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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 pKa and cyclization rate constants kc in water at 25°C for 2-bromo-4-chloro-N-(4-nitrophenyl)butanamide [pKa = 11.64 ± 0.01; kc = (1.94 ± 0.03) × 10-2 s-1], 4-chloro-N-(4-nitrophenyl)butanamide [pKa = 13.35 ± 0.02; kc = (1.60 ± 0.02) × 10-2 s-1 and 4-chloro-2-methyl-N-(4-nitrophenyl)butanamide [pKa = 13.55 ± 0.03; kc = (7.61 ± 0.11) × 10-2 s-1]. The pKa and kc 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 kc = (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 1-1, 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 1-1], 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 [k3/k-1 = (1.40 ± 0.04) × 102 1 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