A mechanism for efficient proton-transfer catalysis. Intramolecular general acid catalysis of the hydrolysis of 1-arylethyl ethers of salicylic acid

Abstract

The tert-butyl (1) and 1-arylethyl ethers (2) of salicylic acid are hydrolyzed with efficient general acid catalysis by the ortho-COOH group. The half-life of the neutral COOH form of the tert-butyl ether is 15.2 min at 39°, and the estimated acceleration by the COOH group of 2, X = Me, Y = H is 2.13 × 105. The salicylate leaving group from 2 (X = Me, Y = H) has an effective pKa of 2.9, compared with a nominal pKa of 8.52. Analysis of substituent effects in both arylethyl and leaving groups provides the most detailed available mechanistic insight into a reaction involving efficient intramolecular proton-transfer catalysis. The mechanism is very different from classical general acid-base catalysis. Proton transfer takes place very rapidly within a developing strong hydrogen bond, and though an integral part of the C—O cleavage process is practically uncoupled from it. "Strategic delay" of the proton-transfer step, relative to C—O cleavage, makes a significant contribution to efficiency by setting up the conditions for the formation of the strong, intramolecular hydrogen bond.Key words: catalysis, carboxyl, hydrogen bond, proton transfer, enzyme mechanism.

Research Article: Computer‐Assisted Design of Pro‐drugs for Antimalarial Atovaquone

“…This is in accordance with previously reported studies by Kirby and Fife that indicate the importance of water in the mechanistic pathway for the proton transfer in such systems (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)51).…”

“…Our choice is based on Kirby's experimental kinetic studies that indicate that the rate-limiting step in these processes (processes 1-6, Scheme 2) is a transfer of a proton from the carboxylic group into the neighboring ether oxygen. In addition, the proton transfer rate is largely affected by the formation of strong hydrogen bonding in the products and consequently in the transition state leading to them (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Hence, it is feasible to assume that the rate of the proton transfer will be dependent on the structural features of the enzyme model as evident from the different experimental rate values determined for processes 1-6.…”

Quantum Mechanical Calculations for Reaction Path of O-R Bond Breakage in Some of Cefpodoxime Prodrugs

“…Beyond the transition state the (O22) anion and the H proton unite leading to form the end products of cefpodoxime acid and alkenes as a result of the final geometrical minimization, GMin (7-10) [12][13][14]. The activation energy of the proton transfer is largely depended on the property of the linker carriers [22][23][24][25]. The transfer of the proton from the ethyl ester group into the neighboring carboxylic oxygen at the transition state was illustrated in Figs.…”

Design, Synthesis, andIn VitroKinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations

“…Values in the order of 10 9 –10 13  M have been reported for the EM parameter in intramolecular processes occurring through nucleophilic addition. On the other hand, EM values less than 10 M were measured for proton transfer processes until recently where values of 10 10 were reported by Kirby on the hydrolysis of some enzyme models [40–46, 89–92]. …”

“…Using DFT, molecular mechanics, and ab initio at different levels, numerous enzyme model processes were calculated for determining the factors governed their rates. These processes include (i) intramolecular acid-catalyzed hydrolysis of N-alkylmaleamic acid derivatives [38, 39]; (ii) proton transfers between two oxygen atoms and between oxygen and nitrogen in Kirby's acetals [40–48]; (iii) proton transfer between two oxygen atoms in nonflexible (rigid) systems as studied by Menger and Ladika [49–53]; (iv) acid-catalyzed ring-closing reactions of hydroxy-acids as investigated by Milstien and Cohen [54–57] and Menger and Ladika [49–53]; and (v) S N 2-based cyclization reactions as researched by Brown and van Gulick [58], Bruice and Pandit [59, 60], and Galli and Mandolini [61]. …”