Mechanistic investigation on 2-aza-spiro[4,5]decan-3-one formation from 1-(aminomethyl)cyclohexylacetic acid (gabapentin)

Abstract

The intramolecular cyclization of the amino acid gabapentin has been studied in the pH range 2.24–11.15 at 80 °C in buffered solutions and constant ionic strength, and monitoring the progress of the process by fluorimetric method and proton NMR spectroscopy. From the profile of log k 0 versus pH two different acid–base equilibria are involved. The maximum rate is observed above pH 9.80 and the minimum rate has been measured between pH 5.15 and 6.21. The p K a1 and p K a2 have been determined by potentiometric titration to be 3.72 and 9.37, respectively. The buffer effect and the solvent kinetic isotopic effect suggest that the reaction is subject to general acid and general base catalysis. The process is sensitive to the gabapentin concentration (pH 10.45) and the pseudo-first order rate constant decrease with increasing the reagent concentration above 5.50×10 −2 M.