Isotope Effects and the Mechanism of Photoredox-Promoted [2 + 2] Cycloadditions of Enones.

C kinetic isotope effects (KIEs) for the photoredox-promoted [2 + 2] cycloaddition of enones were determined in homocoupling and heterocoupling examples. The only significant KIEs were observed at the β carbon, indicating that C-C bond formation is irreversible. However, these KIEs were much lower than computational predictions, suggesting that product selectivity is determined in part by a step prior to C-C bond formation.

Energy Read-out as a Probe of Kinetically Hidden Transition States.

The initial energy in a reactive intermediate is derived from the transition state the intermediate but can affect selectivity the intermediate. In this way an observable selectivity can report on a prior, kinetically hidden mechanistic step. This new type of mechanistic probe is demonstrated here for the oxidation of 1-methylcyclobutanol by phthaloyl peroxide/BuNBr, and it supports a hypobromite chain mechanism in place of the previously proposed hydrogen atom transfer mechanism.

Vibrationally Hot and Cold Triplets. Sensitizer-Dependent Dynamics and Localized Vibrational Promotion of a Di-π-methane Rearrangement.

Large intramolecular C kinetic isotope effects (KIEs) for the di-π-methane rearrangement of benzobarrelene fit with statistical expectations from heavy-atom tunneling when a low-energy sensitizer is employed, but much lower KIEs are observed with higher-energy sensitizers. These results in combination with trajectory studies suggest that the excess vibrational energy available from triplet energy transfer leads to hot and nonstatistical dynamics in the rearrangement.

Solvation Dynamics and the Nature of Reaction Barriers and Ion-Pair Intermediates in Carbocation Reactions.

Additions of acids to 1,3-dienes are conventionally understood as involving discrete intermediates that undergo an ordinary competition between subsequent pathways to form the observed products. The combined experimental, computational, and dynamic trajectory study here suggests that this view is incorrect, and that solvation dynamics plays a critical role in the mechanism. While implicit solvent models were inadequate, QM/QM' trajectories in explicit solvent provide an accurate prediction of the experimental selectivity in the addition of HCl to 1,3-pentadiene.

Bond Memory in Dynamically Determined Stereoselectivity.

The carboborative ring contraction of cyclohexenes exhibits an abnormal selectivity pattern in which a formally concerted double migration gives rise to predominant but not exclusive inversion products. In dynamic trajectories, the inversion and retention products are formed from the same transition state, and the trajectories accurately account for the experimental product ratios. The unusual origin of the selectivity is the dynamically retained non-equivalence of newly formed versus pre-existing bonds after the first bond migration.

Comment on "Activation of methane to CH : A selective industrial route to methanesulfonic acid".

Díaz-Urrutia and Ott (Reports, 22 March 2019, p. 1326) report a selective conversion of methane to methanesulfonic acid that is proposed to occur by a cationic chain reaction in which CH adds to sulfur trioxide (SO) to form CH-S(O)O This mechanism is not plausible because of the solvent reactivity of CH , the non-nucleophilicity of the sulfur atom of SO, and the high energy of CH-S(O)O^.

Labelling and determination of the energy in reactive intermediates in solution enabled by energy-dependent reaction selectivity.

Any long-lived chemical structure in solution is subject to statistical energy equilibration, so the history of any specific structure does not affect its subsequent reactions. This is not true for very short-lived intermediates because energy equilibration takes time. Here, this idea is applied to achieve the 'energy labelling' of a reactive intermediate.

Failure and Redemption of Statistical and Nonstatistical Rate Theories in the Hydroboration of Alkenes.

Our previous work found that canonical forms of transition state theory incorrectly predict the regioselectivity of the hydroboration of propene with BH 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.

Mechanistic Studies of Formal Thioboration Reactions of Alkynes.

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.

Ir-Catalyzed ortho-Borylation of Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions.

A strategy for affecting ortho versus meta/para selectivity in Ir-catalyzed C-H borylations (CHBs) of phenols is described. From selectivity observations with ArylOBpin (pin = pinacolate), it is hypothesized that an electrostatic interaction between the partial negatively charged OBpin group and the partial positively charged bipyridine ligand of the catalyst favors ortho selectivity. Experimental and computational studies designed to test this hypothesis support it.

Concert along the Edge: Dynamics and the Nature of the Border between General and Specific Acid-Base Catalysis.

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.

Dynamics and the Regiochemistry of Nitration of Toluene.

The regiochemistry of the nitration of toluene by NOBF 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/NOBF encounter complex, yet the trajectories require an extraordinary 3 ps to descend an exergonic slope.

Controlling Selectivity by Controlling Energy Partitioning in a Thermal Reaction in Solution.

The comparison of experimental and predicted kinetic isotope effects in the α-cleavage of alkoxy radicals is used here to judge the applicability of statistical rate theories. It is found that the governing rate theory and the statistical versus nonstatistical nature of the cleavage depend on the cleavage barrier and how much energy is imparted to the radical. The latter can then be controlled by changing the size of substituents in the system.

Dynamically Complex [6+4] and [4+2] Cycloadditions in the Biosynthesis of Spinosyn A.

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.

Controlling Selectivity by Controlling the Path of Trajectories.

Consideration of the role of dynamic trajectories in [1,2]- and [2,3]-sigmatropic rearrangements suggests a counterintuitive approach to controlling the selectivity. In our hypothesis, [2,3] selectivity can be promoted by reaction conditions that thermodynamically disfavor the [2,3] rearrangement step and thereby make the transition state later. The application of this idea has led to a successful prescription for dictating the selectivity in Stevens/Sommelet-Hauser rearrangements of ammonium ylides.

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.

Isotope effects, dynamic matching, and solvent dynamics in a Wittig reaction. Betaines as bypassed intermediates.

The mechanism of the Wittig reaction of anisaldehyde with a stabilized ylide was studied by a combination of (13)C kinetic isotope effects, conventional calculations, and molecular dynamics calculations in a cluster of 53 THF molecules. The isotope effects support a cycloaddition mechanism involving two sequential transition states associated with separate C-C and P-O bond formations. However, the betaine structure in between the two transition states is bypassed as an equilibrated intermediate in most trajectories.

Racing carbon atoms. Atomic motion reaction coordinates and structural effects on Newtonian kinetic isotope effects.

Intramolecular (13)C kinetic isotope effects were determined for the dimerization of methacrolein. Trajectory studies accurately predict the isotope effects and support an origin in Newton's second law of motion, with no involvement of zero-point energy or transition state recrossing. Atomic motion reaction coordinate diagrams are introduced as a way to qualitatively understand the selectivity.

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.

Isotope effects and heavy-atom tunneling in the Roush allylboration of aldehydes.

Intermolecular (13)C kinetic isotope effects (KIEs) for the Roush allylboration of p-anisaldehyde were determined using a novel approach. The experimental (13)C KIEs fit qualitatively with the expected rate-limiting cyclic transition state, but they are far higher than theoretical predictions based on conventional transition state theory. This discrepancy is attributed to a substantial contribution of heavy-atom tunneling to the reaction, and this is supported by multidimensional tunneling calculations that reproduce the observed KIEs.

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.

Isotope-induced desymmetrization can mimic isotopic perturbation of equilibria. On the symmetry of bromonium ions and hydrogen bonds.

The desymmetrizing effect of isotopic substitution on the geometry of otherwise symmetrical structures can be surprisingly large when there is anharmonic coupling between a desymmetrizing mode and modes whose zero-point energies are strongly isotope-dependent. This phenomenon is found to account for experimental observations that had been previously interpreted as implying asymmetry in bromonium ions and in hydrogen phthalate ions in aprotic solvents. The unlabeled structures are concluded to have the higher symmetry found in computed structures.