Click Chemistry

1. CLICK CHEMISTRY
Hussein Ali Kadhim Kyhoiesh
‫كاظم‬ ‫علي‬‫حسين‬‫كحويش‬

2. Introduction "Click chemistry” is a new concept of chemical synthesis rather than a new
chemical synthesis technology, which opens up new ways for chemists to develop
chemical synthesis pathways. It is a powerful and practical method for
synthesizing a large number of new compounds at low cost by linking carbon and
heteroatoms (C-X-C) via rapid, reliable and selective chemical reactions using
readily available raw materials [1,2].
 Click chemistry can also be called as Linkage Chemistry, Dynamic,
Combinatorial Chemistry or Quick Linking Combinatorial Chemistry. Click
chemistry, also known as tagging, describes the reaction that joins molecular
fragments as simple, efficient and versatile as clicking a mouse.
 The classic click chemistry starts from the Copper-catalyzed Azide-Alkyne
Cycloaddition (CuAAC) reaction [3] see Fig.1.

3.  The discovery of the Cu(I)-catalyzed Azide-Alkyne Cyclo-addition (CuAAC)
reaction in 2002 [4] had a deep impact on the evolution of click chemistry. It
demonstrated great usefulness and application in diverse fields such as materials
science, bioconjugation, and drug discovery.
 Sulfur (VI) fluoride exchange (SuFEx) is a new type of click chemistry that
enables the synthesis of covalently linked modules via SVI hubs.
 Li et al. [5] have reported thionyl tetrafluoride (SOF4) as the first multidimensional
SuFEx connector. SOF4 resides in between the commercially mass-produced gases
SF6 and SO2F2, and, like them, is readily synthesized on scale. Under SuFEx catalysis
conditions, SOF4 reliably seeks out primary amino groups [R-NH2] and becomes
permanently anchored via a tetrahedral iminosulfur-(VI) link. The selectivity of
SO2F2 and SOF4 to aromatic hydroxyl and amino groups is shown in Fig. 2. A.

4.  The difluoride groups offer two further SuFExable handles, which can be
sequentially exchanged to create 3-dimensional covalent departure vectors from the
tetrahedral sulfur (VI) hub. Fig. 2. B. shows the multidimensional tetrahedral
production starting from thionyl tetrafluoride as an example [8].

5. 2. Characteristics of Click Chemistry Reaction [9]
1) Click chemistry reactions use readily available raw materials.
2) The majority of click chemistry reactions involve the formation of carbon-
heteroatom (mainly nitrogen, oxygen, sulfur) bonds.
3) Click chemistry reactions are simple to perform under mild conditions and are
rarely affected by water and oxygen.
4) Click chemistry reactions are highly stereoselective, highly yielding and produce
by-products that are non-toxic.
5) Click chemistry reactions are usually exothermic.

6. 7) Click chemistry reactions is characterized by high thermodynamic driving force
(>84kJ/mol).
8) Click chemistry reactions produce the products that can be purified simply by
crystallization and distillation without complex chromatographic separation needed.
9) Click chemical reaction is also characterized with high yield and low cost.
3. Types of Click Chemistry Reaction
1) Cycloaddition reaction
Cycloaddition reaction usually joins unsaturated reactants to form a variety of five-
membered and six-membered heterocycles, which fully realizes the idea of click
chemistry and covers a wide range of reactions, such as the Diels-Alder reaction [10-
12]. The reactive groups for the cycloaddition reaction are usually non-polar. Both
azide and alkynyl

7. groups can be easily introduced into the desired compound structure.
Their 1,3-dipolar cycloaddition has become the most widely used click
chemistry reaction because it is simple to perform and stereospecific,
can be conducted in water or organic solvents under mild conditions
without significant interferences and create only the by-products that are
easily removed [13]. It is thus called as “Cream of the Crop” [14].
2) Nucleophilic ring-opening reaction
The nucleophilic ring-opening reaction is realized mainly by the
nucleophilic ring-opening of ternary heteroatom rings, such as epoxy

8. derivatives, aziridines, cyclic sulfates, cyclic sulfamides, aziridinium
ions, cyclosulfonium ions and so on [15]. Their internal tension energy
is released during the ring-opening reaction. Among these ternary
heterocyclic compounds, epoxy derivatives and aziridinium ions are the
most commonly used substrates for click chemical reactions [16,17].
Their ring-opening produces various highly selective compounds.

10. 3) Carbonyl condensation reaction
The reactions of aldehydes or ketones with 1, 3-diols to produce 1, 3- dioxolane [36], the
reaction of aldehydes with hydrazines or hydroxylamine ethers to produce hydrazones or oximes [18], and
the reaction of α-/β-carbonyl aldehydes and ketones with esters to form heterocyclic compounds [19], etc.
are the most widely used carbonyl condensation reactions. For example, the acetals of D-isoascorbic acid
containing 1, 3-dioxolane can be obtained by the carbonyl condensation reaction of linear saturated
aliphatic aldehyde with D- isoascorbic acid in N, N-dimethylacetamide using p-toluenesulfonic acid as the
catalyst and cyclohexane as the water-carrying agent [20]. The reaction is shown below.

12. 4) Addition reaction of carbon-carbon multibonds
The click reaction of thiol–ene/yne is a typical addition reaction of carbon-carbon multibonds
discovered after Huisgen reaction. Such reaction is usually carried out under UV irradiation that initiate the
click reaction of unsaturated bonds with thiol using a photoinitiator. It is characterized with wide application
scope [21]. The click reaction of thiol-ene is a simple metalfree- catalyzed reaction and has become an
efficient tool for curing reaction and polymer modification. Alkynyl is also an ideal material for click
chemistry reaction because it can form a variety of structures and is stable under normal conditions [22-23].
Because the reaction mechanisms of the thiol-ene and thiol-yne are very similar, only the click reaction of
thiol-ne is discussed here to elaborate the addition reaction of carbon-carbon multibonds.

14. 4. APPLICATION OF CLICK CHEMISTRY REACTION
Click chemistry has been rapidly developed and applied in a variety of fields, such as DNA
[24], self-assembly [25], surface modification [26], supramolecular chemistry [27], dendritic molecules
[28], functional polymers [29], combinatorial chemistry [30], proteomics [31], biocomposites [32],
biomedicine [33].
O’Brien et al. [34] have developed a new strategy (SnapFect; see Fig. 7) for nucleic acid
transfection to cells that does not use electrostatic interactions, but uses an integrated method combining
biorthogonal liposome fusion, click chemistry, and cell surface engineering.