title: Enhanced clickability of doubly sterically-hindered aryl azides.
abstract: Steric character is one of the most fundamental factors to determine the reactivity of the substrate in organic synthesis. In bimolecular reaction, the sterically-bulky group situated close to the reactive center generally prevents the approach of the reaction partner retarding the bond formation. This report describes, to the contrary, significantly enhanced reactivity of 2,6-disubstituted phenyl azides observed in catalyst-free 1,3-dipolar cycloaddition with alkynes, unexpectedly reacting faster than unsubstituted phenyl azide and even more faster than unhindered alkyl azide, despite the steric hindrance adjacent to the reactive azido group. Experimental and computational studies have indicated that the steric hindrance eliciting the inhibition of resonance between azido group and the aromatic ring is the primary cause of this apparently-paradoxical phenomenon. This is the first type of steric acceleration, indicating a possibility of designing a highly reactive functional group by strategically locating it in the sterically-congested environment.
authors.affiliation: Laboratory of Chemical Biology, Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Shiraishi
authors.forename: Kimiyuki
authors.initials: K
authors.lastname: Kanno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Kohei
authors.initials: K
authors.lastname: Johmoto
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Uekusa
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
mesh_terms: D001386:Azides / Q000737:chemistry*; D008968:Molecular Conformation; D013056:Spectrophotometry, Ultraviolet
chemical_list: D001386:Azides