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Int. J. Mol. Sci. 2015, 16(6), 12174-12184; doi:10.3390/ijms160612174

Acetic Acid-Catalyzed Formation of N-Phenylphthalimide from Phthalanilic Acid: A Computational Study of the Mechanism

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
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Academic Editor: Habil. Mihai V. Putz
Received: 31 March 2015 / Revised: 27 April 2015 / Accepted: 25 May 2015 / Published: 28 May 2015
(This article belongs to the Special Issue Chemical Bond and Bonding 2015)
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Abstract

In glacial acetic acid, phthalanilic acid and its monosubstituents are known to be converted to the corresponding phthalimides in relatively good yields. In this study, we computationally investigated the experimentally proposed two-step (addition-elimination or cyclization-dehydration) mechanism at the second-order Møller-Plesset perturbation (MP2) level of theory for the unsubstituted phthalanilic acid, with an explicit acetic acid molecule included in the calculations. In the first step, a gem-diol tetrahedral intermediate is formed by the nucleophilic attack of the amide nitrogen. The second step is dehydration of the intermediate to give N-phenylphthalimide. In agreement with experimental findings, the second step has been shown to be rate-determining. Most importantly, both of the steps are catalyzed by an acetic acid molecule, which acts both as proton donor and acceptor. The present findings, along with those from our previous studies, suggest that acetic acid and other carboxylic acids (in their undissociated forms) can catalyze intramolecular nucleophilic attacks by amide nitrogens and breakdown of the resulting tetrahedral intermediates, acting simultaneously as proton donor and acceptor. In other words, double proton transfers involving a carboxylic acid molecule can be part of an extensive bond reorganization process from cyclic hydrogen-bonded complexes. View Full-Text
Keywords: phthalanilic acid; intramolecular cyclization; N-phenylphthalimide; acetic acid catalysis; computational chemistry; double proton transfer; concerted bond reorganization phthalanilic acid; intramolecular cyclization; N-phenylphthalimide; acetic acid catalysis; computational chemistry; double proton transfer; concerted bond reorganization
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Takahashi, O.; Kirikoshi, R.; Manabe, N. Acetic Acid-Catalyzed Formation of N-Phenylphthalimide from Phthalanilic Acid: A Computational Study of the Mechanism. Int. J. Mol. Sci. 2015, 16, 12174-12184.

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