Alkynes to Reactive Intermediates via Cycloaddition Reactions: Structure, Reactivity, and Mechanism

Abstract

Reactive intermediates are highly reactive molecules featured by having short lifetimes. Their generations, structures, and reactivities are essential to the field of chemistry and have been attracting increasing attention. More often than not, the generation of a reactive intermediate invokes the use of catalysts, reagents, additives or irradiation. Direct generation of reactive intermediates under thermal, uncatalyzed, reagent- additive-free conditions remains a less explored but attractive strategy. The simple and straightforward setup of thermal reactions make it cost-efficient, reproducible, scalable, and practical for synthesis. More importantly, it also provides a platform for the discovery of novel reactivities and enables the construction of complex molecules. An alkyne is a particularly interesting functional group that can be further converted into reactive intermediates. On the one hand, alkynes generally have ample kinetic stability to render them easy to prepare, easy to handle, and shelf-stability that makes many of them commercially available. On the other, alkynes have inherently weak pi-bonds that can provide considerable favorable enthalpic contribution when they participate in a transformation, which can be a pivotal thermodynamic driving force for a thermal reaction. Furthermore, the high degree of unsaturation of an alkyne confers versatile modes of reactivities between alkynes and their reaction partners. These features synergistically make alkynes ideal precursors to reactive intermediates. Yet there remains a gap between alkynes and reactive intermediates, cycloaddition reactions provide a potential bridge for commuting. In this document, I will demonstrate how thermal, additive-free cycloaddition approaches convert alkynes into reactive intermediates including: i) strained reactive intermediates such as benzynes, 1,2,4-cyclohexatrienes, and 6-aza-1,2,4-cylcohexatrienes; ii) bond-deficient reactive intermediates such, a,3-dehydrotoluenes (DHTs), and free carbenes. DFT computations have provided crucial guidance for the reaction design and revealed valuable mechanistic insights across my entire research.