Mechanism and catalysis of 2-methyl-3-thiosemicarbazone formation. Second change in rate-determining step and evidence for a stepwise mechanism for proton transfer in a simple carbonyl addition reaction

Abstract

2-Methyl-3-thiosemicarbazone formation fromp-chlorobenzaldehyde undergoes a change in rate-determining step at high pH, similar to that at low pH, from rate-determining dehydration of the carbinolamine intermediate to partially rate-determining attack of the nucleophile on the carbonyl group. The attack step is subject to general base catalysis. Brpnsted plots for tertiary amines and oxygen anions exhibit breaks for bases of less than 6. This curvature is consistent with that expected for a simple rate-determining proton transfer reaction between the dipolar addition intermediate ± and the catalyzing base. However, the break occurs at a higher than expected from the estimated value for T= of 3.1. Better agreement is found for a preassociation mechanism with rapid, stepwise proton transfer within an encounter complex after the formation of T±. According to this mechanism, N-C bond formation within an encounter complex that contains the base catalyst is rate determining with strong bases and there is a change to rate-determining proton transfer with weaker bases. The magnitude of the observed catalytic constants is consistent with that expected for such a mechanism, but is significantly smaller than expected for a concerted mechanism. General acid catalysis of 2-methyl-3-thiosemicarbazide addition to p-chlorobenzaldehyde by carboxylic and cacodylic acids closely resembles that observed for the addition of other weakly basic amines (a -0.2). It is suggested that general acid, unlike general base, catalysis involves some stabilization of the transition state for carbon-nitrogen bond formation by the catalyst. Agrowing body of evidence concerning general gests that in some cases these proton transfers proacid-base catalysis of complex reactions involving ceed by discrete steps, rather than by a process that is proton transfers to or from electronegative atoms sug-4648) and the National Institute of Child Health and Human Develop-(1) Supported by grants from the National Science Foundation (GB ment of the National Institutes of Health (HD 01247).Sayer, Jencks / Mechanism and Catalysis of 2-Methyl-3-thiosemicarbazone Formation (11) J.

Reaction of Hydantoin with Boronic Acids

“…-Reactions were conducted in H 2 O using a catalytic amount of Et 3 N [11], and all new compounds have been prepared in good-to-excellent yields and characterized by a number of physical methods including multinuclear NMR spectroscopy. Interestingly, we have found that addition of (2-formylphenyl)boronic acid to hydantoin gave the unexpected fused azaborine 1.…”

Investigation of Catalysis by Acids, Bases, Other Small Molecules and Enzymes

“…11.7 (A) E1cB mechanism for the elimination reactions of 4-nitrophenylethylpyridinium ions catalysed by OH − ; deprotonation is rate limiting at pK a 's below the breakpoint; data are from reference [16] and the line is calculated from Eqaution 11.11. (B) Effect of increasing 3-quinuclidinol buffer concentration on the rate constants for 2-methyl-3-thiosemicarbazone formation from 4-chlorobenzaldehyde at pH 11.10; results are consistent with a change in the rate-limiting step from proton transfer to formation of the intermediate; data from reference [8].…”

“…For example, the plot in Fig. 11.5A for the general base-catalysed reactions of 4-chlorobenzaldehyde with a substituted hydrazine has a breakpoint at pK HB a = 6.09 which is larger than that estimated for the postulated tetrahedral intermediate (pK HS a = 3.1) [8]. This difference is greater than the likely uncertainty in the pK a estimation and led to the proposal of a preassociation mechanism (see Section 11.2.5.3) rather than a conventional Eigen-type proton transfer mechanism.…”

“…11.5 (A) Eigen-type plot for the general base-catalysed reactions of 4-chlorobenzaldehyde with a substituted hydrazine[8]; the line is calculated from log k B = −0.341 − log(1 + 10 6.09−pK a ). (B) Eigen-type plot for general acid catalysis in the reaction of cyanic acid (HNCO) with aniline, and an alternative interpretation[9]; the dashed line has a Brønsted slope of −0.19 and the break at pK a near 10 in the solid line is consistent with proton transfer to an addition intermediate (PhNH 2 + CONH − ).…”

Synthesis, Characterization, and Antifungal Activity of Boron‐Containing Thiosemicarbazones

“…Reactions were conducted in H 2 O using a catalytic amount of HCOOH [10], and all new compounds have been prepared in good-to-excellent yields and characterized by a number of physical methods including multinuclear NMR spectroscopy. Interestingly, addition of 2-formylphenylboronic acid to the thiosemicarbazides gave the corresponding 2,3,1-benzodiazaborines 1 -3 (Scheme 1).…”