Phenyl azide, cyclooctyne

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). 

Since these first reports on the reactions of cycloalkynes with isobenzofuran and phenyl azide, a wide range of other alkynophile cycloaddition partners have become known, as conceptually illustrated with model compounds in reactions with cyclooctyne in Fig. 4. It becomes immediately clear that cycloalkynes can undergo... 

Ess DH, Jones GO, Houk KN (2008) Transition states of strain-promoted metal-free click chemistry 1,3-dipolar cycloadditions of phenyl azide and cyclooctynes. Org Lett 10 1633-1636... 

In early work on the chemistry of cycloalkynes, cyclononyne was shown to react slowly with phenyl azide to give the cycloadduct in 82% yield however, the strain energy in cyclooctyne is significantly greater, calculated to be 77.5 kJ moP which accounts for the fact that a reaction of cyclooctyne with phenyl azide was reported to proceed like an explosion and resulted in the formation of the 1,2,3-triazole shown in Scheme 2 [13]. The use of cyclooctyne derivatives has been exploited in considerable detail recently, particularly because reactions can be carried out in biological systems where metal-catalysed reactions cannot be used because of toxicity problems (for reviews see [14, 15] see for example [16-19]). 

Scheme 2 The reaction of phenyl azide with cyclooctyne...

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