Computational prediction of some properties of 3-substituted cyclooctynes and assessment of their synthetic accessibility via anionic vinyl bromide precursors

Cyclooctyne, a strained cyclic alkyne, readily engages in “click reactions” with alkyl azides to form 1,2,3-triazoles. While there have been previous studies on the effects of substitution on the cyclooctyne framework in an effort to tune reactivity, little work has been directed towards substitution of one of the propargyl methylene groups despite the fact that such substitution is likely to have dramatic reactivity-tuning effects. We have modelled eight cyclooctyne derivatives substituted at the propargyl site using the ω B97X-D/aug-cc-pVDZ density functional theory (DFT) method. The energies of these derivatives relative to the unsubstituted cyclooctyne suggests greater stabilization. Furthermore, calculated global electrophilicity indexes suggest that most will have higher reactivity toward nucleophiles such as alkyl azides. Finally, we predict the feasibility of the synthesis of these derivatives via computational optimization of appropriately substituted vinyl anion precursors. In almost all cases there is spontaneous elimination of a bromide leaving group and formation of the desired substituted cyclooctyne. The work here suggests that propargyl-substituted cyclooctynes are promising synthetic targets that may exhibit enhanced reactivities beyond that of the unsubstituted compound.