α- and β-Lapachone Isomerization in Acidic Media: Insights from Experimental and Implicit/Explicit Solvation Approaches.

Combined experimental and mixed implicit/explicit solvation approaches were employed to gain insights into the origin of switchable regioselectivity of acid-catalyzed lapachol cyclization and α-/β-lapachone isomerization. It was found that solvating species under distinct experimental conditions stabilized α- and β-lapachone differently, thus altering the identity of the thermodynamic product. The energy profile for lapachol cyclization revealed that this process can occur with low free-energy barriers (lower than 8.0 kcal mol ). For α/β isomerization in a dilute medium, the computed enthalpic barriers are 15.1 kcal mol (α→β) and 14.2 kcal mol (β→α). These barriers are lowered in concentrated medium to 11.5 and 12.6 kcal mol , respectively. Experimental determination of isomers ratio was quantified by HPLC and NMR measurements. These findings provide insights into the chemical behavior of lapachol and lapachone derivatives in more complex environments.