Selective azide–alkyne cycloaddition reactions of azidoalkylated calixarenes

Equimolar CuAAC (copper(I)-catalyzed azide–alkyne cycloaddition) reactions between phenyl propargyl ether and calix[4]arenes having multiple azidoalkyl groups arranged at their narrow rims were studied. Despite the azide groups being actually present in at least two-fold excess with respect to the alkyne molecules, exhaustive oligo(triazoles) were selectively formed in most cases leaving a significant part of the starting oligo(azides) unreacted. The number and mutual arrangement of the azidoalkyl groups at the calix[4]arene core did not affect the selectivity of the multiple CuAAC reactions. An increase of the length of the spacers between the calixarene core and the azide units from two to four methylene groups decreased the selectivity but still kept the reaction far from the statistically expected outcome. Outstanding results were obtained with the hybrid calixarenes having alternating propargyl and azidoalkyl groups at their narrow rims. Attempts to involve these compounds in CuAAC reactions with low-molecular azides or alkynes failed due to polymer/oligomer formation. Instead, heating these compounds in o-xylene in the absence of any additive led to unique highly constrained calix[4]arenes doubly bridged by 1,5-disubstituted 1,2,3-triazole-containing units, which were formed selectively or even exclusively in the copper-free azide–alkyne Huisgen cycloaddition.