic acid field. Fluorescent azides and alkynes also produced by such
companies as Active Motif Chromeon[25] and Cyandye