Malonylcoenzyme A models. Part 2. The methylene deprotonation step of the E1cB acyl transfer of malonic acid thiolmonoesters
Abstract
The deprotonation of the α-methylene site in S-aryl hydrogenthiomalonates (HO2CCH2COSR) was general-base catalysed. Nitrogen bases fit a single Bronsted correlation for this deprotonation step with slope 0.59 for primary, secondary, and tertiary amines. In general, amines followed saturation kinetics, but hydroxylamine followed the rate law kobs=k1[NH2OH]+k2[NH2OH]2; nevertheless, the k1 parameter fitted the Bronsted correlation for nitrogen bases. Oxygen-based buffers fitted an independent Bronsted correlation with β 0.42 and were slightly less reactive than nitrogen bases for a given catalyst pKa. Saturation kinetics were observed for thiolysis of S-4-chlorophenyl hydrogenthiomalonate, implying a ketenoid (E1cB) pathway for malonyl transfer. The primary isotope effect (H/D) for N-methylmorpholine catalysed deprotonation (dedeuteriation) of HO2C. CH2COSPh and DO2C.CD2COSPh was ca. 3.6. The second-order rate constant for ethylamine attack on S-4-chlorophenyl hydrogen-(2,2-dimethyl)thiomalonate was 600-fold smaller than that estimated at lower buffer concentrations for S-4-chlorophenyl hydrogenthiomalonate, in accord with a general-base catalysed deprotonation mechanism for the latter. The 2,2-dimethylmalonate ester showed a marked rate of attack of water on the monoanion probably reflecting intramolecular general-base catalysis by the –CO2– group. Second-order rate constants for hydroxide ion attack on S-phenyl and S-4-chlorophenyl hydrogenthiomalonates were measured.