Ring-chain Tautomerism Trends in 3-(4’-alkyl-2’-oxobut-4’-yl)-4-hydroxycoumarins: Substituent Steric Bulk Controls Solution Composition and Equilibrium Thermodynamics of Alkyl Warfarin Analogs; Structural and Computational Analysis

Abstract

As for warfarin, alkyl analogs of 3-(2’-oxo-4’-alkylbut-4’-yl)-4-hydroxycoumarins in solution display equilibria between trans hemiketal ⇋ open, and open ⇋ cis hemiketal tautomers. A steric trend is observed for the reactions by variable temperature NMR in CDCl₃, with ΔG (kJ/mol, 298 K) for trans ⇋open, open ⇋ cis and alkyl substituents: methyl (+ 0.3, -0.3), n-pentyl (-2.6, + 3.0), isopropyl (-2.8, + 5.0), cyclohexyl (-4.3, + 7.2), neopentyl (-6.3, + 5.7) and t-butyl (<-13, >+13) in CDCl₃. The trans ⇋ open reactions typically are entropically favored but decreasingly enthalpically favored with substituent size. For the open ⇋ cis reactions, enthalpic terms increasingly favor ring opening, while entropic contributions favoring open forms are moderated by greater conformational flexibility in the cyclic forms. Similar results were observed in d₆-dmso. In the solid state, (R)-3-(2’-oxopent-4’-yl)-4-hydroxycoumarin crystallizes in the monoclinic system (P 2₁, Z = 6) with one trans and two cis hemiketal tautomers comprising the asymmetric unit. Racemic (±)-3-(2’-oxonon-4’-yl)-4-hydroxycoumarin crystallizes in the triclinic system (P -1) as the cis (2R,4R / 2 S,4 S) hemiketals. Though the alkyl warfarins typically crystallize as their cyclic hemiketals (cis or trans) even with substituents as bulky as neopentyl, the t-butyl analog, racemic 3-(2’-oxo-5’,5’-dimethylhex-4’-yl)-4-hydroxycoumarin crystallizes in the monoclinic system (P 2₁/c) as the open coumarin tautomer, and its solutions also contain only the open form. These structures, augmented by literature determinations of alkyl warfarins and derivatives alkyl ketals, include (2 S,4 S)-trans-2-ethoxy-2-methyl-3,4-dihydro-4-cyclohexyl-2 H,5 H-pyrano[3,2-c] (1)benzopyran-5-one (P 2₁2₁2₁). From 23 determinations including six reported here, embedded dihydropyran ring conformations provide a structural basis for the steric interactions in the cyclic forms. Alkyl groups in trans isomers distort the nearby coumarin carbonyl oxygen toward the opposite side of the coumarin ring. Computations (DFT) corroborate the relative stabilities of the cyclic hemiketals with the smaller substituents, but underestimate the importance of solvent on stabilization of the open tautomers. Sterimol analysis of the ΔΔGs for the open – cyclic reactions, relative to the methyl substituent, support a general steric model for the alkyl substituent-related changes in the tautomeric equilibria.

Graphical Abstract

As alkyl groups (substituted for the phenyl in warfarin) increase in bulk from methyl to t-butyl, solutions increasingly favor the open tautomer over the cyclic hemiketals, and “t-butyl warfarin” crystallizes in the open form.