Mechanisms and Substituent Effects of Metal-Free Bioorthogonal Reactions

Reactions that occur under physiological conditions find diverse uses in the chemical and biological sciences. However, the limitations that biological systems place on chemical reactions restrict the number of such bioorthogonal reactions. A profound understanding of the mechanistic principles and structure-reactivity trends of these transformations is therefore critical to access new and improved versions of bioorthogonal chemistry. The present article reviews the mechanisms and substituent effects of some of the principal metal-free bioorthogonal reactions based on inverse-electron demand Diels-Alder reactions, 1,3-dipolar cycloadditions, and the Staudinger reaction. Mechanisms of modified versions that link these reactions to a dissociative step are further discussed. The presented summary is anticipated to aid the advancement of bioorthogonal chemistry.