Our previous work found that canonical forms of transition state theory incorrectly predict the regioselectivity of the hydroboration of propene with BH3 in solution. In response, it has been suggested that alternative statistical and nonstatistical rate theories can adequately account for the selectivity. This paper uses a combination of experimental and theoretical studies to critically evaluate the ability of these rate theories, as well as dynamic trajectories and newly developed localized statistical models, to predict quantitative selectivities and qualitative trends in hydroborations on a broader scale. The hydroboration of a series of terminally substituted alkenes with BH3 was examined experimentally, and a classically unexpected trend is that the selectivity increases as the alkyl chain is lengthened far from the reactive centers. Conventional and variational transition state theories can predict neither the selectivities nor the trends. The canonical competitive nonstatistical model makes somewhat better predictions for some alkenes but fails to predict trends, and it performs poorly with an alkene chosen to test a specific prediction of the model. Added nonstatistical corrections to this model make the predictions worse. Parametrized Rice–Ramsperger–Kassel–Marcus (RRKM)-master equation calculations correctly predict the direction of the trend in selectivity versus alkene size but overpredict its magnitude, and the selectivity with large alkenes remains unpredictable with any parametrization. Trajectory studies in explicit solvent can predict selectivities without parametrization but are impractical for predicting small changes in selectivity. From a lifetime and energy analysis of the trajectories, “localized RRKM-ME” and “competitive localized noncanonical” rate models are suggested as steps toward a general model. These provide the best predictions of the experimental observations and insight into the selectivities.

Several formal heteroborylative cyclization reactions have been recently reported, but little physical–organic and mechanistic data are known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second-order globally and first-order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ΔG‡ = 27.1 ± 0.1 kcal mol–1 at 90 °C, ΔH‡ = 13.8 ± 1.0 kcal mol–1, and ΔS‡ = −37 ± 3 cal mol–1 K–1, measured over the range 70–90 °C. Carbon kinetic isotope effects supported a rate-determining AdE3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a ρ+ of −1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(C6F5)3), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a postcyclization zwitterionic intermediate. Kinetic studies via UV–vis spectroscopy with this boron reagent found second-order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl3 as an activating agent showed why BCl3, in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents and then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate.

Reactions that involve a combination of proton transfer and heavy-atom bonding changes are normally categorized by whether the proton transfer is occurring during the rate-limiting step, as in the distinction between general and specific acid–base catalysis. The experimental and computational study here of a β-ketoacid decarboxylation shows how the distinction between the two mechanisms breaks down near its border due to the differing time scales for proton versus heavy-atom motion. Isotope effects in the decarboxylation of benzoylacetic acid support a transition state in which the proton transfer is complete. In quasiclassical trajectories passing through this transition state, the new O–H bond after proton transfer undergoes several vibrations before heavy-atom motion completes the reaction. The bonding changes are thus temporally separated at a “dynamic intermediate” structure that acts equivalently to an ordinary intermediate in the trajectories, including the reversal of trajectories at the intermediate when the second “step” fails, but the structure is not an energy minimum. The results define a border between mechanisms where the usual energetic definition of intermediates is not meaningful.

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.

The regiochemistry of the nitration of toluene by NO2+BF4– in dichloromethane is accurately predicted from trajectories in explicit solvent. Simpler models and approaches based on transition state theory fail to account for the selectivity. Potential of mean force calculations find no free-energy barrier for reaction of the toluene/NO2+BF4– encounter complex, yet the trajectories require an extraordinary 3 ps to descend an exergonic slope. The selectivity is decided late in long trajectories because their completion requires solvent and counterion reorganization. The normal descriptive understanding of the regiochemistry based on transition-state energies is unsupported.

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.