Selective transition state stabilization via hyperconjugative and conjugative assistance: stereoelectronic concept for copper-free click chemistry.

Dissection of stereoelectronic effects in the transition states (TSs) for noncatalyzed azide-alkyne cycloadditions suggests two approaches to selective transition state stabilization in this reaction. First, the formation of both 1,4- and 1,5-isomers is facilitated via hyperconjugative assistance to alkyne bending and C···N bond formation provided by antiperiplanar σ-acceptors at the propargylic carbons. In addition, the 1,5-TS can be stabilized via attractive C-H···F interactions. Although the two effects cannot stabilize the same transition state for the cycloaddition to α,α-difluorocyclooctyne (DIFO), they can act in a complementary, rather than competing, fashion in acyclic alkynes where B3LYP calculations predict up to ∼1 million-fold rate increase relative to 2-butyne. This analysis of stereoelectronic effects is complemented by the distortion analysis, which provides another clear evidence of selective TS stabilization. Changes in electrostatic potential along the reaction path revealed that azide polarization may create unfavorable electrostatic interactions (i.e., for the 1,5-regioisomer formation from 1-fluoro-2-butyne and methyl azide). This observation suggests that more reactive azides can be designed via manipulation of charge distribution in the azide moiety. Combination of these effects with the other activation strategies should lead to the rational design of robust acyclic and cyclic alkyne reagents for fast and tunable "click chemistry". Further computational and experimental studies confirmed the generality of the above accelerating effects and compared them with the conjugative TS stabilization by π-acceptors.

Citation

Brian Gold, Nikolay E Shevchenko, Natalie Bonus, Gregory B Dudley, Igor V Alabugin. Selective transition state stabilization via hyperconjugative and conjugative assistance: stereoelectronic concept for copper-free click chemistry. The Journal of organic chemistry. 2012 Jan 6;77(1):75-89

Mesh Tags

Substances

PMID: 22077877

search → result