Strain and stereoelectronics in cycloalkyne click chemistry

Due to the broad interest to cycloalkynes in metal-free click chemistry, we present a focused review summarizing current approaches to structural and electronic modifications of cycloalkynes. We illustrate how the combination of reactant destabilization and transition state stabilization can lead to the design of more reactive cycloalkynes that are, paradoxically, less strained. We discuss the concept of ring strain in cycloalkynes and show that increased ring strain does not always equate to increased click reactivity. We summarize direct and remote electronic effects that can be used to enhance click reactivity in cycloalkynes and show how inclusion of transition state stabilizing stereoelectronic effects is essential for the rational design of the cycloalkyne click reagents.