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 k_obs=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 pK_a. 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.