Distinguishing between the concerted second-order mechanism for beta-eliminations and nonconcerted mechanisms with discrete carbanion intermediates is very difficult experimentally, but the ability of quantum chemistry to find stationary points of the free-energy surface in liquid-phase solutions, even for complex reagents, provides a new tool for elucidating such mechanisms. Here we use liquid-phase density functional theory calculations to find transition states and intermediates on the free-energy surfaces of four base-initiated alpha,beta-eliminations of acetoxy and mesyloxy esters and their analogous thioesters. The geometries, free energies, and charge distributions of these structures support a stepwise irreversible first-order elimination from a conjugate base (E1cB(I)) mechanism with acetoxy ester 3, acetoxy thioester 4, and mesyloxy thioester 6. However, mesyloxy ester 5, which has an excellent nucleofuge and a less-acidic proton, follows a concerted but asynchronous E2 mechanism with an E1cB-like transition state. The anti transition state is more favorable than the syn one, even for the poorer nucleofuge and more-acidic thioesters. The article includes a general scheme for describing liquid-phase reactions in terms of free-energy surfaces.
There are two stereochemical classes of hydratase-dehydratase enzymes. Those that catalyze the addition of water to alpha, beta-unsaturated thioesters give syn addition-elimination stereochemistry, whereas those that catalyze the addition of water to conjugated carboxylate substrates give anti stereochemistry. This dichotomy could reflect different adaptive advantages or contingencies of separate evolutionary histories. Determination of the nonenzymatic stereochemistry of deuterium oxide addition to fumarate and to S-crotonyl N-acetylcysteamine has provided direct evidence for the importance of the contingencies of evolutionary history, rather than chemical efficiency, in the pathways of these hydratase-dehydratase enzymes.
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As part of a comprehensive investigation of electronic effects on the stereochemistry of base-catalyzed 1,2-elimination reactions, we observed a new syn intramolecular pathway in the elimination of acetic acid from beta-acetoxy esters and thioesters. 1H and 2H NMR investigation of reactions using stereospecifically labeled tert-butyl (2R*,3R*)-3-acetoxy-2,3-2H2-butanoate (1) and its (2R*,3S*) diastereomer (2) shows that 23 +/- 2% syn elimination occurs. The elimination reactions were catalyzed with KOH or (CH3)4NOH in ethanol/water under rigorously non-ion-pairing conditions. By contrast, the more sterically hindered beta-trimethylacetoxy ester produces only 6 +/- 1% syn elimination. These data strongly support an intramolecular (Ei) syn path for elimination of acetic acid, most likely through the oxyanion produced by nucleophilic attack at the carbonyl carbon of the beta-acetoxy group. The analogous thioesters, S-tert-butyl (2R*,3R*)-3-acetoxy-2,3-2H2-butanethioate (3) and its (2R*,3S*) diastereomer (4), showed 18 +/- 2% syn elimination, whereas the beta-trimethylacetoxy substrate gave 5 +/- 1% syn elimination. The more acidic thioester substrates do not produce an increased amount of syn stereoselectivity even though their elimination reactions are at the E1cb interface.
Experimental data on the stereoselectivity of base-catalyzed 1,2-elimination reactions that produce conjugated carbonyl compounds are scarce in spite of the importance of these reactions in organic and biochemistry. As part of a comprehensive study in this area, we have synthesized stereospecifically-deuterated beta-tosyloxybutanoate esters and thioesters and studied the stereoselectivity of their elimination reactions under non-ion pairing conditions. With the availability of both the (2R*,3R*) and (2R*,3S*) diastereomers the innate stereoselectivity could be determined unambiguously. (1)H and (2)H NMR data show that these substrates produce 5-6% syn elimination, the usual amount for acyclic substrates undergoing E2 reactions. Contrary to earlier suggestions, activation by a carbonyl group has virtually no influence upon the stereoselectivity. Elimination of the (2R*,3R*) diastereomer of the beta-tosyloxyester and thioester produces 21-25% of the (Z)-alkene, much more than observed with a poorer beta-nucleofuge. A relatively large amount of (Z)-alkene product seems to be a good marker for an E2 pathway, in which the transition state is E1cB-like, rather than an E1cB(irrev) mechanism. Syn KIE values were higher than those for anti elimination for the esters as well as the thioesters. Experimental challenges to the synthesis of stereospecifically-deuterated beta-tosyloxyesters are discussed.
Many mechanistic and stereochemical studies have focused on the breaking of the C-H bond through base-catalyzed elimination reactions. When we began our research, however, chemists knew almost nothing about the stereospecificity of addition-elimination reactions involving conjugated acyclic carbonyl compounds, even though the carbonyl group is a pivotal functional group in organic chemistry. Over the last 25 years, we have studied the addition-elimination reactions of β-substituted acyclic esters, thioesters, and ketones in order to reach a comprehensive understanding of how electronic effects influence their stereochemistry. This Account brings together our understanding of the stereochemistry of 1,2-elimination and proton-transfer reactions, describing how each study has built upon previous work and contributed to our understanding of this field. When we began, chemists thought that anti stereospecificity in base-catalyzed 1,2-elimination reactions occurred via concerted E2 mechanisms, which provide a smooth path for anti elimination. Unexpectedly, we discovered that some E1cBirrev reactions produce the same anti stereospecificity as E2 reactions even though they proceed through diffusionally equilibrated, "free" enolate-anion intermediates. This result calls into question the conventional wisdom that anti stereochemistry must result from a concerted mechanism. While carrying out our research, we developed insights ranging from the role of historical contingency in the evolution of hydratase-dehydratase enzymes to the influence of buffers on the stereochemistry of H/D exchange in D2O. Negative hyperconjugation is the most important concept for understanding our results. This idea provides a unifying view for the largely anti stereochemistry in E1cBirrev elimination reactions and a basis for understanding the stereoelectronic influence of electron-withdrawing β-substituents on proton-transfer reactions.
The stereochemistry of base-catalyzed H/D exchange on 13 β-substituted ethyl butanoates in ethanol-d has been studied in order to analyze the steric and electronic factors which control the diastereoselectivity of electrophilic attack on enolate anions. Electrophilic deuteration of the enolate anion also determines the stereoselectivity of 1,4-conjugate addition of ethanol-d to α,β-unsaturated esters. Experimental conditions were selected which rigorously exclude the effects of ion pairing and aggregation. The research showed that stereoelectronic factors generally produce higher stereoselection than steric effects do. Electronegative heteroatom substituents at C-3 produced a 10:1 ratio of the 2R*,3R*/2R*,3S* 2-deuteriobutanoates. In the most stable transition states for electrophilic attack, these electronegative substituents occupy an antiperiplanar position to the forming C−D bond. Only with a β-tert-butyl substituent did steric effects produce high stereoselection, and it fell off rapidly with a decrease in carbon branching. Protonation of acyclic β-ethoxy aldehyde and ketone enolates follows the same diastereoselectivity pattern as the β-ethoxy ester enolate, but protonation of the cyanocarbanion from a β-ethoxy nitrile gives much lower stereoselection.
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