Acid-Catalyzed Z-E Isomerization of γ-Alkylidenebutenolides: An Experimental and DFT Study

Abstract

The Z-E isomerization of γ-alkylidenebutenolide analogues to natural nostoclides and other natural butenolides was investigated using 1 H nuclear magnetic resonance (NMR) and high performance liquid chromatography (HPLC) data as well as density functional theory (DFT) calculations at the ωB97x-D/6-31G(d,p) level, including solvent effects with the polarizable continuum solvation approach. The experimental data supported the Z to E isomerization of γ-alkylidenebutenolides under acid catalysis. Newly prepared samples have predominantly Z configuration, which partially isomerizes to the E isomer under acidic conditions. Density functional theory studies corroborate the experimental findings. While neutral γ-alkylidenebutenolides are more stable in the Z form, protonation of the γ-lactone carbonyl group results in preferential stabilization of the E isomer.

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“…Protonation of E - 1a results in the formation of conjugate acid E - 1a H + that allows for free rotation around the single bond to form Z - 1a H + . The same mechanism was suggested for acid-catalyzed E → Z isomerization of γ-alkylidenebutenolides . The p K a of Z - 1a H + of 0.75 was determined in methanol by titration with triflic acid (Table and Figure S47) because titration in aqueous buffer solutions required large amounts of added acid to see any spectroscopic changes (the corresponding value in water is estimated to be −0.45).…”

“…The same mechanism was suggested for acid-catalyzed E → Z isomerization of γalkylidenebutenolides. 55 The pK a of Z-1aH + of 0.75 was determined in methanol by titration with triflic acid (Table 1 and Figure S47) because titration in aqueous buffer solutions required large amounts of added acid to see any spectroscopic changes (the corresponding value in water is estimated 56 to be −0.45). The protonated form 1bH + is a weaker acid with pK a of 6.9 (Table 1), determined spectrometrically (Figure S49).…”