1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Part II: Ethosuximide, 3-Ethyl-3-Methyl-2,5-Pyrrolidinedione, and Comparisons with Analogs

Abstract

The 60 MHz 1H NMR spectra of racemic ethosuximide, 1, have been studied in detail with the achiral shift reagent, tris(6,6,7,7,8,8,8-hepta-fiuoro-2,2-dimethyl-3,5-octanedionato)europium(III), 2, and the chiral tris(3-trifluoromethylhydroxymethylene)- d-camphorato]europium(III), 3. Enantiomeric shift differences, ΔΔδ, were clearly observed for the CH3 of the ethyl group of 1 at molar ratios of 3:1 as low as 0.0385, with ΔΔδ valaues of about 12 Hz seen at a 3:1 ratio of 0.340 for CDCl3 solutions at 28°, 0.634 molal in 1. Smaller ΔΔδ values were also seen for the quaternary methyl and for one of the hydrogens at C-4. Parallel studies with 2 were performed to support assignments. Results are compared with a group of important drugs that are structurally related, including ethotoin, mephenytoin, glutethimide, methsuximide, phensuximide, and paramethadione, in terms of steric and basicity effects. Correlations of both lanthanide-induced shift (Δδ) and ΔΔδ could generally be made from simple electronic considerations related to infrared carbonyl stretching frequencies. Of the 28 sets of Δδ values assigned for the substrates, 3 gave significantly larger values than 2 in only two cases.