A Tale of Two Heterocycles: How Oxygen and Sulfur Shape Divergent Kemp Reactivity

ABSTRACT The Kemp elimination is a well‐studied reaction that proceeds through the deprotonation of carbon‐3 of benzisoxazoles, coupled with irreversible ring opening by cleavage of the labile O‐N bond. The base‐catalyzed reaction is concerted, with no detectable intermediate. Due to their compositional and structural similarities, benzisothiazoles are also candidates for Kemp elimination reactions; however, little information was previously available on these compounds. We found that benzisothiazoles also undergo Kemp elimination, and we have characterized the Kemp product. As previously observed with benzisoxazoles, reactions of benzisothiazoles are significantly accelerated by polar, aprotic solvents and by the presence of electron‐withdrawing groups (EWG) on the six‐membered ring. In mixed water/DMSO systems, we found a strong inverse linear relationship between the logarithm of the second‐order rate constant and the mole fraction of water for both benzisoxazoles and benzisothiazoles. Linear free‐energy relationship (LFER) analyses reveal opposing solvent‐dependent behavior between the two heterocycles: DMSO steepens substituent sensitivity in benzisoxazoles relative to water but dampens it in benzisothiazoles. Extrapolation of the chemically controlled regime suggests that transitioning from water to pure DMSO produces a remarkable ~14‐order‐of‐magnitude increase in the intrinsic chemical reactivity of 5‐nitrobenzisoxazole, compared to an ~7‐order‐of‐magnitude acceleration for 5‐nitrobenzisothiazole. This divergence highlights fundamental differences in how protic and aprotic media stabilize the localized phenolate versus the soft, polarizable thiophenolate anion.