Chemistry Reference
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such as crystallization or distillation, and the product must be stable under physiologi-
cal conditions. Click processes proceed rapidly to completion and also tend to be highly
selective for a single product: we think of these reactions as being spring-loaded for a
single trajectory.”
A summary of these criteria is presented in Figure 3.1.
In contrast to some belief, click chemistry is not limited to CuAAC or its copper-
free version—referred to as strain-promoted azide-alkyne cycloaddition (SPAAC)
[3]—because other spring-loaded reactions own the essential “click” attributes. Of
special importance are click reactions occurring in the absence of metal catalysts
[4] because this allows their extensive use for bioconjugation without damaging the
delicate molecules that are involved. Among these metal-free reactions are the sister
reactions consisting of the additions of thiols to inactivated alkenes (thiol-ene cou-
pling, TEC) [5] and alkynes (thiol-yne coupling, TYC) [5b, 6]. Under photochemical
conditions both reactions occur by a free-radical chain reaction mechanism while
they are promoted by traces of a photoinitiator (Scheme 3.1). Thus, TEC allows the
introduction of a single thiol fragment across the terminal carbon-carbon double bond
in an anti-Markovnikov fashion (monohydrothiolation) to give a thioether while TYC
enables the addition of two thiol residues across the carbon-carbon triple bond and
leads to a dithioether derivative (bis-hydrothiolation). Both photoaddition reactions
can proceed at near-visible wavelengths (
365-405 nm) and therefore can be
conducted in sealed glass vials using a handheld UV lamp. In general the reactions
occur with fast kinetics with reaction times of the order of minutes. No special care
is needed to exclude air and moisture while pure water or mixtures of water and
polar solvents (Dimethylformamide [DMF], methanol) can be employed as reaction
media. In general only a slight excess of thiol is used with respect to the number of
alkene or alkyne groups to be hydrothiolated and therefore the only byproduct that is
formed is the corresponding disulfide arising from the radical homocoupling of thiol
residues. Significantly, both reactions lead to the formation of robust carbon-sulfur
bonds that in addition of being flexible and sterically nondemanding, are stable under
a wide range of chemical environments such as basic and acid media. Thus, while the
click status of TEC and TYC can be anticipated on the light of the above features, it
=
High yields
Stable compounds
Modular
Wide in scope
Chemoselective
Single reaction trajectory
Oxygen and water compatible
No solvent or a benign solvent
Easy purification
Stereospecific
Readily available reagents
FIGURE 3.1
Sharpless criteria for a click process.
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