SPAAC cycloaddition

POC-click is formed by thermo-cross-linking the mixture of pre-POC-N (azide-containing POC prepolymer) and pre-POC-Al (alkyne-containing POC prepolymer) the process applies synchronous binary cross-link mechanism, esterification, and thermal click reaction, and the residual azide groups on the surface of POC-click film or scaffold paved the way of surface bioconjugation through strain-promoted alkyne-azide cycloaddition (SPAAC), another copper-free click reaction. 

Strain-promoted azide-alkyne cycloaddition (SPAAC)... 

The successful preparation of cycloalkynes also opened up the possibility to explore their unique chemical reactivity. In fact, the transient existence of the cycloalkyne species could initially only be indirectly corroborated by fast in situ trapping of the smaller-sized rings (seven carbons and below) before decomposition [31]. While not strictly applicable to cyclooctyne, which is the smallest cyclic alkyne that can be isolated and stored in pure form, Blomquist already noted that nevertheless careful exclusion of air was requisite to avoid rapid decomposition. More importantly, he was also the first to observe that cyclooctyne reacts explosively when treated with phenyl azide, forming a viscous liquid product [8]. This remark is in fact the first historic administration of a process that has now become known as strain-promoted azide-alkyne cycloaddition (SPAAC). 

Strain-promoted azide-alkyne cycloaddition (SPAAC), since its inception in 2004, has firmly established itself as a powerful click chemistry tool. The commercial access of starting materials, its ease of operation, the nowadays practical reaction... 

Scheme 3 Summary of photo-triggered cycloaddition reactions useful in biological applications, a Reactions between aUcenes and photochemically generated 1,3-dipoles or 1,3-ienes. b SPAAC between photoprotected cyclooctynes and azides...

Fig. 1 Cycloaddition reactions employed in nucleic acid labeling with reporter groups (green star). A Cu -mediated azide-alkyne cycloaddition (CuAAC) of a terminal alkyne with an azide. B Strain-promoted azide-alkyne cycloaddition (SPAAC) of an azide with a cyclooctyne derivative. C Staudinger ligation of an azide with a phosphine derivative (not a cycloaddition reaction, see below). D Norbornene cycloaddition of a nitrile oxide as 1,3-dipole and a norbornene as dipolarophile. E Inverse electron-demand Diels- Alder cycloaddition reaction between a strained double bond (norbornene) and a tetrazine derivative. F Photo-cUck reaction of a push-pull-substituted diaiyltetrazole with an activated double bond (maleimide)...

Describe the main criteria that should be satis ed for a reaction to be called a click reaction How would you justify the inclusion of the following reactions into the pantheon of click reactions (a) Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions (b) strain-promoted azide-alkyne coupling (SPAAC) reactions (c) Diels-Alder (DA) cycloaddition reactions (d) thiol-ene (TE) reactions and (e) thiol-yne (TY) reactions ... 

Figure 10.13 Classification of different types of chemical cross-linking (Kharkar et al., 2013). CuAAC, Cu-catalyzed azide-alkyne addition SPAAC, strain-promoted azide-alkyne cycloaddition.

Click chemistry is commonly used in organic synthesis due to its high yield and its rapid kinetic. Although Cu-catalyzed allqme-azide cycload-dition, also called CuAAC, is the most utilized one, " " the intrinsic toxicity of the copper catalyst and its associated removal difficulties limit its application in biology. For instance, to improve dendrimer s water solubility, PEG groups are often incorporated via this method but a recent study conducted by Week and coworkers has observed substantial copper contamination in them. Copper-free strain promoted allq ne-azide cycloaddition (SPAAC) has been more and more employed to avoid this drawback.Nevertheless this last method introduces rigid cyclooctatriazole units that can modify the dendrimer scaffold and thus its properties. 

Scheme 9.30 (a) The strain-promoted azide-alkyne [3-1-2] cycloaddition (SPAAC) as developed by Wittig and Krebs and reintroduced/reexploited by Bertozzi and co orkers in 2004 [76, 77]. (b) The biotinylated cyclooctene analog for selective biomolecule modification studies [76]. 

Generation of chemical patterns with photoreactive polymers photo-Diels-Alder surface anchoring followed by azide-alkyne click reaction to immobilize fluorescent dyes, (a) SPAAC strain-promoted azide-alkyne cycloaddition and (b) CuAAC Cu(l)-catalyzed azide-alkyne cycloaddition. (Source Adapted with permission from Reference [36d].)... 

The orthogonal modification of a-alkyne, m-azido heterotelechelic polystyrene via sequential nitrile oxide-alkyne and azide-alkyne Huisgen cycloadditions was reported by the group of Lutz [36]. Alternatively, Su et al. reported a sequential triple chck modification of polyhedral oligomeric silsesquioxanes (POSS), involving strain-promoted azide-alkyne cycloaddition (SPAAC), copper-catalyzed azide-alkyne cycloaddition (CuAAC), and thiol-ene click coupling (TECC) [37]. 

Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC) Reactions... 

Due to the toxicity of the heavy metals to living cells and biomolecules such as DNA, the application of these methods are limited in biomaterial chemistry and chemical biology. As a metal-free approach, Bertozzi and coworkers have developed a strain-promoted 1,3-dipolar cycloaddition reaction (SPAAC) between azide 2 and cyclooctyne 5 to form 1,2,3-triazoles 6 for bioconjugate chemistry, which provided only very limited regioselectivity (Scheme 4.1d) [4]. Moreover, due to the complexity of the required substrates, this method was not suitable for straightforward synthetic applications. 

Sequential click strategies were utihzed by Zhang, Cheng, and coworkers to precisely construct new surfactants based on polyhedral oligomeric silsesquiox-ane (POSS), tethering cychc polymers [109]. The general synthetic approach involves different types of click chemistries sequentially performed strain-promoted azide-alkyne cycloaddition (SPAAC), CuAAC for POSS—polymer conjugation, and thiol-ene reactions for POSS surface functionalization. 

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