Isotope Effects and the E2 Mechanism

The E2 mechanism as outlined in the preceding two sections receives support from studies of the dehydrohalogenation of alkyl halides that contain deuterium (D = H) instead of protium ( H) at the p carbon. The fundamental kinds of reactions a substance undergoes are the same regardless of which isotope is present, but the reaction rates can be different. 

A C—D bond is 12 kJ/mol stronger than a C—H bond, making the activation energy for breaking a C—D bond slightly greater than that of an analogous C—H bond. Consequently, the rate constant k for an elementary step in which a C—D bond breaks is smaller than for a C—H bond. This difference in rate is expressed as a ratio of the respective rate constants ( h/ d) and is a type of kinetic isotope effect. Because it compares to H, it is also referred to as a deuterium isotope effect. 

Typical deuterium isotope effects for reactions in which C—H bond breaking is ratedetermining lie in the range kn/k = 3-8. K the C—H bond breaks after the rate-determining step, the overall reaction rate is affected oidy slightly and ku/kj) = 1-2. Thus, measuring the deuterium isotope effect can tell us if a C—Hbond breaks in the rate-determining step. 

According to the E2 mechanism for dehydrohalogenation, a base removes a proton from the p carbon in the same step as the halide is lost. This step, indeed it is the only step in the mechanism, is rate-determining. Therefore, eliminahon by the E2 mechanism should exhibit a deuterium isotope effect. This prediction was tested by comparing the rate of elimination in the reaction  

Choose the compound in the following pairs that undergoes E2 elimination at the faster rate. 

In its most stable conformation, the trans stereoisomer has no (3 hydrogens anti to Br all four are gauche. Strain increases significantly in going to the E2 transition state, and the rate of elimination is slower than for the cis stereoisomer. 

Use curved arrows to show the bonding changes in the reaction of c/s-4-ferf-butylcyclohexyl bromide with potassium ferf-butoxide [KOCCCHslal. Be sure your drawing correctly represents the spatial relationship between the leaving group and the proton that is lost. 

Effects that arise because one spatial arrangement of electrons (or orbitals or bonds) is more stable than another are called stereoelectronic effects. There is a stereoelec-tronic preference for the anti coplanar arrangement of proton and leaving group in E2 reactions. Although coplanarity of the p orbitals is the best geometry for the E2 process, modest deviations from it can be tolerated. 

Stereoelectronic effects are also important in the dehydrohalogenation of acyclic alkyl halides by an E2 pathway. Again, the most favorable arrangement for the hydrogen and the halide being lost is anti coplanar. In the formation of 2-methyl-2-butene from 2-bromo-2-methylbutane shown on page 208, the elimination of HBr occurs readily from the conformation on the left but not from the one on the right. 

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A second piece of evidence in support of the E2 mechanism is provided by a phenomenon known as the deuterium isotope effect. For reasons that we won t go into, a carbon-hydrogen bond is weaker by about 5 kj/mol (1.2 kcal/mol) than the corresponding carbon-rfaiiferiwm bond. Thus, a C-H bond is more easily broken than an equivalent C-D bond, and the rate of C-H bond cleavage is faster. For instance, the base-induced elimination of HBv from l-bromo-2-phenylethane proceeds 7.11 times as fast as the corresponding... 

Among the evidence for the existence of the E2 mechanism are (1) the reaction displays the proper second-order kinetics (2) when the hydrogen is replaced by deuterium in second-order eliminations, there is an isotope effect of from 3 to 8, consistent with breaking of this bond in the rate-determining step. However, neither of these results alone could prove an E2 mechanism, since both are compatible with other mechanisms also (e.g., see ElcB p. 1308). The most compelling evidence for the E2 mechanism is found in stereochemical smdies. As will be illustrated in the examples below, the E2 mechanism is stereospecific the five atoms involved (including the base) in the transition state must be in one plane. There are two ways for this to happen. The H and X may be trans to one another (A) with a dihedral angle... 

Isotope effects and element effects associated with hydron-transfer steps during methoxide promoted dehydrohalogenation reactions of jo-CF3C6H4C HClCH2X (X=Br, Cl, or F) have also been discussed, with regard to distinction between E2 and multi-step pathways. The Arrhenius behaviour of hydrogen isotope effects was used to calculate the amounts of internal hydrogen return associated with the two-step mechanism. 

Another method of seeking evidence of the EIcBirr mechanism is to exam heavy-atom isotope effects in the leaving group. Of course, these should be much more significant in an E2 process because the bond is breaking in the transition state. For example, Thibblin and co-workersfound that in the base-induced elimination of an alkyl halide in which the p-carbon is unusually acidic (indene derivative, 12), moderately strong bases (triethylamine and methoxide) lead to a significant Cl/ Cl isotope effect = 1.010 1.009, where a maximum effect of... 

Pines and Manassen [7] suggested that tertiary alcohols are dehydrated by the El mechanism involving the formation of more or less free car-bonium ions, secondary alcohols by a mechanism lying somewhere between El and E2 (i.e. synchronous with a ionic contribution) and primary alcohols by a concerted E2 mechanism. However, the large kinetic isotope effect for the dehydration of fully deuterated tert-butanol on alumina [122] indicates that, even in this case, some synchrony must exist. Alumina strongly prefers the concerted process and with other catalysts the situation may differ. 

CONTENTS Preface, C. Allen Bush. Thermodynamic Solvent Isotope Effects and Molecular Hydrophobicity, Terrence G. Oas and Eric J. Toone. Membrane Interactions of Hemolytic and Antibacterial Peptides, Karl Lohner and Richard M. Epand. Spin-Labeled Metabolite Analogs as Probes of Enzyme Structure, Chakravarthy Narasimhan and Henry M. Miziorko. Current Perspectives on the Mechanism of Catalysis by the Enzyme Enolase, John M. Brewer and Lukasz Leb-ioda. Protein-DNA Interactions The Papillomavirus E2 Proteins as a Model System, Rashmi S. Hedge. NMR-Based Structure Determination for Unlabeled RNA and DNA, Philip N. Borer, Lucia Pappalardo, Deborah J. Kenwood, and Istvan Pelczer. Evolution of Mononuclear to Binuclear CuA An EPR Study, William E. Antholine. Index. 

Mechanistic Studies of Alcohol Dehydration on Zeolites. - Gentry and Rudham and Jacobs et al have proposed mechanisms for the dehydration of propan-2-ol and butan-2-ol on X-zeolites. Both groups of workers are in basic agreement about the mechanism, which involves the formation of oxonium and carbonium ions. The formation of olefins from the above alcohols appeared to occur via an El -like mechanism and this was supported very strongly by the behaviour of butan-2-ol, which gave a primary isotope effect, but an absence of one for C 3- H, rules out the E2 mechanism. 

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