Unveiling the reactivity of 2-(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 -bicyclo[6.1.0]nonyne (-BCN) with 2-pyran-2-one, 2-thiopyran-2-one, 2-pyran-2-thione and 2-thiopyran-2-thione. These 2-(thio)pyran-2-(thi)ones have displayed different reactivity towards -BCN. Density functional theory (DFT) calculations show, in agreement with experiments, that -BCN reacts significantly faster with 2-thiopyran-2-one compared to other 2-(thio)pyran-2-(thi)one derivatives because of the lower distortion energy. Experimentally determined second-order rate constants for the reaction of a 2-pyran-2-thione with different strained derivatives, including a 1-methylcyclopropene derivative and several cycloalkynes (-BCN, (1,8)-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.