Abstract
A nearly forgotten reaction discovered more than 60 years ago—the cycloaddition of a cyclic alkyne and an organic azide, leading to an aromatic triazole—enjoys a remarkable popularity. Originally discovered out of pure chemical curiosity, and dusted off early this century as an efficient and clean bioconjugation tool, the usefulness of cyclooctyne–azide cycloaddition is now adopted in a wide range of fields of chemical science and beyond. Its ease of operation, broad solvent compatibility, 100 % atom efficiency, and the high stability of the resulting triazole product, just to name a few aspects, have catapulted this so-called strain-promoted azide–alkyne cycloaddition (SPAAC) right into the top-shelf of the toolbox of chemical biologists, material scientists, biotechnologists, medicinal chemists, and more. In this chapter, a brief historic overview of cycloalkynes is provided first, along with the main synthetic strategies to prepare cycloalkynes and their chemical reactivities. Core aspects of the strain-promoted reaction of cycloalkynes with azides are covered, as well as tools to achieve further reaction acceleration by means of modulation of cycloalkyne structure, nature of azide, and choice of solvent.
Highlights
The spontaneous reaction of cycloalkynes with an organic azide, in all its simplicity, is a fascinating organic chemical transformation
Another explanation lies in the current commercial availability of the cyclooctynes dibenzoannulated cyclooctyne (DIBO), DIBAC, and BCN, the three of which have dominated the field of strain-promoted azide–alkyne cycloaddition (SPAAC) in the past years
We recently concluded that the apparent slower reaction of electron-poor azides in SPAAC only holds for benzoannulated cyclooctynes, while in combination with more electronrich cyclooctynes, azides can react by a second, inverse electrondemand mechanism (i.e., SPAAC) as well [20]
Summary
The spontaneous reaction of cycloalkynes with an organic azide, in all its simplicity, is a fascinating organic chemical transformation. By mixing and stirring, without the necessity of reagents, catalysts, or carefully controlled reaction conditions, a stable triazole product is formed by fast and selective cycloaddition of cycloalkyne with azide. As will become clear throughout this chapter, the latter reaction has firmly established itself as a powerful and versatile chemical process with broad academic and commercial applications. Core to the chemistry lies a highly strained, medium-sized cyclic alkyne, most prominently a cyclooctyne. The synthesis and chemical reactivity of cyclic alkynes is broadly delineated, with particular emphasis on undoubtedly the most important of applications of cycloalkynes: cycloaddition with an organic azide, leading to the formation of a stable triazole
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