Acceleration of 1,3-Dipolar Cycloadditions by Integration of Strain and Electronic Tuning

The 1,3-dipolar cycloaddition between azides and alkynes provides new means to probe and control biological processes. A major challenge is to achieve high reaction rates with stable reagents. The optimization of alkynyl reagents has relied on two strategies: increasing strain and tuning electronics. We report on the integration of these strategies. A computational analysis suggested that a CH -> N aryl substitution in dibenzocyclooctyne (DIBO) could be beneficial. In transition states, the nitrogen of 2-azabenzo-benzocyclooctyne (ABC) engages in an n ->pi* interaction with the C=O of alpha-azidoacetamides and forms a hydrogen bond with the N-H of alpha-diazoacetamides. These dipole-specific interactions act cooperatively with electronic activation of the strained pi-bond to increase reactivity. We found that ABC does indeed react more quickly with alpha-azidoacetamides and alpha-diazoacetamides than its constitutional isomer, dibenzoazacyclooctyne (DIBAC). ABC and DIBAC have comparable chemical stability in a biomimetic solution. Both ABC and DIBO are accessible in three steps by the alkylidene carbene-mediated ring expansion of commercial cycloheptanones. Our findings enhance the accessibility and utility of 1,3-dipolar cycloadditions and encourage further innovation.

Automated summary

The study integrated two strategies to optimize alkynyl reagents for achieving high reaction rates. Computational analysis indicated that aryl substitution could be beneficial for increasing reactivity. Experimental results showed that interactions between the new reagents and amino dipolarophile contribute to enhanced reaction efficiency.