Daniel A. Singleton

A Case Study of the Mechanism of Alcohol-Mediated Morita Baylis–Hillman Reactions. The Importance of Experimental Observations

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.

Dynamics and the Failure of Transition State Theory in Alkene Hydroboration

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. High-level 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 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.

Control Elements in Dynamically Determined Selectivity on a Bifurcating Surface

The mechanism and the nature of the dynamically determined product selectivity in Diels-Alder cycloadditions of 3-methoxycarbonylcyclopentadienone (2) with 1,3-dienes was studied by a combination of product studies, experimental kinetic isotope effects, standard theoretical calculations, and quasiclassical trajectory calculations. The low-energy transition structures in these reactions are structurally balanced between [4pi(diene) + 2pi(dienone)] and the [2pi(diene) + 4pi(dienone)] modes of cycloaddition. The accuracy of these structures and their bispericyclic nature is supported by the experimental isotope effects. Trajectories passing through these transition structures can lead to both [4pi(diene) + 2pi(dienone)] and [2pi(diene) + 4pi(dienone)] cycloadducts, and the mixture of products obtained varies with the structure of the diene. The factors affecting this selectivity are analyzed. The geometry of the transition structure is a useful predictor of the major product, but the selectivity is also guided by the shape of the energy surface as trajectories approach the products and by how trajectories cross the transition state ridge.

Outer-Sphere Direction in Iridium C–H Borylation

The NHBoc group affords ortho selective C-H borylations in arenes and alkenes. Experimental and computational studies support an outer sphere mechanism where the N-H proton hydrogen bonds to a boryl ligand oxygen. The regioselectivities are unique and complement those of directed ortho metalations.

Electronic effects in iridium C-H borylations: insights from unencumbered substrates and variation of boryl ligand substituents.

Experiment and theory favour a model of C-H borylation where significant proton transfer character exists in the transition state.

Experimental evidence for heavy-atom tunneling in the ring-opening of cyclopropylcarbinyl radical from intramolecular 12C/13C kinetic isotope effects.

The intramolecular (13)C kinetic isotope effects for the ring-opening of cyclopropylcarbinyl radical were determined over a broad temperature range. The observed isotope effects are unprecedentedly large, ranging from 1.062 at 80 degrees C to 1.163 at -100 degrees C. Semiclassical calculations employing canonical variational transition-state theory drastically underpredict the observed isotope effects, but the predicted isotope effects including tunneling by a small-curvature tunneling model match well with experiment. These results and a curvature in the Arrhenius plot of the isotope effects support the recently predicted importance of heavy-atom tunneling in cyclopropylcarbinyl ring-opening.

Isotope effects and the distinction between synchronous, asynchronous, and stepwise Diels–Alder reactions

Abstract A variety of symmetrical or nearly symmetrical Diels–Alder reactions are studied by a combination of experimental isotope effects, theoretical calculations, and rate observations. Becke3LYP calculations predicted highly asynchronous transition structures for Diels–Alder reactions of bis(boryl)acetylenes, dialkyl acetylenedicarboxylates, triazolinediones, and dialkyl maleates. Rate observations and kinetic isotope effects are consistent with these predictions, though the experimental support for the calculated structures is notably ambiguous in some cases. A concerted mechanism is supported for the retro-Diels–Alder reaction of norbornene. Overall, Diels–Alder reactions appear to be only very weakly biased toward synchronous transition states.

Entropic Intermediates and Hidden Rate-Limiting Steps in Seemingly Concerted Cycloadditions. Observation, Prediction, and Origin of an Isotope Effect on Recrossing

An unusual intramolecular kinetic isotope effect (KIE) in the reaction of dichloroketene with cis-2-butene does not fit with a simple asynchronous cycloaddition transition state, but it can be predicted from trajectory studies on a bifurcating energy surface. The origin of the KIE is related to a high propensity for transition state recrossing in this system, with heavier masses recrossing less. The KIE can also be predicted by a statistical model that treats the cycloaddition as a stepwise mechanism, the rate-limiting second step being associated with an entropic barrier for formation of the second carbon-carbon bond. The relevance of this stepwise mechanism to other asynchronous but seemingly concerted cycloadditions is suggested by examination of organocatalytic Diels-Alder reactions.

Recrossing and Dynamic Matching Effects on Selectivity in a Diels-Alder Reaction **

The products from the hetero-Diels-Alder reaction of acrolein with methyl vinyl ketone arise from a single transition state and trajectory studies accurately predict the selectivity. In an extension of the dynamic matching idea of Carpenter, the product formed is determined by the direction of motion passing through the transition state. Recrossing of the cycloaddition transition state occurs extensively and decreases formation of the minor product.

Transition-State Geometry Measurements from 13C Isotope Effects. The Experimental Transition State for the Epoxidation of Alkenes with Oxaziridines

We here suggest and evaluate a methodology for the measurement of specific interatomic distances from a combination of theoretical calculations and experimentally measured (13)C kinetic isotope effects. This process takes advantage of a broad diversity of transition structures available for the epoxidation of 2-methyl-2-butene with oxaziridines. From the isotope effects calculated for these transition structures, a theory-independent relationship between the C-O bond distances of the newly forming bonds and the isotope effects is established. Within the precision of the measurement, this relationship in combination with the experimental isotope effects provides a highly accurate picture of the C-O bonds forming at the transition state. The diversity of transition structures also allows an evaluation of the Schramm process for defining transition-state geometries on the basis of calculations at nonstationary points, and the methodology is found to be reasonably accurate.