Kinetics and mechanism of formation and decomposition of substituted 1‐phenylpyrrolidin‐2‐ones in basic medium

A study of chemical behaviour of substituted 4‐chloro‐ N ‐phenylbutanamides in aqueous solutions of sodium hydroxide showed that the substrate first undergoes ring closure to give substituted 1‐phenylpyrrolidin‐2‐ones, which are subsequently hydrolysed to substitution derivatives of sodium 4‐amino‐ N ‐phenylbutanoates. Kinetic measurements provided the values of dissociation constants p K a and cyclization rate constants k c in water at 25 °C for 2‐bromo‐4‐chloro‐ N ‐(4‐nitrophenyl)butanamide [p K a  = 11.64 ± 0.01; k c  = (1.94 ± 0.03) × 10 −2 s −1 ], 4‐chloro‐ N ‐(4‐nitrophenyl)butanamide [p K a  = 13.35 ± 0.02; k c  = (1.60 ± 0.02) × 10 −2 s −1 ] and 4‐chloro‐2‐methyl‐ N ‐(4‐nitrophenyl)butanamide [p K a  = 13.55 ± 0.03; k c  = (7.61 ± 0.11) × 10 −2 s −1 ]. The p K a and k c values of individual derivatives differ depending on the substitution at the α‐position of the butanamide skeleton. In methanolic sodium methoxide solutions, the course of ring closure of 2‐bromo‐4‐chloro‐ N ‐(4‐nitrophenyl)butanamide is of similar nature but slower [ K  = 60.10 ± 0.08 and k c  = (6.52 ± 0.05) × 10 −3 s −1 ]. The subsequent hydrolyses of substituted 1‐phenylpyrrolidin‐2‐ones to substituted 4‐aminobutanoic acids also have different courses with different derivatives and depend on the substituents in the aromatic and/or heterocyclic moiety. The rate‐limiting step of hydrolysis of 1‐(4‐nitrophenyl)pyrrolidin‐2‐one consists of the non‐catalysed decomposition of the tetrahedral intermediate. In the case of 3‐bromo‐1‐(4‐nitrophenyl)pyrrolidin‐2‐one at sodium hydroxide concentrations below 0.1 mol l −1 , the rate‐limiting step is the second reaction pathway, i.e. the hydroxide ion‐catalysed decomposition of the tetrahedral intermediate. At sodium hydroxide concentrations above 0.1 mol l −1 , the rate‐limiting step shifts to formation of the tetrahedral intermediate. This formation of the intermediate is 140 times slower than its hydroxide ion‐catalysed decomposition [ k 3 / k −1  = (1.40 ± 0.04) × 10 2 l mol −1 ]. Introduction of a 3‐bromo substituent into 1‐(4‐nitrophenyl)pyrrolidin‐2‐one results in acceleration of all the reaction steps of hydrolysis and increases the acidity of the intermediate. Copyright © 2002 John Wiley & Sons, Ltd.