Synthesis of Hydrofluoroolefin-Based Iodonium Reagent via Dyotropic Rearrangement and Its Utilization in Fluoroalkylation.

[1,2]-shift of atoms in alkyl fragments belongs to the class of dyotropic rearrangements. Various atoms, including halogens can be involved in the migration, however participation of iodine is unprecedented. Herein, we report our experimental and DFT studies on the oxidation triggered dyotropic rearrangement of iodo and chloro functions via butterfly-type transition state to demonstrate the migrating ability of λ3 -iodane centre. With the exploitation of dyotropic rearrangement we designed and synthesized a novel fluoroalkyl iodonium reagent from industrial feedstock gas HFO-1234yf. We demonstrated that the hypervalent reagent serves as an excellent fluoroalkylation agent for various amines and nitrogen heterocycles.

Synthesis of Imidazolidin-2-ones and Imidazol-2-ones via Base-Catalyzed Intramolecular Hydroamidation of Propargylic Ureas under Ambient Conditions.

The first organo-catalyzed synthesis of imidazolidin-2-ones and imidazol-2-ones via intramolecular hydroamidation of propargylic ureas is reported. The phosphazene base BEMP turned out to be the most active organo-catalyst compared with guanidine and amidine bases. Excellent chemo- and regioselectivities to five-membered cyclic ureas have been achieved under ambient conditions, with a wide substrate scope and exceptionally short reaction times (down to 1 min). A base-mediated isomerization step to an allenamide intermediate is the most feasible reaction pathway to give imidazol-2-ones, as suggested by DFT studies.

Assessing Hypervalency in Iodanes.

The so-called hypervalent iodane compounds are very useful and versatile reactants and oxidizing agents in modern organic chemistry. The hypercoordinated central iodine in these compounds hints at a hypervalent state, which is often stressed to justify their reactivity. In this study a theoretical analysis of the electronic structure of a large, representative set of hypercoordinated iodane compounds has been carried out. We observed that the iodonium is not hypervalent in these compounds. In contrast, the analysis reveals a variation of the iodine valence state from a normal octet state to hypovalent depending on the ligands, but irrespective of the coordination number. On the basis of the calculations the reactivity of these compounds can be ascribed to the strong unquenched charge separation present in these molecules which represents a compromise between Coulomb interaction and the resistance of iodonium toward hypervalency. In extreme cases this leads to hypovalency and enhanced reactivity.

Design of Trifluoroalkenyl Iodonium Salts for a Hypervalency-Aided Alkenylation-Cyclization Strategy: Metal-Free Construction of Aziridine Rings.

The synthesis of fluorinated compounds and their use as pharmaceutical ingredients or synthetic building blocks have been in the focus of chemical and medicinal research. However, the efficient synthesis of trifluoromethylated nitrogen heterocycles is sometimes challenging. Herein, we disclose a simple aziridination process that relies on the use of amines and novel alkenyl iodonium reagents for the synthesis of strained, trifluoromethylated heterocycles. With the utilization of a newly designed and bench-stable but highly reactive hypervalent alkenyl iodonium species, these three-membered-ring heterocyclic compounds can be efficiently constructed from simple amines under mild conditions in the absence of transition-metal catalysts. The special reactivity of the new trifluoropropenyl synthon towards nucleophilic centers could be exploited in more general cyclization and alkenylation reactions in the future.

DFT calculations on the mechanism of copper-catalysed tandem arylation-cyclisation reactions of alkynes and diaryliodonium salts.

We present a computational mechanistic study on the copper(III)-catalysed carboarylation-ring closure reactions leading to the formation of functionalised heterocycles. We have performed DFT calculations along selected routes and compared their free energy profiles. The calculations considered two viable options for the underlying mechanism which differ in the order of the oxazoline ring formation and the aryl transfer steps. In our model transformation, it was found that the reaction generally features the aryl transfer-ring closing sequence and this sequence shows very limited sensitivity to the variation of the substituent of the reactants. On the basis of the mechanism the origin of the stereoselectivity is ascribed to the interaction of the Cu ion with the oxazoline oxygen driving the ring-closure step selectively.

Understanding and Exploitation of Neighboring Heteroatom Effect for the Mild N-Arylation of Heterocycles with Diaryliodonium Salts under Aqueous Conditions: A Theoretical and Experimental Mechanistic Study.

The mechanism of arylation of N-heterocycles with unsymmetric diaryliodonium salts is elucidated. The fast and efficient N-arylation reaction is interpreted in terms of the bifunctionality of the substrate: The consecutive actions of properly oriented Lewis base and Brønsted acid centers in sufficient proximity result in the fast and efficient N-arylation. The mechanistic picture points to a promising synthetic strategy where suitably positioned nucleophilic and acidic centers enable functionalization, and it is tested experimentally.

Prebiotic NH3 Formation: Insights from Simulations.

Simulations of prebiotic NH3 synthesis from NO3⁻ and NO2⁻ on pyrite surfaces under hydrothermal conditions are reported. Ab initio metadynamics calculations have successfully explored the full reaction path which explains earlier experimental observations. We have found that the reaction mechanism can be constructed from stepwise single atom transfers which are compatible with the expected reaction time scales. The roles of the hot-pressurized water and of the pyrite surfaces have been addressed. The mechanistic picture that emerged from the simulations strengthens the theory of chemoautotrophic origin of life by providing plausible reaction pathways for the formation of ammonia within the iron-sulfur-world scenario.

Rearrangements of Cycloalkenyl Aryl Ethers.

Rearrangement reactions of cycloalkenyl phenol and naphthyl ethers and the acid-catalyzed cyclization of the resulting product were investigated. Claisen rearrangement afforded 2-substituted phenol and naphthol derivatives. Combined Claisen and Cope rearrangement resulted in the formation of 4-substituted phenol and naphthol derivatives. In the case of cycloocthylphenyl ether the consecutive Claisen and Cope rearrangements were followed by an alkyl migration. The mechanism of this novel rearrangement reaction is also discussed.

Pyrite in contact with supercritical water: the desolation of steam.

The supercritical water-pyrite interface has been studied by ab initio molecular dynamics simulation. Extreme conditions are relevant in the iron-sulfur world (ISW) theory where prebiotic chemical reactions are postulated to occur at the mineral-water interface. We have investigated the properties of this interface under such conditions. We have come to the conclusion that hot-pressurized water on pyrite leads to an interface where a dry pyrite surface is in contact with the nearby SC water without significant chemical interactions. This picture is markedly different from that under ambient conditions where the surface is fully covered with adsorbed water molecules which is of relevance for the surface reactions of the ISW hypothesis.

Challenges in modelling homogeneous catalysis: new answers from ab initio molecular dynamics to the controversy over the Wacker process.

We present here a review of the mechanistic studies of the Wacker process stressing the long controversy about the key reaction steps. We give an overview of the previous experimental and theoretical studies on the topic. Then we describe the importance of the most recent Ab Initio Molecular Dynamics (AIMD) calculations in modelling organometallic reactivity in water. As a prototypical example of homogeneous catalytic reactions, the Wacker process poses serious challenges to modelling. The adequate description of the multiple role of the water solvent is very difficult by using static quantum chemical approaches including cluster and continuum solvent models. In contrast, such reaction systems are suitable for AIMD, and by combining with rare event sampling techniques, the method provides reaction mechanisms and the corresponding free energy profiles. The review also highlights how AIMD has helped to obtain a novel understanding of the mechanism and kinetics of the Wacker process.

Mechanistic study of silver-mediated furan formation by oxidative coupling.

Density functional calculations and experiments have been carried out to unravel the mechanism of a silver-mediated furan formation by oxidative coupling. Various possible reaction paths were considered and the most favorable channel has been identified on the basis of the calculated solvent-corrected Gibbs free-energy profiles. The mechanism represented by this route consists of a radical and a subsequent ionic route. The silver cation has a double role in the mechanism: it is the oxidant in the radical steps and the catalyst for the ionic steps, which is in accordance with the experimental observations. The two most important aspects of the optimal route are the formation of a silver-acetylide, reacting subsequently with the enolate radical, and the aromatic furan-ring formation in a single step at the latter, ionic segment of the reaction path. Our findings could explain several experimental observations, including the "key-promoter role" of silver, the preference for ionic cyclization, and the reduced reactivity of internal acetylides.

Photoinduced Decarboxylative Borylation of N-Hydroxyphthalimide Esters with Hypoboric Acid.

We developed a visible-light-driven photochemical transformation in which activated primary, secondary, and tertiary alkylcarboxylic acids were converted into the corresponding boronic esters in the absence of catechol and any added photocatalyst. The procedure relies on the utilization of hypoboric acid and redox-active esters of alkylcarboxylic acids to ensure a simple and economic procedure. Quantum chemical calculations and mechanistic considerations provide deeper insights into the mechanism of photochemical borylation reactions.

Reactivity models of hydrogen activation by frustrated Lewis pairs: synergistic electron transfers or polarization by electric field?

Two alternative qualitative reactivity models have recently been proposed to interpret the facile heterolytic cleavage of H2 by frustrated Lewis pairs (FLPs). Both models assume that the reaction takes place via reactive intermediates with preorganized acid/base partners; however, they differ in the mode of action of the active centers. In the electron transfer (ET) model, the hydrogen activation is associated with synergistic electron donation processes with the simultaneous involvement of active centers and the bridging hydrogen, showing similarity to transition-metal-based and other H2-activating systems. In contrast, the electric field (EF) model suggests that the heterolytic bond cleavage occurs as a result of polarization by the strong EF present in the cavity of the reactive intermediates. To assess the applicability of the two conceptually different mechanistic views, we examined the structural and electronic rearrangements as well as the EFs along the H2 splitting pathways for a representative set of reactions. The analysis reveals that electron donations developing already in the initial phase are general characteristics of all studied reactions, and the related ET model provides qualitative interpretation for the main features of the reaction pathways. On the other hand, several arguments have emerged that cast doubt on the relevance of EF effects as a conceptual basis in FLP-mediated hydrogen activation.

Effect of temperature and substitution on Cope rearrangement: a symmetry perspective.

Many reactions feature symmetry variation along the reaction path on the potential energy surface. The interconversion of the point group symmetry of the stationary points can be characteristic of these processes. Increasing the temperature, however, leads to the loss of symmetry in its traditional yes-no language. We find that in such cases the instantaneous distance of the molecular structure from its symmetric counterpart is a suitable collective variable that can describe the reaction process. We show that this quantity, the continuous symmetry measure (CSM), has a positive linear relationship with temperature, implying that even highly symmetric molecules should be considered as asymmetric above 0 K. Using ab initio molecular dynamics, we simulate the temperature-induced Cope rearrangements of several fluxional molecules and employ different CSMs to follow the reaction progress. We use this methodology to demonstrate the validity of important concepts governing these reactions: Woodward-Hoffmann rules and TS aromaticity. Statistical analysis of the CSM distributions reveals that ligands connected to the carbon frame have profound effect on the reaction course. In particular, our results show that lower temperatures tend to enhance the differences between the TS-stabilizing effect of the substituents.

Prediction of Redox Power for Photocatalysts: Synergistic Combination of DFT and Machine Learning.

The accurate prediction of excited state properties is a key element of rational photocatalyst design. This involves the prediction of ground and excited state redox potentials, for which an accurate description of electronic structures is needed. Even with highly sophisticated computational approaches, however, a number of difficulties arise from the complexity of excited state redox potentials, as they require the calculation of the corresponding ground state redox potentials and the estimation of the 0-0 transition energies (E0,0). In this study, we have systematically evaluated the performance of DFT methods for these quantities on a set of 37 organic photocatalysts representing 9 different chromophore scaffolds. We have found that the ground state redox potentials can be predicted with reasonable accuracy that can be further improved by rationally minimizing the systematic underestimations. The challenging part is to obtain E0,0, as calculating it directly is highly demanding and its accuracy depends strongly on the DFT functional employed. We have found that approximating E0,0 with appropriately scaled vertical absorption energies offers the best compromise between accuracy and computational effort. An even more accurate and cost-effective approach, however, is to predict E0,0 with machine learning and avoid the use of DFT for excited state calculations. Indeed, the best excited state redox potential predictions are achieved with the combination of M062X for ground state redox potentials and machine learning (ML) for E0,0. With this protocol, the excited state redox potential windows of the photocatalyst frameworks could be adequately predicted. This shows the potential of combining DFT with ML in the computational design of photocatalysts with preferred photochemical properties.

The nature of [PdCl(2)(C(2)H(4))(H(2)O)] as an active species in the Wacker process: new insights from ab initio molecular dynamics simulations.

First-principles molecular dynamics coupled with metadynamics have been used to gain a deeper insight into the reaction mechanism of the Wacker process by determining the nature of the active species. An explicit and dynamic representation of the aqueous solvent, which was essential for modeling this reaction, was efficiently included into the simulations. Prompted by our earlier results, which showed that the configuration of the catalytically active species [PdCl(2)(H(2)O)(C(2)H(4))] was crucial in the subsequent steps of the Wacker process, herein we focused on the preceding equilibria that led to the formation of both the cis and trans isomers. Starting from the initial catalyst, [PdCl(4)](2-), the free-energy barriers for the forward and backward reactions were calculated. These results confirmed the relevance of the trans intermediate in the reaction mechanism, whilst conversely, they showed that the cis configuration played no role in it. This sole participation of the trans intermediate has some very important implications; besides the mechanistic interpretation of the initial steps in the Wacker reaction mechanism, the analysis of these equilibria provides additional information about the chemical nature of these ligand-substitution processes.

Mechanism of the Pechmann reaction: a theoretical study.

One of the most widespread synthetic routes to coumarins is the condensation of esters and phenols via the Pechmann reaction. Despite the industrial and technological importance of the reaction, its mechanism is still poorly understood. We have explored several possible reaction paths by DFT calculations at the M05-2X/6-31+G* level. Amphoteric groups and the solvent have a crucial role in the frequent proton-transfer steps of the mechanisms; therefore, we have employed a mixed solvent model, where we combined the implicit PCM model together with an explicit water molecule placed at the actual proton transfer region. The Gibbs free-energy profiles of the possible routes suggest that three parallel channels (featuring water elimination, trans-esterification, and electrophilic attack) operate simultaneously. Enolic routes have prohibitively high activation barriers rendering these paths untenable. The calculated profiles indicate that in each feasible route the first elementary step has the highest activation energy. Reaction intermediates identified on the free-energy profiles can explain several experimental observations.

Multiscale Modeling of Electronic Spectra Including Nuclear Quantum Effects.

Theoretical prediction of electronic absorption spectra without input from experiments is no easy feat, as it requires addressing all of the factors that affect line shapes. In practice, however, the methodologies are limited to treat these ingredients only to a certain extent. Here, we present a multiscale protocol that addresses the temperature, solvent, and nuclear quantum effects as well as anharmonicity and the reconstruction of the final spectra from individual transitions. First, quantum mechanics/molecular mechanics (QM/MM) molecular dynamics is conducted to obtain trajectories of solute-solvent configurations, from which the corresponding quantum-corrected ensembles are generated through the generalized smoothed trajectory analysis (GSTA). The optical spectra of the ensembles are then produced by calculating vertical transitions using time-dependent density-functional theory (TDDFT) with implicit solvation. To obtain the final spectral shapes, the stick spectra from TDDFT are convoluted with Gaussian kernels where the half-widths are determined by a statistically motivated strategy. We have tested our method by calculating the UV-vis spectra of a recently discovered acridine photocatalyst in two redox states. Vibronic progressions and broadenings due to the finite lifetime of the excited states are not included in the methodology yet. Nuclear quantization affects the relative peak intensities and widths, which is necessary to reproduce the experimental spectrum. We have also found that using only the optimized geometry of each molecule works surprisingly well if a proper empirical broadening factor is applied. This is explained by the rigidity of the conjugated chromophore moieties of the selected molecules, which are mainly responsible for the excitations in the spectra. In contrast, we have also shown that other parts of the molecules are flexible enough to feature anharmonicities that impair the use of other techniques such as Wigner sampling.

The ortho effect in directed C-H activation.

The success of transition metal-catalysed ortho-directed C-H activation is often plagued by the effects of undesirable interactions between the directing group (DG) and other groups introduced into the aromatic core of the substrate. In particular, when these groups are in neighbouring positions, their interactions can affect profoundly the efficacy of the C-H activation by transition metals. In this work we introduce a simple substrate-only-based model to interpret the influence of steric hindrance of a group in ortho position to the DG in directed ortho-C-H bond activation reactions, and coined the term Ortho Effect (OE) for such situations. We consider simple descriptors such as torsion angle and torsional energy to predict and explain the reactivity of a given substrate in directed C-H activation reactions. More than 250 examples have been invoked for the model, and the nature of the ortho effect was demonstrated on a wide variety of structures. In order to guide organic chemists, we set structural and energetic criteria to evaluate a priori the efficiency of the metalation step which is usually the rate-determining event in C-H activations, i.e. we provide a simple and general protocol to estimate the reactivity of a potential substrate in C-H activation. For borderline cases these criteria help set the minimum reaction temperature to obtain reasonable reaction rates. As an example for the practical applicability of the model, we performed synthetic validations via palladium-catalysed 2,2,2-trifluoroethylation reactions in our lab. Furthermore, we give predictions for the necessary reaction conditions for several selected DGs.

The Wacker process: inner- or outer-sphere nucleophilic addition? New insights from ab initio molecular dynamics.

The Wacker process consists of the oxidation of ethylene catalyzed by a Pd(II) complex. The reaction mechanism has been largely debated in the literature; two modes for the nucleophilic addition of water to a Pd-coordinated alkene have been proposed: syn-inner- and anti-outer-sphere mechanisms. These reaction steps have been theoretically evaluated by means of ab initio molecular dynamics combined with metadynamics by placing the [Pd(C(2)H(4))Cl(2)(H(2)O)] complex in a box of water molecules, thereby resembling experimental conditions at low [Cl(-)]. The nucleophilic addition has also been evaluated for the [Pd(C(2)H(4))Cl(3)](-) complex, thus revealing that the water by chloride ligand substitution trans to ethene is kinetically favored over the generally assumed cis species in water. Hence, the resulting trans species can only directly undertake the outer-sphere nucleophilic addition, whereas the inner-sphere mechanism is hindered since the attacking water is located trans to ethene. In addition, all the simulations from the [Pd(C(2)H(4))Cl(2)(H(2)O)] species (either cis or trans) support an outer-sphere mechanism with a free-energy barrier compatible with that obtained experimentally, whereas that for the inner-sphere mechanism is significantly higher. Moreover, additional processes for a global understanding of the Wacker process in solution have also been identified, such as ligand substitutions, proton transfers that involve the aquo ligand, and the importance of the trans effect of the ethylene in the nucleophilic addition attack.