Distortion-interaction Analysis Research Articles

Modelling on a Biomimetic [Cu-O-Cu]2+-mediated Methane-to-Methanol Conversion Unveils the Site for Methane Activation.

The Cu-O-Cu core exhibits methane-to-methanol conversion, mirroring the reactivity of the copper-containing enzyme pMMO. Herein, we computationally examined the reactivity of a biomimetic Cu-O-Cu core towards methane-to-methanol conversion. The oxygen atom of the Cu-O-Cu core abstracts hydrogen present in the C-H bond of methane. The spin density at the bridging oxygen helps to abstract hydrogen from the C-H bond. We modulated the spin density of the bridging oxygen by substituting only a single copper atom of the Cu-O-Cu core by metals (M) such as Fe, Co, and Ag. These substitutions result in bimetallic [Cu-O-M]2+ models. We observed that the energy barriers for the C-H activation step and the subsequent rebound step vary with the metal M. [Cu-O-Ag]2+ exhibits the highest reactivity for M2M conversion, while [Cu-O-Fe]2+ displays the lowest reactivity. To understand the different reactivity of these models towards M2M conversion, we employed distortion-interaction analysis, orbital analysis, spin density analysis, and quantum theory of atoms in molecules analysis. Orbital analysis reveals that all four adducts follow a hydrogen atom transfer mechanism for C-H activation. Further, spin density analysis reveals that a higher spin density on the bridging oxygen leads to a lower C-H activation barrier.

In Silico Investigation of Palladium-Catalyzed Chemoselective Monoalkoxycarbonylation of 1,3-diynes for Conjugated Enynes Synthesis.

The palladium-catalyzed monoalkoxycarbonylation of 1,3-diynes provides a chemoselective method for the construction of synthetically useful conjugated enynes. Here, in silico unraveling the detailed mechanism of this reaction and the origin of chemoselectivity were conducted. It is shown that the alkoxycarbonylation reaction preferably proceeds by a NH-Pd pathway, which including three substeps: hydropalladation, CO migratory insertion and methanolysis. The effectiveness of the NH-Pd catalytic system is attributed to the alkynyl-palladium π-back-bonding interaction, C-H⋅⋅⋅π interaction in reactant moiety and d-pπ conjugation between the Pd center and alkenyl group. The hydropalladation step was identified as the rate- and chemoselectivity-determining step, and the first alkoxycarbonylation requires a much lower energy barrier in comparison with the second alkoxycarbonylation, in line with the experimental outcomes that the monoalkoxycarbonylation product was obtained in high yield. Distortion-interaction analysis indicates the more favorable monoalkoxycarbonylation (compared to double alkoxycarbonylation) is caused by steric effect.

Mapping the Catalytic-Space for the Reactivity of Metal-free Boron Nitride with O2 for H2O-Mediated Conversion of Methane to HCHO and CO.

Transition-metal based catalysts have been widely employed to catalyze partial oxidation of light alkanes. Recently, metal-free hexagonal-boron nitride (h-BN) has emerged as a promising catalyst for the oxidation of CH4 to HCHO and CO; however, the intricate catalytic surface of h-BN at molecular and electronic levels remains inadequately understood. Key questions include how electron-deficient boron atoms in h-BN reduce O2, and whether the partial oxidation of methane over h-BN exhibits similarities to traditional transition-metal catalysts. In our study, we computationally-mapped in-detail the surface catalytic-space of h-BN for methane oxidation. We considered different structures of h-BN and show that these structures contain numerous sites for O2 binding and therefore various routes for methane oxidation are possible. The activation barriers for methane oxidation via various paths varies from ~83 to ~123 kcal mol-1. To comprehend the differences in activation barriers, we employed geometrical, orbital and distortion/interaction analysis (DIA). Orbital analysis reveals that methane activation over h-BN in presence of dioxygen follows a standard hydrogen atom transfer mechanism. It is also shown that water plays an intriguing role in reducing the barrier for HCHO and CO formation by acting as a bridge.

Mechanistic Details of the Titanium-Mediated Polycondensation Reaction of Polyesters: A DFT Study

In this work, the mechanism of polyester polycondensation catalysed by titanium catalysts was investigated using density functional theory (DFT). Three polyester polycondensation reaction mechanisms, including the Lewis acid mechanism (M1), the coordination of the ester alkoxy oxygen mechanism (M2) and the coordination of the carboxy oxygen mechanism (M3), were investigated. Three reaction mechanisms for the polycondensation reaction of diethyl terephthalate (DET) were investigated using Ti(OEt)4 and cationic Ti(OEt)3+ as the catalyst. The results show that the polycondensation reaction of the Lewis acid mechanism exhibits similar energy barriers to the catalyst-free condition (42.6 kcal/mol vs. 47.6 kcal/mol). Mechanism M3 gives the lowest energy barrier of 17.5 kcal/mol, indicating that Ti(OEt)4 is the active centre for the polycondensation reaction. The catalytic efficiency of Ti(OEt)3+ is lower than that of Ti(OEt)4 catalysts due to its higher DET distortion energy (67.6 kcal/mol vs. 37.4 kcal/mol) by distortion–interaction analysis.

Theoretical insight into the acceptorless dehydrogenation catalyzed by the transition metal bifunctional catalysts: Mechanism and metal effect

In this paper, the density functional theory study was performed to investigate the reaction mechanism of acceptorless dehydrogenation catalyzed by bifunctional catalysts. The calculation results indicate that the catalyst bearing the Co(III) center adopts the inner-sphere stepwise dehydrogenation mechanism. The H2 formation was found to be the rate-determining step, and the proton-shuttle type transition state effectively reduces the activation energy barrier. Furthermore, the catalytic activities of the noble metals (Rh and Ir) were investigated and compared. The results suggest that the noble metals prefer the outer-sphere bifunctional transfer mechanism for the dehydrogenation reaction. Frontier molecular orbital analysis shows that the HOMO-LUMO gap of the active species increases along with the periodic number, which leads to a weakening of the coordination strength of the substrate to the metal center, resulting in the different mechanistic selectivity toward dehydrogenation reaction. In addition, based on the distortion-interaction analysis, the different activation energy barrier in the H2 formation step is illuminated. The reduced ionic radii of the Co result in lower deformation energies of the catalyst and substrate structures in the H2 formation transition state, thus lowering the activation energy barrier. Our results reveal the advantages of base metal in dehydrogenation reactions, which is expected to provide theoretical guidance for future catalyst design.

Chloride-Mediated Alkene Activation Drives Enantioselective Thiourea and Hydrogen Chloride Co-Catalyzed Prins Cyclizations.

The mechanism of chiral hydrogen-bond donor (HBD) and hydrogen chloride (HCl) co-catalyzed Prins cyclizations was analyzed through a combination of experimental and computational methods and revealed to involve an unexpected and previously unrecognized mode of alkene activation. Kinetic and spectroscopic studies support the participation of a catalytically active HCl·HBD complex that displays reduced Brønsted acidity relative to HCl alone. Nevertheless, rate acceleration relative to the HCl-catalyzed background reaction as well as high levels of enantioselectivity are achieved. This inverse Brønsted correlation is ascribed to chloride-mediated substrate activation in the rate-limiting and enantiodetermining cyclization transition state. Density functional theory (DFT) calculations, distortion-interaction analysis, and quasiclassical dynamics simulations support a stepwise mechanism in which rate acceleration and enantioselectivity are achieved through the precise positioning of the chloride anion within the active site of the chiral thiourea to enhance the nucleophilicity of the alkene and provide transition-state stabilization through local electric field effects. This mode of selective catalysis through anion positioning likely has general implications for the design of enantioselective Brønsted acid-catalyzed reactions involving π-nucleophiles.

Interplay between the Directing Group and Multifunctional Acetate Ligand in Pd-Catalyzed anti-Acetoxylation of Unsymmetrical Dialkyl-Substituted Alkynes.

The cooperative action of the acetate ligand, the 2-pyridyl sulfonyl (SO2Py) directing group on the alkyne substrate, and the palladium catalyst has been shown to be crucial for controlling reactivity, regioselectivity, and stereoselectivity in the acetoxylation of unsymmetrical internal alkynes under mild reaction conditions. The corresponding alkenyl acetates were obtained in good yields with complete levels of β-regioselectivity and anti-acetoxypalladation stereocontrol. Experimental and computational analyses provide insight into the reasons behind this delicate interplay between the ligand, directing group, and the metal in the reaction mechanism. In fact, these studies unveil the multiple important roles of the acetate ligand in the coordination sphere at the Pd center: (i) it brings the acetic acid reagent into close proximity to the metal to allow the simultaneous activation of the alkyne and the acetic acid, (ii) it serves as an inner-sphere base while enhancing the nucleophilicity of the acid, and (iii) it acts as an intramolecular acid to facilitate protodemetalation and regeneration of the catalyst. Further insight into the origin of the observed regiocontrol is provided by the mapping of potential energy profiles and distortion–interaction analysis.

Synthesis of Alkenylboronates from N-Tosylhydrazones through Palladium-Catalyzed Carbene Migratory Insertion.

The palladium-catalyzed oxidative borylation reaction of N-tosylhydrazones has been developed. The reaction features mild conditions, broad substrate scope, and good functional group tolerance. It thus represents a highly efficient and practical method for the synthesis of di-, tri-, and tetrasubstituted alkenylboronates from readily available N-tosylhydrazones. One-pot Suzuki coupling and other transformations highlight the synthetic utility of the approach. DFT calculations have revealed that palladium-carbene formation and subsequent boryl migratory insertion are the key steps in the catalytic cycle. The high stereoselectivity observed in the formation of trisubstituted alkenylboronates has been explained by distortion-interaction analysis and NBO analysis.

Fluorine Effects for Tunable C–C and C–S Bond Cleavage in Fluoro-Julia–Kocienski Intermediates

Classical Julia–Kocienski fluoroolefination represents an indispensable platform for the construction of monofluoroalkenes. Nevertheless, its complex multistep mechanistic manifold along with the u...

Insights into the Regioselectivity of Hydroheteroarylation of Allylbenzene with Pyridine Catalyzed by Ni/AlMe3 with N-Heterocyclic Carbene: The Concerted Hydrogen Transfer Mechanism.

The hydroheteroarylation of allylbenzene with pyridine as catalyzed by Ni/AlMe3 and a N-heterocyclic carbene ligand has recently been established. Density functional calculations revealed that the common stepwise pathway, which involves the C-H oxidative addition of pyridine-AlMe3 before the migratory insertion of allylbenzene, is unlikely as the migratory insertion needs to overcome a prohibitively high energy barrier. In contrast, the ligand-to-ligand hydrogen transfer pathway is more favorable in which the hydrogen is transferred directly from the para-position of pyridine-AlMe3 to C2 of allylbenzene. Our distortion-interaction analysis and natural bond orbital analysis indicate that the interaction energy is strongly correlated with the extent of the charge transfer from the alkene (hydrogen acceptor) to the pyridine-AlMe3 (hydrogen donor), which dictates the selectivity of the H-transfer to the C2 position of allylbenzene. Then, the subsequent C-C reductive elimination of the regioselective linear product is facilitated by the steric hindrance of the IPr ligand. Understanding these key factors affecting the product regioselectivity is important to the development of catalysts for hydroheteroarylation of alkenes.

Oxidative Addition Promoted C–C Bond Cleavage in Rh-Mediated Cyclopropenone Activation: A DFT Study

Computational characterization of the oxidation addition promoted in rhodium-catalyzed cyclopropenone activation and conversion via quinolyl-, pyridyl-, and nitrone-directed C–H activation is presented. Our theoretical studies found that a common catalytic cycle for these reactions starts with Rh(III)-mediated concerted metalation–deprotonation or electrophilic deprotonation to afford the aryl-Rh(III) intermediate. Oxidative addition of cyclopropenone to aryl-Rh(III) then gives a cyclorhoda(V)butanone intermediate, leading to the cleavage of the cyclopropene moiety through a concerted three-membered cyclic transition state. Subsequent reductive elimination of the intermediate generates a target C(aryl)–C(acyl) bond. The final product is produced by further transformations with concomitant regeneration of active Rh(III) catalyst. The previously proposed carbonyl insertion mode for the activation of cyclopropenones is excluded by the density functional theory calculations. The directing group effect in cyclopropenone activation was theoretically investigated. Distortion–interaction analysis, noncovalent interaction analysis, and global electrophilicity/nucleophilicity index calculations reveal the lower oxidation addition reactivity with the nitrone directing group, which is coincident with experimental observations. Distortion–interaction analysis was also performed to reveal the regioselectivity of the oxidative addition with asymmetrical cyclopropenones.

Mechanism and Origin of Enantioselectivity in Nickel-Catalyzed Alkyl-Alkyl Suzuki Coupling Reaction.

Enantioselective Suzuki coupling reactions are a widely used method in asymmetric synthesis of chiral compounds. In an important extension of this protocol, 1-bromo-1-fluoroalkanes were coupled with alkyl-9-BBN using chiral NiCl2L* as the catalyst (where L* = bis(pyrrolidine) ligand) under Suzuki conditions to obtain a product with a stereogenic center bearing a fluorine. In view of the current interest in chiral fluorine-containing compounds as well as lack of clarity on the mechanism of Ni-catalyzed asymmetric Suzuki coupling reactions, we decided to examine various mechanistic pathways of the title reaction. The (U)M06 density functional theory computations have been employed to identify the energetically preferred pathway first and then to probe the origin of high enantioselectivity. In particular, we have compared the likely involvement of different redox couples such as Ni(0)/Ni(II) and Ni(I)/Ni(III) in the catalytic cycle. For the Ni(0)/Ni(II) pathway, both singlet and triplet spin states have been considered whereas a doublet spin multiplicity has been examined in the case of the Ni(I)/Ni(III) system. The most preferred catalytic pathway is found to proceed through a Ni(I)/Ni(III) redox cycle with key mechanistic steps such as (a) a transmetalation involving the transfer of the alkyl group of 9-BBN to the Ni-catalyst, (b) an oxidative addition of bromo(fluoro) alkane to give a penta-coordinate Ni(III) intermediate, and (c) an enantio-controlling reductive elimination (RE) that facilitates the C-C bond formation between the Ni-bound fluoroalkyl and alkyl moieties to yield the final product. The transmetalation is found to be the turnover determining transition state (TS) according to the activation span model. The RE is found to be the enantio-controlling step, wherein the TS for the addition of the si prochiral face of the Ni-bound fluoro alkyl moiety to the alkyl group is 4.3 kcal/mol lower than the corresponding re face addition. Distortion-Interaction analysis suggested that the extent of distortion in the catalyst Ni(Br)L* fragment in the si face reductive elimination TS is much lower than in the re face addition, thus making a vital contribution to the energy difference between diastereomeric TS.

Modeling Decomposition of N-Nitrosoamides in a Self-Assembled Capsule.

Density functional theory calculations are employed to investigate the mechanism and energies of the decomposition of N-nitrosoamides in the presence of a resorcinarene-based self-assembled nanocapsule. From experiments, it is known that confinement in the capsule inhibits the thermal decomposition of these compounds. N-Nitrosoamides with both aromatic and aliphatic substituents are considered here and the calculations show that, for both kinds, binding to the capsule leads to a significant increase in the energy barrier of the rate-determining step, the 1,3 N→O acyl transfer reaction. A distortion-interaction analysis is conducted to probe the reasons behind the inhibition of the reaction. In addition, we characterized hypothetical intermediates that might be involved in the formation of the decomposition products inside the capsule. Interestingly, it is found that the capsule stabilizes ion-pair species that are unstable in mesitylene solution. Finally, a possible explanation is proposed for the observed encapsulation of the decomposition product of only one of the substrates.

Theoretical study on the base-controlled selective linear or branched ortho-alkylation of azines catalyzed by rhodium: Mechanisms and the role of base

The detailed theoretical study on the mechanism of the alkylation of 3-trifluoromethylpyridine with acrylamide in the [RhI]/dppe catalytic system is reported, with the aid of the density functional theory (DFT) calculations. It is found that the additive bases play a critical role in switching the regioselectivity. The origin of the regioselectivity involved in these reactions was probed by performing distortion-interaction analysis. For reaction A with KOPiv as the base, the outer-sphere concerted-metallative-deprotonation (CMD) pathway is calculated to be a bit more favorable kinetically compared with the oxidative addition (OA) one and the two mechanisms are competitive. The regioselectivity in this reaction is predicted to be determined by the distortion energies of the migratory insertion transition states. In contrast, for reaction B with K3PO4 as the base, the feasible pathway is the OA one, and the corresponding interaction energies for the olefin migratory insertion into Rh–H bond step could account for the observed regioselectivity.

Probing the Structural and Electronic Effects on the Origin of π-Facial Stereoselectivity in 1-Methylphosphole 1-Oxide Cycloadditions and Cyclodimerization

We have examined the π-facial stereoselectivity in the Diels–Alder reactions of phosphole oxides computationally. The experimentally observed syn-cycloadditions have been rationalized with the Cieplak model and distortion–interaction model. The natural bond orbital analysis suggests that the hyperconjugative interactions are energetically preferred between the antiperiplanar methyl group present in the −P=O unit and the developing incipient (−C–C−) bond in syn-adducts in accordance with the Cieplak model. The distortion–interaction analysis carried out for syn and anti transition states of Diels–Alder reactions of 1-substituted phosphole 1-oxide with different dienophiles reveals that the syn selectivity is favored by distortions and interaction energies compared with the anti selectivity. The formation of a syn adduct is also stabilized by the πCC–σ*PO orbital interaction, and the repulsive n−π interaction destabilizes the anti adduct that leads to the 7.0 kcal/mol thermodynamic preference for the former adduct. Furthermore, the distortion–interaction model rationalizes the formation of stereospecific products in these Diels–Alder reactions, which however is not explicable with the much-debated Cieplak model.

Mechanistic insight into cobalt-catalyzed stereodivergent semihydrogenation of alkynes: The story of selectivity control

Selectivity control is a challenging and important subject in semihydrogenation of alkynes. Here, a combined theoretical and experimental study was performed to reveal the origin of the chemo- and stereoselectivity in cobalt-catalyzed stereodivergent semihydrogenation of alkynes. Three NNP and PNP type pincer ligands were considered in calculation. The computational results show that over-reduction of the alkene is forbidden in this catalytic system because the alkylcobalt(I) intermediate formed by alkene insertion prefers to undergo β-H elimination rather than protonation of the CoC bond. Distortion–interaction analysis along the reaction coordinate suggests that the higher distortion energy during methanol-mediated protonation of the alkylcobalt(I) species suppresses formation of the side product, thereby determined the chemoselectivity. Mechanistic investigation reveals that the active cobalt(I) hydride species formed by pre-catalyst [C] has strong catalytic activity for alkene isomerization. Subsequent control experiments combined with free energy comparison confirms this conclusion and reveals that fast deactivation of catalyst and the weaker reactivity of the cis-alkene intermediate in the presence of the alkyne substrate prevents Z/E alkene isomerization using pre-catalyst [C]. This results in the divergent stereoselectivity in the presence of different cobalt pincer complexes.

Origins of Stereoselectivity in Mannich Reactions Catalyzed by Chiral Vicinal Diamines.

The origins of the enantio- and diastereoselectivities in the Mannich reactions between aldehydes and ketimines catalyzed by chiral vicinal diamines have been determined by density functional theory calculations and distortion-interaction analysis. Computational results indicate a strong energetic preference for hydrogen-bonded nine-membered cyclic transition states. The favored transition states involve eight heavy atoms in the crown (chair-chair) conformation using the nomenclature of the analogous cyclic hydrocarbons. Energetic discrimination in the chirality-imparting step arises from pseudogauche-butane-type interactions in the disfavored transition states, as well as steric clashes between the N-Boc protecting group and the ammonium N-substituents.

Origins of Enantioselectivity in Asymmetric Radical Additions to Octahedral Chiral-at-Rhodium Enolates: A Computational Study

The origin of asymmetric induction in the additions of carbon- and nitrogen-centered radicals to octahedral centrochiral rhodium enolates has been investigated with density functional theory calculations. Computed free energies of activation reproduce the preference for the experimentally observed major enantiomer. Good levels of enantioselectivity are maintained upon replacement of the bulky tert-butyl substituents on the ligands with methyl groups. Distortion-interaction analysis indicates that for both carbon- and nitrogen-centered radicals, which have relatively early and late transition states, respectively, the difference in the distortion energies controls the enantioselectivity. In the enolate derived from the Λ-configured catalyst, the tert-butyl group that shields the si face of the substrate plays the most sterically significant steric role by directly hindering access to the enolate double bond. Exploration of the effect of the N substituent size and shape on the imidazole substrate shows that compared to N-Me, N-iPr and N-Ph variants, the N-o-tolyl variant of the rhodium enolate results in the most substantial improvement in stereodiscrimination, a finding that is in agreement with experimental ee values.

Mechanism, Regio-, and Diastereoselectivity of Rh(III)-Catalyzed Cyclization Reactions of N-Arylnitrones with Alkynes: A Density Functional Theory Study.

Nitrones have been used for rhodium-catalyzed cyclization C-H bond activation and O atom transfer of arylnitrones with alkynes by Chang et al. ( J. Am. Chem. Soc. 2015 , 137 , 4908 - 4911 ). Density functional theory method has been used to study the mechanism, regio-, and diastereoselectivity of type reactions. The results elucidated that the reaction pathway for Rh(III)-catalyzed cyclization of N-arylnitrones with alkyne contains a C-H bond activation, an alkyne insertion into Rh-C bond, a reductive elimination to form a Rh(I) complex, an oxidative addition leading to N-O cleavage, an imine insertion into the Rh-C bond, and the final protonolysis to regenerate the products and the active catalyst. The regioselectivity of this reaction with asymmetric alkyne is controlled by the electronic effect in alkyne insertion type instead of steric effects. The distortion-interaction analysis is also used to explain the regioselectivity. The diastereoselectivity is controlled by the imine insertion step. In this step, the sterically less hindered transition state is favored, leading to stereoselective product formation.

Cinchona Alkaloid-Squaramide Catalyzed Sulfa-Michael Addition Reaction: Mode of Bifunctional Activation and Origin of Stereoinduction.

The mechanism of the enantioselective sulfa-Michael addition reaction catalyzed by a cinchona alkaloid-squaramide bifunctional organocatalyst was studied using density functional theory (DFT). Four possible modes of dual activation mechanism via hydrogen bonds were considered. Our study showed that Houk's bifunctional Brønsted acid-hydrogen bonding model, which works for cinchonidine or cinchona alkaloid-urea catalyzed sulfa-Michael addition reactions, also applies to the catalytic system under investigation. In addition, we examined the origin of the stereoselectivity by identifying stereocontrolling transition states. Distortion-interaction analysis revealed that attractive interaction between the substrates and catalyst in the C-S bond forming transition state is the key reason for stereoinduction in this catalytic reaction. Noncovalent interaction (NCI) analysis showed that a series of more favorable cooperative noncovalent interactions, namely, hydrogen bond, π-stacking, and C-H···π interaction and C-H···F interactions, in the major R-inducing transition state. The predicted enantiometric excess is in good accord with the observed value.