The mechanism of the Morita Baylis–Hillman reaction has been heavily studied in the literature, and a long series of computational studies have defined complete theoretical energy profiles in these reactions. We employ here a combination of mechanistic probes, including the observation of intermediates, the independent generation and partitioning of intermediates, thermodynamic and kinetic measurements on the main reaction and side reactions, isotopic incorporation from solvent, and kinetic isotope effects, to define the mechanism and an experimental mechanistic free-energy profile for a prototypical Morita Baylis–Hillman reaction in methanol. The results are then used to critically evaluate the ability of computations to predict the mechanism. The most notable prediction of the many computational studies, that of a proton-shuttle pathway, is refuted in favor of a simple but computationally intractable acid–base mechanism. Computational predictions vary vastly, and it is not clear that any significant accurate information that was not already apparent from experiment could have been garnered from computations. With care, entropy calculations are only a minor contributor to the larger computational error, while literature entropy-correction processes lead to absurd free-energy predictions. The computations aid in interpreting observations but fail utterly as a replacement for experiment.

Small heavy-atom and secondary hydrogen kinetic isotope effects (KIEs) can provide detailed information about the mechanism of an exceptional range of chemical reactions.1•2 However, there are significant general limitations in methods for the determination of these KIEs. Because absolute rate measurements are rarely sufficiently precise, small KIEs are usually determined in competition reactions of isotopically labeled and unlabeled materials. This is possible only in systems carefully chosen to allow the precise measurement of isotopomer ratios with appropriate analytical techniques, such as scintillation counting for 3H and l4C KIEs. The synthesis of isotopically labeled materials can be arduous, often prohibitively so, and a new synthesis, competition reaction, and analysis are required for each KIE of interest. A broadly useful alternative, particularly for l3C KIEs, is to employ the high precision of isotope ratio mass spectrometry to study KIEs in materials labeled only at natural abundance.3 A major restriction is that each site of interest must be selectively degradable without isotopic fractionation into an analyzable small molecule, most often CO2.The isotope-and position-specific information inherent in NMR techniques seems ideally suited to measuring KIEs at natural abundance. The utility of 2H NMR for determining large 2H KIEs at natural abundance has been established,4 and in theory, all of the individual KIEs in reactions of complex natural abundance materials can be determined simultaneously!5 In practice, however, NMR quantitation has not been sufficiently precise to be useful with small KIEs, the uncertainty in the few cases tried generally rivaling or exceeding the size of the isotope effects.4•5 We report here a simple general method for attaining chemically significant precision while simultaneously measuring all of the KIEs for reactions at natural abundance.As any reaction proceeds, the starting materials are fractionatively enriched in isotopically slower-reacting components. The

The mechanism of the ene reaction of singlet ((1)delta(g)) oxygen with simple alkenes is investigated by a combination of experimental isotope effects and several levels of theoretical calculations. For the reaction of 2,4-dimethyl-3-isopropyl-2-pentene, the olefinic carbons exhibit small and nearly equal (13)C isotope effects of 1.005-1.007, while the reacting methyl groups exhibit (13)C isotope effects near unity. In a novel experiment, the (13)C composition of the product is analyzed to determine the intramolecular (13)C isotope effects in the ene reaction of tetramethylethylene. The new (13)C and literature (2)H isotope effects are then used to evaluate the accuracy of theoretical calculations. RHF, CASSCF(10e, 8o), and restricted and unrestricted B3LYP calculations are each applied to the ene reaction with tetramethylethylene. Each predicts a different mechanism, but none leads to reasonable predictions of the experimental isotope effects. It is concluded that none of these calculations accurately describe the reaction. A more successful approach was to use high-level, up to CCSD(T), single-point energy calculations on a grid of B3LYP geometries. The resulting energy surface is supported by its accurate predictions of the intermolecular (13)C and (2)H isotope effects and a very good prediction of the reaction barrier. This CCSD(T)//B3LYP surface features two adjacent transition states without an intervening intermediate. This is the first experimentally supported example of such a surface and the first example of a valley-ridge inflection with significant chemical consequences.

The cycloadditions of cyclopentadiene with diphenylketene and dichloroketene are studied by a combination of kinetic and product studies, kinetic isotope effects, standard theoretical calculations, and trajectory calculations. In contrast to recent reports, the reaction of cyclopentadiene with diphenylketene affords both [4 + 2] and [2 + 2] cycloadducts directly. This is surprising, since there is only one low-energy transition structure for adduct formation in mPW1K calculations, but quasiclassical trajectories started from this single transition structure afford both [4 + 2] and [2 + 2] products. The dichloroketene reaction is finely balanced between [4 + 2] and [2 + 2] cycloaddition modes in mPW1K calculations, as the minimum-energy path (MEP) leads to different products depending on the basis set. The MEP is misleading in predicting a single product, as trajectory studies for the dichloroketene reaction predict that both [4 + 2] and [2 + 2] products should be formed. The periselectivity does not reflect transition state orbital interactions. The 13 C isotope effects for the dichloroketene reaction are well-predicted from the mPW1K/6−31+G** transition structure. However, the isotope effects for the diphenylketene reaction are not predictable from the cycloaddition transition structure and transition state theory. The isotope effects also appear inconsistent with kinetic observations, but the trajectory studies evince that non-statistical recrossing can reconcile the apparently contradictory observations. B3LYP calculations predict a shallow intermediate on the energy surface, but trajectory studies suggest that the differing B3LYP and mPW1K surfaces do not result in qualitatively differing mechanisms. Overall, an understanding of the products, rates, selectivities, isotope effects, and mechanism in these reactions requires the explicit consideration of dynamic trajectories.Selectivity in cycloadditions may take many forms, e.g., endo/exo stereoselectivity, regioselectivity, facial stereoselectivity, and diene/dienophile role selectivity. When two distinct formally allowed processes are possible, as in the [4 + 2] versus [6 + 4] cycloadditions of cyclopentadiene with tropone, 1 their differentiation is referred to as periselectivity. The underlying framework within which chemists usually understand any of these forms of selectivity is transition state theory (TST). The preferred product would be that involving the lowest-energy transition state, and the degree of selectivity would be determined by the relative energies for separate transition states. Even when there is no enthalpic barrier, reactivity and selectivity can be discussed in terms of free-energy barriers. 2 Qualitative theories of selectivity such as FMO theory may be thought of as a simplified surrogate for TST, easing the task of predicting which cycloaddition barrier is lowest in energy.singleton@mail.chem.tamu.edu. Publisher's Disclaimer: This PDF receipt will only be used as the basis for generating PubMed Central (PMC) documents. PMC ...

Transition state theory fails to accurately predict the selectivity in an example where it is ubiquitously invoked, hydroboration. The hydroboration of terminal alkenes with BH 3 is moderately regioselective, affording an 88:12 -90:10 ratio of anti-Markovnikov:Markovnikov adducts. Highlevel ab initio calculations predict too large of an energy difference between anti-Markovnikov and Markovnikov transition structures to account for the observed product ratio, and the consideration of calculational error, solvent, tunneling, and entropy effects does not resolve the discrepancy. Trajectory studies, however, predict well the experimental selectivity. The decreased selectivity versus transition state theory arises from the excess energy generated as the BH 3 interacts with the alkene, and the observed selectivity is proposed to result from a combination of low selectivity in direct trajectories, moderate RRKM selectivity, and high selectivity after thermal equilibration.The hydroboration of simple alkenes with BH 3 preferentially occurs in an "antiMarkovnikov" 1 fashion. The standard explanation for this preference in the literature, 1,2 reproduced in some form in all general textbooks of organic chemistry, is that the selectivity arises from a greater stability for the anti-Markovnikov transition state over the alternative "Markovnikov" transition state. We find here that transition state theory fails to accurately account for the regioselectivity of hydroboration. Instead, a consideration of dynamic trajectories allows understanding of the selectivity.The addition of BH 3 to terminal alkenes is only moderately regioselective. With simple terminal alkenes such as 1-hexene, the ratio of primary to secondary alcohol products after hydroboration with BH 3 at 0 -25 °C followed by oxidation is approximately 94:6. 1,3 This ratio as it has been observed is a composite of the regioselectivity in three separate steps - 4 but they are more regioselective as well, so the initial reaction of BH 3 is less selective than the composite ratio. Using the observed 1-hexanol/2-hexanol ratio of 97:3 for the reaction of n-butylborane with 1-hexene 5 as a measure of the selectivity of the second and third steps of hydroboration, the regioselectivity for reaction of 1-hexene with BH 3 itself would be ≈88:12. In our hands, the hydroboration of propene-d 6 at 21 °C with 100 equiv of BH 3 •THF (to minimize the contribution of hydroboration by alkylboranes) affords a 90.0:10.0 ratio of primary and secondary alcohols (based on direct analysis of the oxidized reaction mixture by 2 H NMR). Assuming the applicability of transition state theory, the ΔΔG ‡ for the transition states leading to the two products would be 1.1 -1.3 kcal/mol.A variety of gas-phase computational approaches were explored in an attempt to predict this ΔΔG ‡ . 6 CCSD(T)/aug-cc-pvdz calculations were used to locate transition structures 1 ‡ and 2 ‡ for formation of the regioisomeric products from the precursor complex 3. The relative energetics of the anti-Markovnik...

SpnF, an enzyme involved in the biosynthesis of spinosyn A, catalyzes a transannular Diels–Alder reaction. Quantum mechanical computations and dynamic simulations now show that this cycloaddition is not well described as either a concerted or stepwise process, and dynamical effects influence the identity and timing of bond formation. The transition state for the reaction is ambimodal and leads directly to both the observed Diels–Alder and an unobserved [6+4] cycloadduct. The potential energy surface bifurcates and the cycloadditions occur by dynamically stepwise modes featuring an “entropic intermediate”. A rapid Cope rearrangement converts the [6+4] adduct into the observed [4+2] adduct. Control of nonstatistical dynamical effects may serve as another way by which enzymes control reactions.

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The mechanism of the dirhodium tetracarboxylate catalyzed cyclopropanation of alkenes with both unsubstituted diazoacetates and vinyl- and phenyldiazoacetates was studied by a combination of (13)C kinetic isotope effects and density functional theory calculations. The cyclopropanation of styrene with methyl phenyldiazoacetate catalyzed by Rh(2)(octanoate)(4) exhibits a substantial (13)C isotope effect (1.024) at the terminal olefinic carbon and a smaller isotope effect (1.003-1.004) at the internal olefinic carbon. This is consistent with a highly asynchronous cyclopropanation process. Very similar isotope effects were observed in a bisrhodium tetrakis[(S)-N-(dodecylbenzenesulfonyl)prolinate] (Rh(2)(S-DOSP)(4) catalyzed reaction, suggesting that the chiral catalyst engages in a very similar cyclopropanation transition-state geometry. Cyclopropanation with ethyl diazoacetate was concluded to involve an earlier transition state, based on a smaller terminal olefinic isotope effect (1.012-1.015). Density functional theory calculations (B3LYP) predict a reaction pathway involving complexation of the diazoesters to rhodium, loss of N(2) to afford a rhodium carbenoid, and an asynchronous but concerted cyclopropanation transition state. The isotope effects predicted for reaction of a phenyl-substituted rhodium carbenoid with styrene match within the error of the experimental values, supporting the accuracy of the theoretical calculations and the rhodium carbenoid mechanism. The accuracy of the calculations is additionally supported by excellent predictions of reaction barriers, stereoselectivity, and reactivity trends. The nature of alkene selectivity and diastereoselectivity effects in these reactions is discussed, and a new model for enantioselectivity in Rh(2)(S-DOSP)(4)-catalyzed cyclopropanations is presented.