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Review
, 374 (2), 16

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

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Review

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

Jan Dommerholt et al. Top Curr Chem (Cham).

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.

Keywords: Azide; BCN; Cyclooctyne; DIBAC; Strain-promoted cycloaddition.

Figures

Fig. 1
Fig. 1
Oxidative decomposition of cycloalka-1,2-dione dihydrazone, leading to medium-sized cycloalkynes (n = 1–5)
Fig. 2
Fig. 2
Formation of cycloalkynes by fragmentation of 1,2,3-selenadiazole (top) or dehydrohalogenation (bottom)
Fig. 3
Fig. 3
Reaction of cycloheptyne with 1,3-diphenylisobenzofuran or phenyl azide, leading to bicyclic oxanorbornene (left) or phenyltriazole (right), respectively
Fig. 4
Fig. 4
Select examples of cycloaddition reactions of cyclooctyne
Fig. 5
Fig. 5
Overview of functionalized cyclooctynes suitable for conjugation reactions, grouped by year of discovery. OCT cyclooctyne, MOFO monofluorinated cyclooctyne, DIFO difluorocyclooctyne, DIMAC dimethoxyazacyclooctyne, DIBO dibenzocyclooctyne, DIBAC dibenzoazacyclooctyne, BARAC biarylazacyclooctynone, BCN bicyclononyne, TMDIBO 2,3,6,7-tetramethoxy-DIBO, S-DIBO sulfonylated DIBO, COMBO carboxymethylmonobenzocyclooctyne, PYRROC pyrrolocyclooctyne
Fig. 6
Fig. 6
Negligible influence of azidobenzene para-substitution on reaction rate with dibenzoannulated cyclooctyne
Fig. 7
Fig. 7
Relationship between nature of the azide, structure of cyclooctyne and reaction rate constants. Reaction rate constants were determined in CD3CN:D2O = 3:1
Fig. 8
Fig. 8
Fluorogenic azide probes for cycloaddition with alkynes
Fig. 9
Fig. 9
Fluorogenic alkynes for cycloaddition with azides

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