A Theoretical Study on the Metal-free Triazole Formation Through 1,3-Dipolar Cycloaddition of Benzyl Azide and Oxanorbornadiene

The development of selective and site-specific bioorthogonal conjugation methods is an important topic in chemical biology [1]. The term bioorthogonal chemistry refers to any chemical reaction that can occur inside of living systems without interfering with native biochemical processes [2].Strain-promoted [3+2] azide–alkyne cycloaddition is a bioorthogonal reaction which is modified by eliminating a cytotoxic copper catalyst [3]. In this work, we performed density functional theory (B3LYP and m06-2x) calculations on the possible 1,3-dipolar cycloaddition reaction pathways of benzyl azide with phenyl acetylene andoxanorbornadiene. The calculated activation energy of the ―strain-promoted‖ cycloaddition reaction ofoxanorbornadieneis lower than the strain-free phenyl acetylene cycloaddition because of thesmaller distortion energy of the former reaction.The molecular mechanism of these reactions was established by ELF topological analysis of the changes of the electron density along the IRC.