The Curious Case of Aqueous Warfarin: Structural Isomers or Distinct Excited States?

Sakpal, Sushil S.; Ghosh, Deborin; Manae, Meghna A.; Hazra, Anirban; Bagchi, Sayan

doi:10.1021/acs.jpcb.0c10824

Cited by 4 publications

(2 citation statements)

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“…The assignment of the absorptions in the ultraviolet spectra between open and cyclic (cis or trans) warfarin forms remains a topic of study. [55] Coumarin methyl ketals and open methyl ethers of warfarin share many spectral similarities with the parent hemiketals and open enol, respectively. [25,26] By NMR, warfarin proved to be too insoluble in water (1.28 x 10 -5 M or 3.9 mg/L, 25 o C, [9]) but in aqueous base, warfarin was quite soluble, and it has been found in the open enolate form.…”

Section: Discussionmentioning

confidence: 99%

“…The structure of warfarin in solution has been studied by a variety of spectroscopic methods, generally proceeding from the assumption that the heterocycle was a coumarin. Ultraviolet spectroscopy and circular dichroism have proved useful in determining the warfarin tautomers (open or cyclic) in non-aqueous solvents (like methanol) and in water as a function of pH [28,53]. Warfarin has been assigned the coumarin cyclic form in water at or below its pKa (5) by about 20:1 over the open form.…”

Section: Discussionmentioning

confidence: 99%

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Warfarin tautomers in solution: a structural, computational and thermodynamic study

Osborne,

Danielyan,

Hoang

et al. 2023

Preprint

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Variable temperature NMR spectroscopic measurements on (S)-warfarin [open-form: 3-(1’-phenyl-3’-oxobut-1’-yl)-4-hydroxycoumarin] in CDCl3, CD3OD and d6-DMSO generally showed tautomeric compositions in the order trans (2S,4S) coumarin hemiketal > cis (2R,4S) coumarin hemiketal > open (S) coumarin enol in slow dynamic equilibrium over temperature ranges rising modestly from ambient. A computational (DFT - M06-2X) examination of the lower energy tautomers including coumarin and chromone open and cyclic forms (gas phase, chloroform or DMSO fields) was consistent with the general solution compositions. The crystal and molecular structures for model compounds of the major solution tautomers are reported: (2S,4S)-warfarin methyl ketal [orthorhombic, P212121], (2R,4S)-warfarin methyl ketal [orthorhombic, P212121], (rac)-warfarin-4-methyl ether [monoclinic, P21/n], and the open chromone (S)-warfarin-2-methyl ether [monoclinic, P21, Z = 8]. A combination of direct integration and line-fitting methods were used to determine solution (S)-warfarin tautomer compositions. As temperatures were increased, the concentrations of the open coumarin form increased at the expense of the cyclic hemiketals. Equilibrium constants were used to determine the standard free-energy differences for the two open-cyclic equilibria (trans hemiketal open, open cis hemiketal, respectively) in three solvents: CDCl3 [+ 3.7(4), -2.8(6) kJ/mol], CD3OD [+ 7.6(16), -4.7(9) k/mol], d6-DMSO [+ 3.5(7), -1.1(2) kJ/mol]. Standard enthalpy and entropy differences were also determined from van’t Hoff analysis. Rates of the respective reactions were estimated from line-widths for the cyclic hemiketals and solution equilibrium compositions for each species. Eyring analysis gave ΔG‡, ΔH‡, and ΔS‡, respectively, for the forward and reverse reactions of coumarin trans hemiketal open-form and for the open-form cis hemiketal. Negative entropic contributions to the observed transition state energies were consistent with solvent or solute ordering in the prototropic reactions. Open-form NMR signals were broader than could be accounted for by the open-cyclic equilibria alone, increasingly so in polar and protic solvents and with rising temperatures. While a conformational equilibrium may operate, an increasingly faster intermediate dynamic equilibrium between open coumarin-chromone tautomers may be a more likely explanation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%