Stereoelectronic Control of Cycloadditions and Fragmentations

The stereoelectronic control of reactivity provides a special, yet necessary challenge. Pericyclic reactions play an important role in the development of theoretical organic chemistry, and they enable many practical synthetic processes. Because bond-breaking and bond forming are closely coordinated in the TS, the reaction path of neutral pericyclic reactions does not involve radical, carbocationic, or carbanionic intermediates controllable by the usual choice of resonance patterns. This difficulty is well illustrated by the lack of reliable and convenient means of exerting electronic control over Huisgen dipolar cycloaddition reactions, e.g., the azide-alkyne cycloaddition. Current strategies for accelerating azide-alkyne cycloadditions involve catalysis (CuAAC) and reactant destabilization (SPAAC). CuAAC is fast, selective and widely used, but the toxicity and redox properties of Cu render it unsuitable for important areas of chemical biology and nanotechnology. The SPAAC alternative results in a non-specific increase in reactivity that can be associated with poor stability and selectivity. It is clear that alkynes activated solely using reactant destabilization are getting close to the limits of practical utility. Provided within is a general strategy for transition state (TS) stabilization of the concerted pericyclic processes via carefully optimized electronic substituent effects. Computational predictions are followed by experimental studies which benchmarked and validated the choice of theoretical methods. This work highlights two strategies for selective TS stabilization in catalyst-free azide-alkyne cycloadditions: hyperconjugation and H-bonding. When these strategies are combined and stereoelectronically optimized, the combination of these TS-stabilizing effects should lead to ~1 million fold acceleration. Alkynyl crown ethers provide a scaffold for transition state stabilization, where propargylic C-O bonds within the macrocycle are constrained for hyperconjugative assistance. Preorganization of σ-acceptors into the optimal arrangement for hyperconjugative interactions alleviates a portion of the entropic penalty for reaching the TS. Optimal alignment can be reinforced, and transition state stabilization can be further amplified, by binding positively charged ions to the crown ether core, highlighting the potential for applications in ion sensing. Future work into optimizing cavities that fully utilize stronger binding in the TS can provide an alternative strategy for TS stabilization, providing alkynes that can be activated by the presence of external stimuli. An important feature of the new approach is stereoelectronic amplification, which is achieved by optimal positioning of σ-acceptors at the endocyclic bonds that are antiperiplanar to the breaking alkyne π-bonds. In strained alkynes, such hyperconjugative stabilization is present in the starting materials, relieving strain to provide stability, but becomes stronger in the TS, providing an accelerating effect overall. Also described is a radical cascade that provides the first documented example for the control of chemical reactivity via selective transition state (TS) stabilization due to the through-bond (TB) interaction of non-bonding orbitals, providing a conceptually new approach for the control of radical reactivity. The rarity of homolytic C-C scission results from the strength of this bond (~80 kcal/mol for the parent C-C bond in ethane). This transformation becomes thermodynamically favorable and kinetically accessible via careful design of radical leaving groups. The energetic penalty for breaking a strong σ-bond can be compensated by gaining aromaticity in the product and by formation of a stabilized 2-center, 3-electron "half-bond" in the departing radical fragment. These effects become important even at the relatively early stages of the reaction, providing selective transition state stabilization and effectively accelerating the fragmentation. The weakened σ-bond is able to participate in highly stabilizing through-bond interactions between the initial radical adduct and the lone pair present in the incipient fragment, eliminating >80% of the energy cost for C-C bond cleavage. Such stereoelectronic design of radical leaving groups leads to a new and convenient route to Sn-functionalized aromatics.