Hydroxy-group participation in the hydrolysis of amides and its effective concentration in the absence of strain effects

Abstract

Rate constants are reported for the alkaline- and acid-catalysed hydrolysis of endo-6-hydroxybicyclo[2.2.1]-heptane-endo-2-carboxamides in aqueous solution. The product of the acid-catalysed reaction is endo-6-hydroxybicyclo[2.2.1]heptane-endo-2-carboxylic acid lactone and this lactone is also formed as an intermediate in alkaline solution before giving the hydroxy-acid anion as the product. The effective concentration of the intramolecular alkoxide ion group is ca. 10⁸M. This is in good agreement with the maximum entropic advantage predicted for intramolecular reactions as the system is thought to be free of major strain energy and solvation effects. Variation of substituents in the amine leaving group gives a β_1g value of +0.30 for the hydroxide-ion-catalysed lactonisation reaction. This is interpreted in terms of rate-limiting breakdown of the tetrahedral intermediate in which there is considerable positive charge on the amine nitrogen. Mechanisms consistent with this involve either proton transfer from water to the amine nitrogen occurring synchronously with carbon–nitrogen bond fission or a stepwise process in which the nitrogen of the tetrahedral intermediate is fully protonated and the rate-limiting step is either diffusion apart of this intermediate and hydroxide ion or collapse of this intermediate with hydroxide ion acting as a ‘spectator’. The β_1g value for the acid-catalysed lactonisation reaction is 0.0.