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Diels-Alder Reactivities of Cyclic Dienes and Dienophiles

  • Author(s): Levandowski, Brian
  • Advisor(s): Houk, Kendall
  • et al.

Since the discovery of the Diels-Alder reaction in 1928, chemical theorists have pursued a deeper understanding of the factors controlling reactivity and stereoselectivity for this reaction. Cyclopentadiene and cyclopropene are unusual, in that they exhibit rapid Diels-Alder reactivity despite their lack of activating electron withdrawing or donating groups. The rapid reactivities of cyclopentadienes result from the minimal distortion required of cyclopentadiene to achieve the envelope-like geometry adopted in the transition state, while the rapid reactivities of cyclopropenes result from reactant distortion and the highly stabilizing orbital interactions present at the transition state.

Substituents at the 3-position of cyclopropenes and the 5-position of cyclopentadienes significantly influence the Diels-Alder reactivity through hyperconjugative interactions of the substituent with the cyclic π-system. Hyperconjugative acceptors stabilize cyclopropenes and decrease the reactivity by invoking aromatic cyclic delocalization of the two π-electrons and the reactivity decreases. The effect is opposite for cyclopentadienes, where hyperconjugative acceptors induce antiaromatic cyclic delocalization of the four π-electrons, destabilizing the diene and promoting reactivity.

The syn and anti π-facial selectivity of 5-substituted cyclopentadienes is related to the electronic nature of the substituent. Experimentally, electron-withdrawing groups provide syn adducts, while electron-donating groups provide anti adducts. Structural analysis of the ground state geometries revealed that ?-acceptors pre-distort the cyclopentadiene into an envelope-like geometry that minimizes the destabilizing effect of the negative hyperconjugation. This envelope geometry resembles the syn transition state geometry and promotes syn selectivity by minimizing the distortion energy required to achieve the syn transition state. Conversely, donors pre-distort in the opposite direction to maximize the stabilizing effect the hyperconjugative interaction towards an envelope geometry that favors the anti cycloaddition.

The computational insights into the reactivities of cyclopentadienes inspired us to develop cyclopentadiene as a bioorthogonal reagent. Bioorthogonal reactions take place rapidly and selectively in biological environments and enable the study of biomolecules in living systems. Highly accurate computational methods were used to screen potential bioorthogonal cyclopentadiene candidates. The screening revealed tetrachlorocyclopentadiene ketals as highly reactive and stable dienes with promising bioorthogonal potential. To verify our prediction, the Murphy group bioconjugated a tetrachlorocyclopentadiene ketal it to a peptide and labeled the peptide with trans-cyclooctene dye. Some cyclopentadienes are now considered viable bioorthogonal reagents.

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