Abstract

The 60 MHz <sup>1</sup>H NMR spectra of racemic ethosuximide, <i>1,</i> have been studied in detail with the achiral shift reagent, <i>tris</i>(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), <i>2,</i> and the chiral <i>tris</i>(3-trifluoromethylhydroxymethylene)-<i>d</i>-camphorato]europium(III), <i>3.</i> Enantiomeric shift differences, ΔΔδ, were clearly observed for the CH<sub>3</sub> of the ethyl group of <i>1</i> at molar ratios of <i>3:1</i> as low as 0.0385, with ΔΔδ values of about 12 Hz seen at a <i>3:1</i> ratio of 0.340 for CDCl<sub>3</sub> solutions at 28°, 0.634 molal in <i>1.</i> Smaller ΔΔδ values were also seen for the quaternary methyl and for one of the hydrogens at C-4. Parallel studies with <i>2</i> 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, <i>3</i> gave significantly larger values than <i>2</i> in only two cases.

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