Unveiling the reactivity of 2 H -(thio)pyran-2-(thi)ones in cycloaddition reactions with strained alkynes through density functional theory studies.

Over the past two decades, click chemistry transformations have revolutionized chemical and biological sciences. Among the different strain-promoted cycloadditions, the inverse electron demand Diels-Alder reaction (IEDDA) has been established as a benchmark reaction. We have theoretically investigated the IEDDA reaction of endo -bicyclo[6.1.0]nonyne ( endo -BCN) with 2 H -pyran-2-one, 2 H -thiopyran-2-one, 2 H -pyran-2-thione and 2 H -thiopyran-2-thione. These 2 H -(thio)pyran-2-(thi)ones have displayed different reactivity towards endo -BCN. Density functional theory (DFT) calculations show, in agreement with experiments, that endo -BCN reacts significantly faster with 2 H -thiopyran-2-one compared to other 2 H -(thio)pyran-2-(thi)one derivatives because of the lower distortion energy. Experimentally determined second-order rate constants for the reaction of a 2 H -pyran-2-thione with different strained derivatives, including a 1-methylcyclopropene derivative and several cycloalkynes ( exo -BCN, (1 R ,8 S )-bicyclo[6.1.0]non-4-yne-9,9-diyl)dimethanol, dibenzocycylooctyne and a light activatable silacycloheptyne, were used to validate the computational investigations and shed light on this reaction.