Structures of (±)-cis-2-hydroxy-4-(2-phenylethyl)- (I) and cis-4-phenyl-2-methyl-3,4-dihydro-2H,5H-pyrano[3,2-c][1]benzopyran-5-one (II)

Ruggiero, G.; Valente, E.; Eggleston, Drake S.

doi:10.1107/s0108270189001034

Cited by 1 publication

(3 citation statements)

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“…[27,56] Analogs in which alkyl groups substitute for the side-chain phenyl also showed increased participations of open tautomers in solution. [15][16][17][18][19]21] None of these studies examined the solution thermodynamics of the open-cyclic warfarin (or analog) equilibrium as a function of temperature.…”

Section: Discussionmentioning

confidence: 99%

“…[33] Structures for cis hemiketals of warfarin analogs and derivatives occur with conformations similar to that for 5. [15,17,20,21,59] Again, computations suggest that for the cis isomers, the aanomer is the more stable conformer but by less than 10 kJ/mol compared to the di-equatorial and β-anomer (Table 7).…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14] Additionally, many warfarin analogs and derivatives with similar co-reactive groups are also found in hemiketal forms by crystallography. [15][16][17][18][19][20][21][22][23][24] In solution, NMR and by UV-VIS spectroscopy has shown that warfarin exists in an equilibrium between the diastereomeric coumarin hemiketals and the intermediate coumarin open form (Scheme 1, 1a -c). [25][26][27][28][29] The question of the heterocycle tautomers, coumarin and chromone, has been studied over years, with spectroscopic assignments typically support the coumarin structure.…”

Section: Introductionmentioning

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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