Dynamic Study of Cyclic-Open Tautomerism in a Warfarin Analog

Danielyan, Edward; Zuniga, Maayan; Hoang, Khoi; Magers, David H.; Osborne, Daniel A.; Valente, Edward J.

doi:10.1007/s10870-023-00984-2

Cited by 2 publications

(2 citation statements)

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“…Higher barriers to cyclizations in CDCl 3 are consistent with the slower rates of cyclization recently seen in a warfarin analog which showed considerable open-cyclic rate dependence on solvent polarity. [45] In d 6 -DMSO, for the transition states, the enthalpic and entropic contributions were larger than in either of the less polar solvents. This may be rationalized by increased conformational exibility of the open tautomer in d 6 -DMSO (vide infra) which requires more work to populate the reactive conformer (gauche A, Scheme 4).…”

Section: Discussionmentioning

confidence: 91%

“…Additionally, in closure of the cyclic hemiketals, both anomeric dispositions of the hydroxy group were modelled in a method we independently adapted. [45] Optimum equilibrium geometries were computed for the singlet ground states of 1a -1f (including the anomers of the cyclic hemiketals). These computations used density functional theory (DFT).…”

Section: Methodsmentioning

confidence: 99%

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

Osborne,

Danielyan,

Hoang

et al. 2023

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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: 91%

Section: Methodsmentioning

confidence: 99%