Reactivity of lactones and GHB formation

Abstract

The behavior of lactones in their hydrolysis reactions is a good indicator of their reactivity as electrophilic molecules. The hydrolysis of four- to six-membered lactones was investigated in neutral (water) and slightly acid media and in water/dioxane media. The following conclusions were drawn: (i) The reactivity of beta-propiolactone in neutral water is more than four times greater than that of beta-butyrolactone, due to the flow of charge caused by the latter's methyl substituent. Reactivity is enthalpy-controlled. (ii) The reactivity of beta-lactones diminishes in water/dioxane media when the percentage of dioxane increases. The increase in the dioxane percentage relaxing the intermolecular hydrogen bonds in the ordered structure of the water reduces H# and simultaneously increases the S# value. (iii) An inverse solvent kinetic isotope effect in the acid-catalyzed hydrolysis of y-butyrolactone and -valerolactone was observed, this being indicative of acyl cleavage. (iv) The H# and S# values permit discrimination between alkyl and acyl cleavage. (v) A correlation was found between the chemical reactivity of lactones and their carcinogenic activity. (vi) The results suggest that orally ingested y-butyrolactone remains largely in its nonhydrolyzed form in the stomach before passing into the blood. (vii) The concentration equilibrium constant of GHB formation at human body temperature is Keq (37 °C) = 0.40. (viii) Study of GHB formation shows that, contrary to earlier results, this is an endothermic process, with rH = 3.6 kJ mol-1.