Moderating strain without sacrificing reactivity: design of fast and tunable noncatalyzed alkyne-azide cycloadditions via stereoelectronically controlled transition state stabilization

Abstract

Recently, we have identified two strategies for selective transition state (TS) stabilization in catalyst-free azide/alkyne cycloadditions. In particular, the transition states for the formation of both 1,4- and 1,5-isomers can be stabilized via hyperconjugative assistance for the C···N bond formation, whereas the 1,5-TS can be stabilized via C-H···X H-bonding interactions. When the hyperconjugative assistance is maximized by the antiperiplanar arrangement of propargylic σ-acceptors relative to the forming bonds, the combination of these TS-stabilizing effects was predicted to lead to ~1 million fold acceleration of the cycloaddition with methyl azide. The present work investigated whether hyperconjugative assistance and H-bonding can be combined with strain activation for the design of even more reactive alkynes and whether reactivity can be turned "on demand." When stereoelectronic amplification is achieved by optimal positioning of σ-acceptors at the endocyclic bonds antiperiplanar to the breaking alkyne π-bonds, the stabilization of the bent alkyne geometry leads to a significant decrease in strain in cyclic alkynes without compromising their reactivity in alkyne-azide cycloadditions. The approach can be used in a modular fashion where the TS stabilizing effects are introduced sequentially until the desired level of reactivity is achieved. A significant increase in reactivity upon the protonation of an endocyclic NH-group suggests a new strategy for the design of click reactions triggered by a pH-change or introduction of an external Lewis acid.