Reactivity of acetanilides in the alkaline hydrolysis reaction: theory vs. experiment

Cheshmedzhieva, Diana; Ilieva, Sylvia; Hadjieva, Boriana; Trayanova, Tsvetelina; Galabov, Boris

doi:10.1080/00268970902799890

Cited by 15 publications

(11 citation statements)

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“…Amides are fundamental functional groups in biochemistry, and their remarkable resistance to hydrolysis is largely responsible for the stability of complex protein structures. Amide hydrolysis has been the focus of numerous experimental investigations 50–53. The recent computational study of Cheshmedzhieva et al52 assessed the ability of several indices to characterize the reactivity of ring‐substituted acetanilides in alkaline hydrolysis reactions.…”

Section: Epn Index For Describing Chemical Reactivitymentioning

confidence: 99%

“…Amide hydrolysis has been the focus of numerous experimental investigations 50–53. The recent computational study of Cheshmedzhieva et al52 assessed the ability of several indices to characterize the reactivity of ring‐substituted acetanilides in alkaline hydrolysis reactions. The theoretical work was supplemented with rate constant measurements (at 25°C) for the hydrolysis of a series of acetanilides with both electron‐donating and electron‐withdrawing para ‐substituents (Scheme ).…”

Section: Epn Index For Describing Chemical Reactivitymentioning

confidence: 99%

“…B3LYP/6‐31+G(d,p) DFT computations were employed to model the alkaline hydrolysis of acetanilides 52. As for the aminolysis of phenyl acetates, the experimental rates of hydrolysis were correlated with various theoretical electronic structure parameters including NBO atomic charges, the electrophilicity index, and the electrostatic potential at the carbon and nitrogen atoms of the reaction center ( V C , V N ).…”

Section: Epn Index For Describing Chemical Reactivitymentioning

confidence: 99%

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Structure–reactivity relationships for aromatic molecules: electrostatic potentials at nuclei and electrophile affinity indices

Galabov

Ilieva

Koleva

et al. 2012

WIREs Comput Mol Sci

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Recent advances have been achieved in the quantitative description of the reactivity of aromatic compounds in terms of simple parameters derived from theoretical computations. The first part of this review surveys the use of electrostatic potentials at nuclei (EPN) in characterizing the reactivity of substituted aromatic compounds when the reaction center is situated outside the aromatic ring. The application of EPN for several typical reactions of substituted aromatic systems is described in detail. The performance of alternative reactivity descriptors, such as theoretical atomic charges, the Parr electrophilicity index, and the experimental Hammett constants, is considered as well. The second part of this review discusses the recently proposed electrophile affinity construct for quantifying reactivity and regiospecificity for the most typical reaction of arenes: electrophilic aromatic substitution. The characterization of reactivity of aromatic molecules in terms of proton affinities and arene nucleophilicity indices is surveyed briefly. C 2012 John Wiley & Sons, Ltd.

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Section: Epn Index For Describing Chemical Reactivitymentioning

confidence: 99%

Section: Epn Index For Describing Chemical Reactivitymentioning

confidence: 99%

Section: Epn Index For Describing Chemical Reactivitymentioning

confidence: 99%

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Structure–reactivity relationships for aromatic molecules: electrostatic potentials at nuclei and electrophile affinity indices

Galabov

Ilieva

Koleva

et al. 2012

WIREs Comput Mol Sci

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“…The plasma exposure of RAB thioether in humans accounted for approximately 50% of the parent drugs (Shirai et al, 2001;Miura et al, 2006); however, the plasma concentrations of OME thioether and LAN thioether were low, which could explain why the chiral inversion of OME and LAN in humans was negligible. Meanwhile, a positive correlation was found between the natural bond orbital charges (Reed et al, 1985(Reed et al, , 1988 of sulfur atoms in these compounds and the reaction rate (Cheshmedzhieva et al, 2009) in GSH (Supplemental Table 1). The change of substituents affected the oxidation-reduction properties of PPIs and their elimination pathways in vivo.…”

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confidence: 93%

Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors

et al. 2019

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Racemic proton pump inhibitors (PPIs) have been developed into pure enantiomers given superior pharmacokinetic profiles. However, after doses of single enantiomer PPIs, different degrees of chiral inversion were observed. We investigated the relationship between chiral inversion and reductive metabolism of PPIs, as well as the mechanism of reductive metabolism. In liver microsomes and Sprague-Dawley rats, PPI thioethers were stereoselectively oxidized to (R)-and (S)-PPIs, indicating that thioethers could be the intermediates of chiral inversion. By comparing the area under the plasma concentration-time curve ratios of thioether to rabeprazole under different routes of administration and blood sampling site, it was determined that thioether was mainly formed in the liver rather than the intestine. The formation rate of PPI thioethers in liver subcellular fractions was significantly higher than that in buffers. Sulfhydryl-blocking agents, such as N-ethylmaleimide, menadione, and ethacrynic acid, inhibited the reductive metabolism of PPIs in vitro, and their corresponding glutathione conjugates were observed. Similar amounts of thioethers were formed in glutathione solutions as in liver subcellular fractions, indicating that biologic reducing agents, instead of reductases, accelerated the reductive metabolism of PPIs. The reduction rates in glutathione solutions were ordered as follows: rabeprazole > omeprazole > lansoprazole > pantoprazole, which was consistent with the natural bond orbital charges of sulfur atoms in these compounds. In conclusion, PPIs were transformed into thioethers by biologic reducing agents in liver, and thioethers continued to be oxidized to two enantiomers, leading to chiral inversion. Furthermore, inhibiting oxidative metabolism of PPIs enhanced reductive metabolism and chiral inversion. s This article has supplemental material available at dmd.aspetjournals.org. ABBREVIATIONS: ABT, 1-aminobenzotriazole; AUC, area under the plasma concentration-time curve; AUC 0-t , area under the plasma concentration-time curve from time 0 to the last quantifiable time point;

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“…Tanto estos estudios, como trabajos experimentales (Cheshmedzhieva et al, 2009) concuerdan en que dicha reacción transcurre a través de la formación de un intermediario tetraédrico.…”

Section: Introductionunclassified

Estudio Teórico sobre la Hidrólisis Ácida de Amidas Alifáticas y Aromáticas

Caglieri

Pagnan

2013

Inf. tecnol.

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ResumenSe realizó un estudio teórico comparativo de la reactividad de las amidas alifáticas Acetamida y Nmetilacetamida y de las amidas aromáticas Benzamida y N-metilbenzamida, frente a la reacción de hidrólisis catalizada por ácido. Esto se hace a través del análisis de los intermediarios de reacción. Se modelaron y determinaron las geometrías de todas las especies que intervienen en la hidrólisis y se calcularon los parámetros geométricos y las energías de los reactivos y productos, empleando dos métodos de estructura electrónica, teoría del funcional de la densidad (DFT) y el modelo Austin (AM1). Los valores obtenidos se compararon con datos experimentales y de literatura observándose una gran concordancia. Siguiendo el mismo procedimiento se determinaron los parámetros geométricos y energías de los intermediarios de reacción, observándose una mayor estabilidad para el intermediario alifático, que reportó una energía inferior comparada con la del aromático. Palabras clave: hidrólisis ácida, amida alifática, amida aromática, teoría del funcional de la densidad, modelo AustinAbstract A comparative theoretical study of reactivity of the aliphatic amides Acetamide and N-methylacetamide and of the aromatic amides Benzamide and N-methylbenzamide for the hydrolysis reaction catalyzed by acid. This is done through the analysis of intermediates of reactions. The geometry of all species involved in the hydrolysis was determined and the energies of all reagents and products were calculated. Two methods of electronic structure, density functional theory (DFT) and the Austin Model 1 (AM1) were used. The calculated values were compared with experimental and literature data. Following the same procedure, the geometric parameters and energies of reaction intermediates were determined, observing greater stability for the aliphatic intermediate, with lower energy compared with the aromatic substances.

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Reactivity of acetanilides in the alkaline hydrolysis reaction: theory vs. experiment

Cited by 15 publications

References 65 publications

Structure–reactivity relationships for aromatic molecules: electrostatic potentials at nuclei and electrophile affinity indices

Structure–reactivity relationships for aromatic molecules: electrostatic potentials at nuclei and electrophile affinity indices

Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors

Estudio Teórico sobre la Hidrólisis Ácida de Amidas Alifáticas y Aromáticas

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