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Tautomerism of 4-phenyl-2,4-dioxobutanoic acid. Insights from pH ramping NMR study and quantum chemical calculations

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Abstract

Aryldiketo acids (ADKs) exhibit the variety of biological activities, mainly due to large affinity toward divalent metal ions. Metal complexation ability of ADKs, as well as interactions with proteins, depend on tautomeric form present in solution. The main aim of this study was to fully explore the tautomeric preferences of 4-phenyl-2,4-dioxobutanoic acid (4PDA), as ADKs representative, in aqueous media at different pH values. 1D and 2D NMR spectroscopy in combination with quantum chemical calculations was applied in order to better understand the tautomeric preferences of 4PDA. The data in highly acidic media are especially interesting since there are no such findings in the literature due to low solubility of ADKs in molecular form. At low pH values, where 4PDA is unionized, the most abundant tautomeric form is enol with keto group closer to phenyl ring. At higher pH values, mixture of two 4PDA ionic forms coexists in solution. Their ratio calculated according to NMR data fits the values predicted using two experimentally determined pK a values. Based on the complexity of 1H NMR spectrum of monoanionic 4PDA form, coexistence of two stable rotamers was assumed. In an alkaline media, 4PDA is mostly present in dianionic form. As π-electrons of dianion are delocalized over an entire keto-enol moiety, spectral distinction between tautomers was not possible. Quantum chemical calculations were used to predict relative stability of tautomers. The predictions were in good accordance with experimental results only in case when explicit water molecule was included in calculations.

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Funding

Ministry of Education, Science, and Technological Development of Serbia supported this work, Grant No. 172035.

Author information

Correspondence to Ilija N. Cvijetić or Tatjana Ž. Verbić.

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The authors declare that they have no conflict of interest.

Additional information

We regret to inform that Branko Drakulić has passed away since completion of this work.

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Cvijetić, I.N., Pešić, M.P., Todorov, M.D. et al. Tautomerism of 4-phenyl-2,4-dioxobutanoic acid. Insights from pH ramping NMR study and quantum chemical calculations. Struct Chem 29, 423–434 (2018). https://doi.org/10.1007/s11224-017-1039-3

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Keywords

  • Aryldiketo acid
  • Keto-enol tautomerism
  • NMR spectroscopy
  • Quantum chemical calculations