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

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.

Rapid cycloaddition of a diazo group with an unstrained dipolarophile

“…This strong regiochemical preference for the anti orientation of the carbonyl groups is consistent with the π-acceptor ester group being a stronger electron-withdrawing substituent than is the σ-acceptor trifluoromethyl group and with the formation of an N–H···F–C hydrogen bond, as has been observed in other contexts. 16 …”

Sulfation Patterns of Saccharides and Heavy Metal Ion Binding

“…[54,55] The surfaces generated by this approach will be characterizedb yu sing atomic force microscopy (AFM)c ontact angle (CA) and ellipsometry.T hese surfaces will enable us to investigate correlations betweens ulfation patterns andmetal ion binding by using label-free electrochemical techniques, especially,E IS and cyclic voltammetry (CV), and to evaluatet he response of different sHA4 to increasing concentrationsofthe heavy metal ions, Cd 2 + ,Hg 2 + ,and Pb 2 + .Inaddition, metal ion binding to the surfacesw ill be verified by X-ray photoelectron spectroscopy (XPS). Next, we will develop ar obust way to covalently anchort he sulfated saccharides to electrodes using the copper-free strainpromoted click reactiont oa void the presence of transition metalsi nt he system.…”

A Phenyl‐Ethynyl‐Macrocycle: A Model Compound for “Geländer” Oligomers Comprising Reactive Conjugated Banisters

“…Single crystals suitable for X-ray analysis were obtained by slowly evaporating the solvent of a solution of 1 in [D 6 ]benzene. [8,9] Of particular interest are the angles of the acetylenes in the strained macrocycle 1. [37] The pair of enantiomers crystalized in one unit cell with two molecules of benzene ( Figure 2c).…”

“…The combination of oligo-para-phenylenes (OP) as backbone with oligo-para-phenylene-di-ethynylenes (OPDE) as helically wrapped banister seems particularly appealing (sketched in Figure 1). [8,9] It is noteworthy that numerous macrocyclic structures based on ethynyl-and/or diethynyl-interlinked aryl systems have been reported. [6,7] To compensate for the considerable dimensional mismatch between both subunits, the rigid linking structure be- tween the OP axis and the helical banister is elongated to an ethynyl-structure, increasing the radius r of the spring-like arrangement of the wrapping OPDE.…”