Intramolecular catalysis of amide hydrolysis by the carboxy-group. Rate determining proton transfer from external general acids in the hydrolysis of substituted maleamic acids

Abstract

The highly efficient intramolecular catalysis by the carboxy-group of the hydrolysis of simple dialkylmaleamic acids is itself subject to external general acid catalysis. The kinetic characteristics of the general acid catalysed reaction are those expected for a diffusion-controlled proton transfer. At high concentrations of general acid, external catalysis disappears. This is shown to result from a change in rate-determining step, and is thus evidence for an intermediate on the reaction pathway. The intermediate can only reasonably be a tetrahedral addition intermediate. Kinetic evidence is now available for all the major steps on the reaction pathway, and the requirements for an enzyme catalyst carrying out the reaction can be specified in detail. The full mechanism specifically implicates the O-protonated amide as the reactive species in dilute acid.Smith, University Chemical Laboratory, Cambridge CB2 1 EW THE heart of any enzymic reaction is a highly efficient multiple interaction between substrate and catalytic groups brought close together in the enzyme-substrate complex. We use the reactions between the same groups held close together on the same molecule as models for the enzymic reactions. In most known systems intramolecular catalysis is much less efficient than enzymic catalysis, but it is becoming clear that the rates of at

Structural effects on reactivity in intramolecular catalysis. The hydrolysis of N-alkylated monoamides derived from norbornene-2,3-dicarboxylic acid

“…1 are consistent with the mechanism in Scheme 2. This mechanism is similar to mechanisms for other reactions in which an adjacent carboxylic acid promotes the hydrolysis of an amide (3,5).…”

“…0 T acids (maleamic acids (3,6) and 2,3-dimethylmaleamic acids (3,5)). Since interactions between functional groups are affected by conjugation, it is important to examine in detail the kinetics of similar reactions in rigid but nonconjugated subCan.…”

“…This transfer may occur with or without acid catalysis (3,5,6). Kinetic analysis of the hydrolysis of amides derived from rigid systems containing neighboring amide and carboxylic acid groups has provided valuable information on the reactivity of tetrahedral intermediates.…”

Stability and Characterization of Protein and Peptide Drugs

“…After proton transfer to the amide group, nucleophilic attack by the carboxylate function forms the cyclic tetrahedral intermediate (Kirby and Lancaster, 1972) which after transfer ofthe proton from the hydroxyl to . the nitrogen breaks down to the anhydride by cleavage of the C-N bond, the rate-determining step (Aldersley et al, 1974;Kluger and Lam, 1978). Subsequently the anhydride is readily hydrolyzed by general acid catalysis.…”

“…4). The particular lability of Asn A2 1 against hydrolysis is due to its position as a eOOH-terminal residue where deamidation is catalyzed by the terminal carboxyl group (Leach and Lindley, 1953;Aldersley et al, 1974).…”