Cycloaddition Transition State Research Articles

Uncovering a general oxidation model of nitrogen-containing oxidant in N-heterocyclic carbene (NHC) catalyzed oxidative reactions of aldehydes

Predicting how oxidants interact with reactive partners to alter the oxidation mechanism is a significant challenge in carbene catalysis. In this study, we investigated several examples to address this issue. Using density functional theory (DFT), we explored N-heterocyclic carbene (NHC)-catalyzed oxidative [2 + 4] annulations of aliphatic aldehydes with α,β-unsaturated ketones, focusing on the role of nitrogen-containing oxidant. Our computational results reveal that a hydrogen-bonding bridge framework, formed during oxidation, is crucial for facilitating π···π stacking interactions between the oxidant and the NHC catalyst. These interactions significantly lower the oxidation energy barrier, enabling a facile hydride transfer. This mechanism was validated across other reactions involving different nitrogen-containing oxidants. Frontier molecular orbital (FMO) analysis demonstrates how the NHC catalyst lowers the cycloaddition energy barrier by altering the orbital overlap from shoulder-to-head to head-to-head. Additionally, this elucidates the origin of stereoselectivity by highlighting energy differences between two reacting components at cycloaddition transition states. The nucleophilic index further predicts the preferred ketone attack site. This work advances our understanding of oxidation mechanisms involving nitrogen-containing oxidants and offers valuable insights for designing potent organic oxidants in organocatalytic oxidative reactions.

Experimental and Theoretical Exploration of the Kinetics and Thermodynamics of the Nucleophile-Induced Fragmentation of Ylidenenorbornadiene Carboxylates.

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with thiol nucleophiles to yield mixtures of four to eight diastereomers depending on the symmetry of the YND substrate. The mixtures of diastereomers fragment via a retro-[4 + 2] cycloaddition with a large variation in rate, with half-lives ranging from 16 to 11,000 min at 80 °C. The diastereomer-enriched samples of propane thiol adducts [YND-propanethiol (PTs)] were isolated and identified by nuclear Overhauser effect spectroscopy (NOESY) correlations. Simulated kinetics were used to extrapolate the rate constants of individual diastereomers from the observed rate data, and it correlated well with rate constants measured directly and from isolated diastereomer-enriched samples. The individual diastereomers of a model system fragment at differing rates with half-lives ranging from 5 to 44 min in CDCl3. Density functional theory calculations were performed to investigate the mechanism of fragmentation and support an asynchronous retro-[4 + 2] cycloaddition transition state. The computations generally correlated well with the observed free energies of activation for four diastereomers of the model system as a whole, within 2.6 kcal/mol. However, the observed order of the fragmentation rates across the set of diastereomers deviated from the computational results. YNDs display wide variability in the rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A Hammett study showed that the electron-rich aromatic rings attached to the ylidene bridge increase the fragmentation rate, while electron-deficient systems slow fragmentation rates.

One-Pot (3 + 2) Cycloaddition-Isomerization-Oxidation of 2,2,2-Trifluorodiazoethane and Styryl Derivatives.

A facile access to 5-aryl-3-trifluoromethylpyrazoles has been developed by a one-pot (3 + 2) cycloaddition-isomerization-oxidation sequence employing 2,2,2-trifluorodiazoethane and styryl derivatives. A broad variety of functional groups and good yields are achieved under mild conditions. Additionally, the functionalization of 3-trifluoromethylpyrazoles was studied. DFT calculations of the cycloaddition transition state energies are consistent with the experimentally observed reactivity.

Visual-Spatial Skills, Strategies, and Challenges to Extract, Represent, and Predict Stereochemical Outcomes of Cycloadditions Using a Hexagonal Prism Reference Frame

The perception of 3D features from 2D representations depend on their number of salient features, recognizable canonical axes, and orientations. Informed by form-perception literature, we proposed a hexagonal prism as an external reference frame to identify positions of elements in relation to each other and the observer when studying Diels–Alder and other cycloaddition reactions. The hexagonal prism reference model (HPRM) provides three-dimensional features to cycloaddition transition states and an external reference to facilitate analysis of their stereochemical characteristics. A study to characterize the visual-spatial skills (VSS) and spatial challenges associated with extracting spatial information, representing spatial relations, and predicting stereochemical outcomes was completed with six graduate and six undergraduate students. Our findings show that different VSS predominate when solving different spatial tasks and that the patterns of VSS utilized by both graduate and undergraduates groups can be used to provide a more in-depth subcategorization of spatial strategies. The HPRM not only provides a resource for students to practice VSS and learn cycloaddition stereoselectivity, but also for instructors to promote effective strategies to predict stereochemistry. Since this study did not identify any nonspatial strategy, the HPRM proved to be effective in promoting students’ visuospatial thinking to solve spatial tasks.

Temperature‐dependent kinetics of the reactions of CH2OO with acetone, biacetyl, and acetylacetone

AbstractTemperature‐dependent rate constants for the reactions of CH2OO with acetone (Ac), biacetyl (BiAc), and acetylacetone (AcAc) have been measured over the range 275–335 K using a flash photolysis, transient absorption spectroscopy technique. The measurements were performed at a total pressure of ∼80 Torr in N2 bath gas, which corresponds to the high‐pressure limit for these reactions. All three reactions show linear Arrhenius plots with negative temperature dependences. Rate constants increase in the order Ac < AcAc « BiAc across the temperature range; at 295 K the rate constants are kAc = (4.8 ± 0.4) × 10–13 cm3 s–1, kAcAc = (8.0 ± 0.7) × 10–13 cm3 s–1, and kBiAc = (1.10 ± 0.09) × 10–11 cm3 s–1. Sensitivity to temperature, characterized by the magnitude of the negative activation energy, increases in the order AcAc < BiAc < Ac (Ea/R values of –1830 ± 170 K, –1260 ± 170 K, and –460 ± 180 K, respectively). CBS‐QB3 calculations show that the Ac and BiAc reactions proceed via formation of an entrance channel complex followed by 1,3‐dipolar cycloaddition to form secondary ozonide products via a submerged transition state. For the BiAc reaction, the rate limiting step appears to be rearrangement of a long‐range van der Waals complex into the short‐range complex that subsequently leads directly to the cycloaddition transition state with a very low energy barrier. The calculations show that two reaction pathways are competitive for AcAc with nearly identical transition state free energies (ΔG° = +10.1 kcal mol–1 at 298 K) found for cycloaddition at the C=O and at the C=C site of the dominant enolone tautomer. The weak temperature dependence observed is likely due to competition between these pathways.

Mechanistic Study on Palladium-Catalyzed Cycloaddition of Vinylethylene Carbonates with α,β-Unsaturated Imines

Vinylethylene carbonates (VECs) have been a versatile synthon for the construction of cyclic oxygenates with a medium-sized ring structure. Zhao’s group first demonstrated the potential of VECs as 1,5-dipoles in medium-sized ring synthesis. In their study, (5 + 4) cyclization between VECs (R1 = Ph) and N-tosyl azadienes occurs predominantly under the catalysis of Pd2(dba)3·CHCl3/dppbz. By contrast, when unsubstituted VECs (R1 = H) were used, the five-membered ring product of (3 + 2) cycloaddition was yielded dominantly. We elucidated the key role of the regioselectivity via the mechanistic study of VEC-participated (3 + 2) and (5 + 4) cycloadditions with DFT calculations. The results indicate that the VEC moiety is close to the α,β-unsaturated imine moiety in the (3 + 2) cycloaddition transition state, and the phenyl group deviates from the conjugation plane and thus results in the higher distortion energy. In the presence of the unsubstituted VEC substrate, the steric hindrance in the (3 + 2) transition state is greatly reduced. Meanwhile, the formation of the five-membered ring is facilitated by the entropic effect, and thus, (3 + 2) dominates over the (5 + 4) cycloaddition in this case.

Insights into N-Heterocyclic Carbene-Catalyzed Oxidative α-C(sp3)-H Activation of Aliphatic Aldehydes and Cascade [2 + 2] Cycloaddition with Ketimines.

Predicting the chemoselectivity of [2 + 2] cyclizations is an important challenge in organic chemistry. Herein, we provided a valuable case for this issue. Density functional theory calculations were performed to systematically study the possible mechanisms and origin of selectivities for the N-heterocyclic carbene (NHC)-catalyzed oxidative α-C(sp3)-H activation of aliphatic aldehydes and the cascade [2 + 2] cycloaddition with ketimines. The [2 + 2] cycloaddition of azolium enolate intermediates to the C═N bond, rather than the C═O bond of ketimine, is revealed to be determined by chemo- and stereoselectivity. By comparing the energy gap between the frontier molecular orbitals (FMOs) of the two reacting parts involved in the [2 + 2] cycloaddition transition states, we propose a new strategy to determine the origin of the reaction chemoselectivity. Moreover, the local nucleophilic index can efficiently predict the active site of ketimines. Further analyses illustrate that NHC can increase the nucleophilicity of aldehydes and the acidity of the α-C(sp3)-H bond, and 3,3',5,5'-tetra- tert-butyl diphenoquinone (DQ) acts as an oxidant and promotes α-C(sp3)-H bond deprotonation. This work is useful not only for understanding the NHC-catalyzed oxidative [2 + 2] annulation but also for developing new applications of the FMO theory in organocatalytic cyclizations.

Insights into base-free OsO4-catalyzed aminohydroxylations employing chiral ligands

Attempts to perform the OsO4-catalyzed enantioselective base-free aminohydroxylation of β,β-disubstituted enoates are described. Low yields and racemic products were obtained in the presence of standard chiral ligands, suggesting the occurrence of a “Second Cycle” process due to slow hydrolysis of the amino alcohol product from the Os metal center. Support for this hypothesis was provided by the slightly improved enantioselectivity (60:40 er) obtained with an amino alcohol ligand. Based on density functional theory calculations, it is proposed that the lack of significant enantioselectivity is due to a low-energy (3 + 2) oxo/imido cycloaddition transition state without the chiral ligand in the Second Cycle that outcompetes protonolysis in the First Cycle.

Ambimodal Dipolar/Diels-Alder Cycloaddition Transition States Involving Proton Transfers.

Quantum mechanical computations and molecular dynamics simulations have been used to elucidate the factors that control reaction outcomes in ambimodal transition states leading to both dipolar and Diels-Alder cycloaddition products, which can interconvert via α-ketol rearrangements. The dipolar cycloaddition pathways were found to be disadvantaged due to the persistence of charge separation after the second C-C formation en route to the dipolar cycloaddition adducts. Structural modifications that result in the stabilization of the charge-separated species lead to an increase in the amount of dipolar cycloadducts formed.

Computational evidence for a reaction pathway bifurcation in Sasaki-type (4 + 3)-cycloadditions.

The current report seeks to validate the existence of a post-transition state bifurcation in the Lewis acid-catalysed (4 + 3)-cycloaddition of butadiene and α-methoxy acrolein. Cycloaddition transition state (TS) structures are shown by intrinsic reaction coordinate (IRC) and potential energy surface (PES) scan calculations to connect directly to both (4 + 3)- and (4 + 2)-products. A second TS, a 1,2-sigmatropic shift which interconverts the products, was also located. Implicit solvent is observed to have a substantial effect of the course of the reaction, with the minimum energy path from the gas phase TS leading to (4 + 2)-product whereas the DCM solvent phase TS leads to (4 + 3)-product. On the basis of these data it is suggested that a number of previously reported (4 + 3)-cycloadditions may also possess reaction pathway bifurcations.

High diastereoselectivity induced by intermolecular hydrogen bonding in [3 + 2] cycloaddition reaction: experimental and computational mechanistic approaches

AbstractA diastereoselective [3 + 2] cycloaddition of N‐aryl substituted maleimides with N,α‐diphenyl nitrone possessing 11‐hydroxyundecyloxy as a flexible substituent was performed. Experimental and comprehensive mechanistic density functional theory studies reveals that intermolecular H‐bonding and steric repulsive interaction predominate exo‐Z and exo‐E cycloaddition transition states, respectively. The reaction proceeded smoothly depending on the reactants and gave a good yield of (syn) cis‐isoxazolidine or (anti) trans‐isoxazolidine as a single diastereomer.

Solvent effect in diastereoselective intramolecular Diels–Alder reactions

In the process of improving the synthesis of a novel class of chiral drug scaffolds, first reported in 2010, we observed that the stereochemical outcome of the key chemical transformation appeared to be correlated to the solvophobicity of the reaction medium. Our mechanistic investigations by NMR monitoring of the reaction confirmed the proposed acylation/intermolecular cycloaddition sequence. The computational studies using DFT methods next predicted exo/endo stereoselectivity (4.3:1 in CHCl3, 1.6:1 in H2O) in agreement with the experimental results (3.3:1 in CHCl3, 1:1 in H2O). The observed stereoselectivity was related to the different level of asynchronicity of the diastereomeric transition states. This leads to different solvent stabilization of the cycloaddition transition state of one diastereomer more than the other.

Activation-strain analysis reveals unexpected origin of fast reactivity in heteroaromatic azadiene inverse-electron-demand diels-alder cycloadditions.

Heteroaromatic azadienes, especially 1,2,4,5-tetrazines, are extremely reactive partners with alkenes in inverse-electron-demand Diels-Alder reactions. Azadiene cycloaddition reactions are used to construct heterocycles in synthesis and are popular as bioorthogonal reactions. The origin of fast azadiene cycloaddition reactivity is classically attributed to the inverse frontier molecular orbital (FMO) interaction between the azadiene LUMO and alkene HOMO. Here, we use a combination of ab initio, density functional theory, and activation-strain model calculations to analyze physical interactions in heteroaromatic azadiene-alkene cycloaddition transition states. We find that FMO interactions do not control reactivity because, while the inverse FMO interaction becomes more stabilizing, there is a decrease in the forward FMO interaction that is offsetting. Rather, fast cycloadditions are due to a decrease in closed-shell Pauli repulsion between cycloaddition partners. The kinetic-thermodynamic relationship found for these inverse-electron-demand cycloadditions is also due to the trend in closed-shell repulsion in the cycloadducts. Cycloaddition regioselectivity, however, is the result of differences in occupied-unoccupied orbital interactions due to orbital overlap. These results provide a new predictive model and correct physical basis for heteroaromatic azadiene reactivity and regioselectivity with alkene dieneophiles.

Mechanism and selectivity of N-triflylphosphoramide catalyzed (3(+) + 2) cycloaddition between hydrazones and alkenes.

Brønsted acid catalyzed (3(+) + 2) cycloadditions between hydrazones and alkenes provide a general approach to pyrazolidines. The acidity of the Brønsted acid is crucial for the catalytic efficiency: the less acidic phosphoric acids are ineffective, while highly acidic chiral N-triflylphosphoramides are very efficient and can promote highly enantioselective cycloadditions. The mechanism and origins of catalytic efficiencies and selectivities of these reactions have been explored with density functional theory (M06-2X) calculations. Protonation of hydrazones by N-triflylphosphoramide produces hydrazonium-phosphoramide anion complexes. These ion-pair complexes are very reactive in (3(+) + 2) cycloadditions with alkenes, producing pyrazolidine products. Alternative 1,3-dipolar (3 + 2) cycloadditions with the analogous azomethine imines are much less favorable due to the endergonic isomerization of hydrazone to azomethine imine. With N-triflylphosphoramide catalyst, only a small distortion of the ion-pair complex is required to achieve its geometry in the (3(+) + 2) cycloaddition transition state. In contrast, the weak phosphoric acid does not protonate the hydrazone, and only a hydrogen-bonded complex is formed. Larger distortion energy is required for the hydrogen-bonded complex to achieve the "ion-pair" geometry in the cycloaddition transition state, and a significant barrier is found. On the basis of this mechanism, we have explained the origins of enantioselectivities when a chiral N-triflylphosphoramide catalyst is employed. We also report the experimental studies that extend the substrate scope of alkenes to ethyl vinyl ethers and thioethers.

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.

Stereoelectronic Effects in Dihapto-Coordinated Complexes of TpW(NO)(PMe3) and Their Manifestation in Diels−Alder Cycloaddition of Arenes

The addition of singly and doubly activated dienophiles to TpW(NO)(PMe3)(5,6-η2-anisole) and TpW(NO)(PMe3)(5,6-η2-1,3-dimethoxybenzene) to generate dihapto-coordinated [2.2.2]bicyclooctadienes and -trienes is explored. The highly functionalized bicyclic scaffolds are isolated from the metal fragment intact. Although moderate yields hinder their synthetic application, a unique stereoelectronic effect is uncovered. Coordination diastereomers of anisoles with the methoxy substituent distal to the PMe3 ligand have faster reaction rates relative to the proximal diastereomer. DFT calculations reveal the metal fragment possesses a dipole that directs positive charge away from the PMe3 ligand, and a polarized cycloaddition transition state is invoked to explain this observation.

Newtonian Kinetic Isotope Effects. Observation, Prediction, and Origin of Heavy-Atom Dynamic Isotope Effects

Intramolecular (13)C kinetic isotope effects were determined for the dimerization of cyclopentadiene. Substantial isotope effects were observed in three positions, despite the C(2) symmetry of the cycloaddition transition state and the absence of dynamical bottlenecks after this transition state. The observed isotope effects were predicted well from trajectory studies by extrapolating the outcomes of trajectories incorporating superheavy isotopes of carbon, ranging from (20)C to (140)C. Trajectory studies suggest that the isotope effects are unrelated to zero-point energy or the geometrical and momentum properties of the transition state. However, steepest-descent paths in mass-weighted coordinates correctly predict the direction of the isotope effects, supporting a novel origin in Newton's second law of motion.

Theoretical Study on the Reaction Mechanism for the Formation of 2-Methylpyridine Cobalt(I) Complex from Cobaltacyclopentadiene and Acetonitrile

Using B3LYP level calculations, the reaction of acetonitrile with cobaltacyclopentadiene complex in singlet and triplet electronic states, to give pyridine cobalt complexes, was studied. While the most favorable path for the singlet reaction passes through a [4+2] cycloaddition transition state, the most favorable triplet reaction follows the reaction mechanism through azacobaltacycloheptatriene. Since the transition state for the singlet reaction path is lower in energy than those for the triplet reaction path, the singlet reaction seems to be more favorable. However, the reactant in the triplet state is more stable than that in the singlet state, suggesting that the two-state reactivity (TSR) mechanism with spin changes is followed. Determination of energy minimum crossing points between singlet and triplet energy surfaces led to the conclusion that the TSR mechanism is more favorable than both the singlet- and triplet-state (single-state reactivity) (SSR) mechanisms. Comparison of a reaction profile be...

Reactivity and Regioselectivity in 1,3-Dipolar Cycloadditions of Azides to Strained Alkynes and Alkenes: A Computational Study

The transition states and activation barriers of the 1,3-dipolar cycloadditions of azides with cycloalkynes and cycloalkenes were explored using B3LYP density functional theory (DFT) and spin component scaled SCS-MP2 methods. A survey of benzyl azide cycloadditions to substituted cyclooctynes (OMe, Cl, F, CN) showed that fluorine substitution has the most dramatic effect on reactivity. Azide cycloadditions to 3-substituted cyclooctynes prefer 1,5-addition regiochemistry in the gas phase, but CPCM solvation abolishes the regioselectivity preference, in accord with experiments in solution. The activation energies for phenyl azide addition to cycloalkynes decrease considerably as the ring size is decreased (cyclononyne DeltaG(double dagger) = 29.2 kcal/mol, cyclohexyne DeltaG(double dagger) = 14.1 kcal/mol). The origin of this trend is explained by the distortion/interaction model. Cycloalkynes are predicted to be significantly more reactive dipolarophiles than cycloalkenes. The activation barriers for the cycloadditions of phenyl azide and picryl azide (2,4,6-trinitrophenyl azide) to five- through nine-membered cycloalkenes were also studied and compared to experiment. Picryl azide has considerably lower activation barriers than phenyl azide. Dissection of the transition state energies into distortion and interaction energies revealed that "strain-promoted" cycloalkyne and cycloalkene cycloaddition transition states must still pay an energetic penalty to achieve their transition state geometries, and the differences in reactivity are more closely related to differences in distortion energies than the amount of strain released in the product. Trans-cycloalkene dipolarophiles have much lower barriers than cis-cycloalkenes.