Distorted amides as models for activated peptide N-C(O) units. 3. Synthesis, hydrolytic profile, and molecular structure of 2,3,4,5-tetrahydro-2-oxo-1,5-propanobenzazepine

Wang, Q. P.; Bennet, Andrew J.; Brown, Robert; Santarsiero, Bernard D.

doi:10.1021/ja00015a033

Cited by 97 publications

(84 citation statements)

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“…Overall, the processes are depicted in eqs. [2] and [3]. The above kinetic methylation studies give results for the position of methylation that are in full accord with what is expected on the basis of AM1 calculations, which show that l b should methylate on nitrogen and I d should methylate on oxygen.…”

Section: Methylation Of 34-dihydro-2-0x0-l4-propanoquinoline (Lb) supporting

confidence: 81%

An AM1 calculational study of the protonation and reactions of 3,4-dihydro-2-oxo-1,4-ethanoquinoline, 3,4-dihydro-2-oxo-1,4-propanoquinoline, 3,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine, 3,3,4,5-tetrahydro-2-oxo-1,5-propanobenzazepine, and N-methyl-4-bromo-2-methylacetanilide

Brown¹,

Wang²

1996

Can. J. Chem.

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Abstract:The gas phase N-and 0-protonation of distorted amides 3,4-dihydro-2-0x0-1.4-ethanoquinoline (la), 3,4-dihydro-2-0x0-l,4-propanoquinoline (lb), 3,3,4,5-tetrahydro-2-0x0-1,5-ethanobenzazepine (lc), and 3,3,4,5-tetrahydro-2-0x0-1,5-propanobenzazepine (16) and normal amides 4-bromo-2,N-dimethylacetanilide (5a) and 2,N-dimethylacetanilide (Sb), along with the N-protonation of benzoquinuclidine (7), has been studied calculationally at the semiempirical level of theory with AM 1. Calculated enthalpies of N-and 0-protonation (proton affinities) indicate that l a , lb, and l c should protonate on nitrogen and Id, 5a, and 5b on oxygen. A satisfactory straight-line relationship between the calculated proton affinities of la, lb, lc, and 7 with experimental solution pK,'s is used to estimate the solution pK, of Id. Results of a calculational study on the gas phase N-and 0 -methylation of lb, lc, and I d are nicely in accord with the findings of an experimental solution phase study of the methylationhydrolysis of l b and Id: while l b methylates on nitrogen, Id methylates on oxygen. A calculational study of possible pathways of hydrolysis of the N-protonated amides indicates that solvolysis of the hydrates of these species represents a viable route for their conversion to ring-opened products.Key words: protonation, methylation, reactions, distorted amides, AM1 calculations.

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Section: Methylation Of 34-dihydro-2-0x0-l4-propanoquinoline (Lb) supporting

confidence: 81%

An AM1 calculational study of the protonation and reactions of 3,4-dihydro-2-oxo-1,4-ethanoquinoline, 3,4-dihydro-2-oxo-1,4-propanoquinoline, 3,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine, 3,3,4,5-tetrahydro-2-oxo-1,5-propanobenzazepine, and N-methyl-4-bromo-2-methylacetanilide

Brown¹,

Wang²

1996

Can. J. Chem.

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“…For the acid-catalyzed hydrolysis of TA1, previous theoretical studies predict a Gibbs activation energy of 39.6 kcal mol À1 for the nucleophilic addition of the carbonyl group for TA1 with two water molecules, [19] which is much higher than the experimental value of 16.7 kcal mol À1 for the analogous compound TA2. [39] Theoretical calculations on the Gibbs hydration energy of the proton show that the first hydration shell of the proton requires at least four water molecules, [72,73] and the predicted Gibbs hydration energy is about À263 kcal mol À1 , showing good agreement with the experimental results of À262.4 [74] and À264.1 kcal mol…”

supporting

confidence: 55%

“…[91] In TS3, there is one additional water molecule involved in the hydrogen-bond interactions with the middle [a] Ref. [39].…”

Section: N-protonated Ta1mentioning

confidence: 99%

“…[39] Herein, we explore the reaction mechanism for the acid-catalyzed hydrolysis and hydration of TA2, and the optimized structures of the species involved in the acid-catalyzed hydrolysis of TA2 in aqueous solution are shown in Figure 6. The predicted relative Gibbs energy profiles and thermodynamic values are summarized in Figure 7.…”

Section: P4-hydromentioning

confidence: 99%

“…The present results show good agreement with the available experimental observations. synthesis and hydrolytic reactivity of a series of twisted amides, Brown et al [37][38][39] established a good relationship between the rate of hydrolysis and the twist angle of the amide bond. In addition, these distorted amides were used to mimic the activated peptide units in the acylation of various proteases.…”

mentioning

confidence: 99%

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Acid‐Catalyzed Reactions of Twisted Amides in Water Solution: Competition between Hydration and Hydrolysis

Wang¹,

Cao²

2011

Chemistry A European J

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The acid-catalyzed reactions of twisted amides in water solution were investigated by using cluster-continuum model calculations. In contrast to the previous widely suggested concerted hydration of the C=O group, our calculations show that the reaction proceeds in a practically stepwise manner, and that the hydration and hydrolysis channels of the C-N bond compete. The Eigen ion (H(3)O(+)) is the key species involved in the reaction, and it modulates the hydration and hydrolysis reaction pathways. The phenyl substitution in the twisted amide not only activates the N-CO bond, but also stabilizes the hydrolysis product through n(N)→π(phenyl) delocalization, leading exclusively to the hydrolysis product of the ring-opened carboxylic acid. Generally, the twisted amides are more active than the planar amides, and such a rate acceleration results mainly from the increase in exothermicity in the first N-protonation step; the second step of the nucleophilic attack is less affected by the twisting of the amide bond. The present results show good agreement with the available experimental observations.

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Eine starke Wasserstoffbrücke zu einem Amid-Stickstoffatom in einem „Amid-Protonenschwamm”: Konsequenzen für Struktur und Reaktivität

1999

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N‐protonierte Amide wurden als Zwischenstufen in biologisch wichtigen Reaktionen vorgeschlagen, ihr spektroskopischer Nachweis steht allerdings noch aus. Der erste Schritt auf dem Weg zu diesem Ziel wurde nun mit dem spektroskopischen und kristallographischen Nachweis einer starken, intramolekularen H‐Brücke zwischen einem geladenen Donor und einem Amid‐N‐Atom in „Protonenschwamm”︁‐Derivaten 1 vollzogen; diese Wechselwirkung hat eine neuartige Reaktivität zur Folge. TfO− = Trifluormethansulfonat.

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Distorted amides as models for activated peptide N-C(O) units. 3. Synthesis, hydrolytic profile, and molecular structure of 2,3,4,5-tetrahydro-2-oxo-1,5-propanobenzazepine

Cited by 97 publications

References 1 publication

An AM1 calculational study of the protonation and reactions of 3,4-dihydro-2-oxo-1,4-ethanoquinoline, 3,4-dihydro-2-oxo-1,4-propanoquinoline, 3,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine, 3,3,4,5-tetrahydro-2-oxo-1,5-propanobenzazepine, and N-methyl-4-bromo-2-methylacetanilide

An AM1 calculational study of the protonation and reactions of 3,4-dihydro-2-oxo-1,4-ethanoquinoline, 3,4-dihydro-2-oxo-1,4-propanoquinoline, 3,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine, 3,3,4,5-tetrahydro-2-oxo-1,5-propanobenzazepine, and N-methyl-4-bromo-2-methylacetanilide

Acid‐Catalyzed Reactions of Twisted Amides in Water Solution: Competition between Hydration and Hydrolysis

Eine starke Wasserstoffbrücke zu einem Amid-Stickstoffatom in einem „Amid-Protonenschwamm”: Konsequenzen für Struktur und Reaktivität

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