Does Activation of the Anti Proton, Rather than Concertedness, Determine the Stereochemistry of Base-Catalyzed 1,2-Elimination Reactions? Anti Stereospecificity in E1cB Eliminations of β-3-Trifluoromethylphenoxy Esters, Thioesters, and Ketones

• Published in: Journal of organic chemistry 2012-03, Vol.77 (6), p.2819-2828
• Main Authors: Mohrig, Jerry R, Beyer, Brandon G, Fleischhacker, Angela S, Ruthenburg, Alex J, John, Seth G, Snyder, Daniel A, Nyffeler, Paul T, Noll, Robert J, Penner, Nicholas D, Phillips, Laura A, Hurley, Heidi L. S, Jacobs, Jon S, Treitel, Corinna, James, Thomas L, Montgomery, Martha P
• Format: Article
• Language: English
• Subjects: Catalysis; Chemistry; Esters - chemistry; Exact sciences and technology; Ketones - chemistry; Kinetics and mechanisms; Labelled compounds chemistry; Magnetic Resonance Spectroscopy; Molecular Structure; Organic chemistry; Phenyl Ethers - chemistry; Protons; Reactivity and mechanisms; Stereoisomerism; Sulfhydryl Compounds - chemistry; Tosyl Compounds - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo300053w

As part of a comprehensive investigation on the stereochemical aspects of base-catalyzed 1,2-elimination reactions, we have studied a set of acyclic carbonyl substrates that react by an irreversible E1cB mechanism with largely anti stereospecificity. 2H NMR data show that these reactions using KOH in EtOH/H2O under non-ion-pairing conditions produce a minimum of 85–89% anti elimination on stereospecifically labeled tert-butyl (2R*,3R*)- and (2R*,3S*)-3-(3-trifluoromethylphenoxy)-2,3-2 H 2-butanoate, S-tert-butyl (2R*,3R*)- and (2R*,3S*)-3-(3-trifluoromethylphenoxy)-2,3-2 H 2-butanethioate, and the related ketones, (4R*,5R*)- and (4R*,5S*)-5-(3-trifluoromethylphenoxy)-4,5-2 H 2-3-hexanone. With both diastereomers of each substrate available, the KIEs can be calculated and the innate stereoselectivities determined. The elimination reactions of the β-3-trifluoromethylphenoxy substrates occur by E1cB mechanisms with diffusionally equilibrated enolate-anion intermediates. Thus, it is clear that anti elimination does not depend solely upon concerted E2 mechanisms. Negative hyperconjugation provides a satisfactory explanation for the anti stereospecificity exhibited by our carbonyl substrates, where the leaving group activates the anti proton, leading to the enolate intermediate. The activation of the anti proton by negative hyperconjugation may also play a role in the concerted pathways of E2 mechanisms. We have also measured the rates of the hydroxide-catalyzed elimination reactions of butanoate, thiobutanoate, and ketone substrates in EtOH/H2O, with β-tosyloxy, acetoxy, and 3-trifluoromethylphenoxy nucleofuges.