Aporphines. 50. Kinetics of solvolysis of N-(2-chloroethyl)norapomorphine, an irreversible dopamine receptor antagonist.

The rates and mechanism of solvolysis of (-)-N-(2-chloroethyl)norapomorphine (NCA, 1c) in aqueous solution have been examined by reversed-phase liquid chromatography (HPLC) to follow the levels of starting material and products. The first-order rate constants for aziridinium ion formation at 25 and 37 degrees C at pH 7.0 are 0.024 and 0.096 min-1, respectively. Determination of the first-order rate constant for the disappearance of NCA as a function of pH has allowed the calculation of an approximate pKa of 6.3 for the tertiary amine, while the influence of reaction conditions (e.g., pH, buffer salt and concentration, and added nucleophiles) on product distribution support the view that NCA solvolysis proceeds through an intermediate aziridinium ion. Application of the HPLC procedure allowed us to observe simultaneously the loss of NCA and the appearance of an intermediate and multiple products at trace levels; it also permitted the facile isolation and subsequent identification of small amounts of hydrolysis products. At pH 7, maximum aziridinium concentration is reached only after 10 min at 37 degrees C and at 25 degrees C after 1 h. Increased temperatures and pH facilitate the rate of aziridinium ion formation, as well as of non-dopamine antagonist solvolysis products. The significance of these findings, including the ease with which buffer ions add to the intermediate ion, are discussed in relation to the use of NCA and its tritiated isomer, [3H]NCA, in dopamine receptor studies.