Origin Of Regioselectivity Research Articles

Noncovalent Interactions in Palladium(II)-Catalyzed Meta-Selective C-H Functionalization: Mechanistic Insights and Origins of Regioselectivity.

The use of noncovalent interactions to control the regioselectivity of transition metal-catalyzed C-H functionalization of arenes has received significant attention in recent years. Herein, we present a mechanistic study based on Density Functional Theory (DFT) of palladium(II)-catalyzed meta-selective C-H olefination employing a noncovalent directing template. We analyze the key steps of the mechanism and discuss the origins of reaction selectivity. The role of the directing template was elucidated, demonstrating its essential function in lowering reaction barriers and controlling selectivity. Our results reveal a competition in activation between ortho- and meta-C-H bonds. Contrary to the previous proposal in the literature, hydrogen bonds between the N-H bonds of the urea moiety and the carbonyl oxygen of the substrate predominantly favor ortho-selectivity over meta-selectivity. DFT results, alongside Quantum Theory of Atoms in Molecules (QTAIM) and Non-Covalent Interaction Index analysis, suggest that secondary interactions between the R group linked to the urea moiety and the catalyst exert a more pronounced influence compared to the aforementioned hydrogen bonds, directing the selectivity towards the meta C-H bond.

Investigations via Kinetics and Multivariate Linear Regression Models of the Mechanism and Origins of Regioselectivity in a Palladium-Catalyzed Aryne Annulation

Investigations via Kinetics and Multivariate Linear Regression Models of the Mechanism and Origins of Regioselectivity in a Palladium-Catalyzed Aryne Annulation

Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydroaminoalkylation of Unactivated Alkenes.

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N-sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tritert-butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % Vbur (min), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

Ni0-Catalyzed Regioselective [2 + 2 + 2] Cyclotrimerization of 1,3-Diynes: An Expeditious Synthesis of Hexasubstituted Alkynyl Benzenes.

In the present work, we demonstrate a regioselective [2 + 2 + 2] cyclotrimerization of 1,3-diynes catalyzed by Ni0 to provide hexasubstituted benzenes (HSBs). HSBs have significant applications as functional materials and pharmaceuticals. The present protocol exhibited remarkable versatility, transforming 1,3-diynes with diverse alkyl, aryl, and heterocyclic groups to the corresponding HSBs. With the help of control experiments and density functional theory (DFT), the mechanism of the reaction and the origin of regioselectivity were elucidated.

Origin of Ligand and Acid Effects on the Pd-Catalyzed Regiodivergent Coupling Reaction of Indazoles and Isoprene: A DFT Study.

Comprehensive computational studies were carried out to explore the mechanisms and origin of regioselectivity in the Pd-catalyzed regiodivergent coupling reaction of indazoles and isoprene. Three different insertion models were investigated for regioselectivity 1,2- or 4,3-insertion with respect to the electrophilic sites on isoprene under two different ligands (L1 and L2) and acids ((PhO)2PO2H, (nBuO)2PO2H) via PdII-H species, allyl-π-PdII-O, and indazoles-acid-assisted PdII-π-allyl. The calculated results show that the PdII-π-allyl coordinated mechanism is the most preferred one. The noncovalent interactions between the less bulky ligand L1, substrates, and (PhO)2PO2- are found to be key factors for 1,2-insertion. The 4,3-insertion selectivity is primarily controlled by the steric repulsion of the t-Bu group of bulky ligand L2 and substrate, as well as the geometry distortion. Therefore, the regioselectivity difference of the 1,2- and 4,3-insertion on electrophilic sites is controlled by the synergistic effect of ligands and acids instead of the size of the ligand. Similarly, nucleophilic site selectivity at N1 or N2 of indazoles is governed by cooperative acid BF3 and solvent iPrOH rather than BF3 alone. Overall, our findings might open a new avenue for designing more efficient regioselective 1,2- or 4,3-addition or N1-/N2-selective nucleophilic reactions.

Asymmetric formal C–C bond insertion into aldehydes via copper-catalyzed diyne cyclization

The formal C–C bond insertion into aldehydes is an attractive methodology for the assembly of homologated carbonyl compounds. However, the homologation of aldehydes has been limited to diazo approach and the enantioselective reaction was rarely developed. Herein, we report an asymmetric formal C–C bond insertion into aldehydes through diyne cyclization strategy. In the presence of Cu(I)/SaBOX catalyst, this method leads to the efficient construction of versatile axially chiral naphthylpyrroles in moderate to excellent yields with good to excellent enantioselectivities. This protocol represents a rare example of asymmetric formal C–C bond insertion into aldehydes using non-diazo approach. The combined experimental and computational mechanistic studies reveal the reaction mechanism, origin of regioselectivity and stereoselectivity. Notably, the chiral phosphine ligand derived from synthesized axially chiral skeleton was proven to be applicable to asymmetric catalysis.

Control of meta-selectivity in the Ir-catalyzed aromatic C-H borylation directed by hydrogen bond interaction: A combined computational and experimental study

The origin of regioselectivity in meta-selective C-H borylation of benzamides directed by hydrogen bond interaction between ligand and substrate is elucidated through combined computational and experimental studies. We discover that a non-directed pathway, in which the urea moiety in ligand recognizes the O atom in Bpin instead of substrate, competes with the directed pathway and erodes the meta-selectivity. The non-directed pathway is sensitive to steric repulsion between Bpin and urea, and thus can be impeded by introducing a bulky substituent into the urea moiety. Accordingly, we optimize the ligand and improve the meta-selectivity in the Ir-catalyzed C-H borylation of some previously reported unsuccessful arenes.

Regio‐ and Stereoselective 1,2‐Oxyhalogenation of Non‐Conjugated Alkynes via Directed Nucleopalladation: Catalytic Access to Tetrasubstituted Alkenes**

AbstractA catalytic 1,2‐oxyhalogenation method that converts non‐conjugated internal alkynes into tetrasubstituted alkenes with high regio‐ and stereoselectivity is described. Mechanistically, the reaction involves a PdII/PdIV catalytic cycle that begins with a directed oxypalladation step. The origin of regioselectivity is the preference for formation of a six‐membered palladacycle intermediate, which is facilitated by an N,N‐bidentate 2‐(pyridin‐2‐yl)isopropyl (PIP) amide directing group. Selectivity for C(alkenyl)−X versus −N (X=halide) reductive elimination from the PdIV center depends on the identity of the halide anion; bromide and iodide engage in C(alkenyl)−X formation, while intramolecular C(alkenyl)−N reductive elimination occurs with chloride to furnish a lactam product. DFT calculations shed light on the origins of this phenomenon.

A molecular electron density theory study on the Chichibabin reaction: The origin of regioselectivity

A Molecular Electron Density Theory (MEDT) study was performed on the nucleophilic amination of pyridine and benzene to elucidate the observed regioselectivity in the Chichibabin reaction. For this purpose, three possible reaction paths were considered between NaNH2 and the 2-, 3- and 4-positions of pyridine. The reaction of NaNH2 and benzene was also investigated. The results indicated that in each reaction, the first step involves the nucleophilic attack of the NH2‾ ion toward the aromatic system to produce an anionic intermediate. The second step, proceeds via hydride elimination of the anionic intermediate to produce the corresponding aromatic amine. This step is more favourable both kinetically and thermodynamically for the reaction at the 2-position of pyridine relative to the 4-position. In contrast to the Parr functions analysis which indicates that the 4-position is activated more electrophilically in pyridine, the PES analysis reveals that the 2-position attack with the NH2‾ ion is more favourable both thermodynamically and kinetically. The results for the reaction of sodium amide and benzene indicated that this reaction is not feasible due to the high activation barriers. In consistent with the experimental results, the ELF analysis indicated that in the first step of the reaction between pyridine and sodium amide, the formation of the C2–N bond takes place via a pseudoradical coupling between the C2 carbon atom of pyridine and the N atom of NaNH2. These variations occur in the second-half of the first step of the reaction. NCI analysis on the reaction revealed that the more attractive forces between the fragments, make the transition states for the 2-position attack more stable relative to the others. Thus, the NCI analysis can satisfactorily describe the observed regioselectivity in the Chichibabin reaction.

Theoretical studies on Mn-catalyzed intermolecular allylic C-H aminations of internal olefins: mechanism, chemo- and regioselectivity

The mechanism, chemo- and regioselectivity of Mn-catalyzed intermolecular C-H amination of internal olefin have been studied using B3LYP functional. The internal allylic C-H amination mechanism involves three steps: PhI extrusion, Hydride transfer and in situ coupling of C and N atoms. More importantly, the origin of regioselectivity is revealed via comparative investigations into aminations of three alkene substrates. Based on our calculated results, one can expect that for a new Mn-catalyzed internal olefin amination system, the regioselectivity toward in situ generation of amine can be significantly increased via the introduction of a bulky, strong electron-withdrawing group on the substrate at the position away from the targeted C-H bond. Such a Mn-catalyzed regioselectivity was theoretically investigated for the first time, which is useful toward the future design and development of highly regioselective amination system.

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study.

An experimental and theoretical investigation on the iridium-catalyzed hydroacylation of C1-substituted oxabenzonorbornadienes with salicylaldehyde is reported. Utilizing commercially available [Ir(COD)Cl]2 in the presence of 5 M KOH in dioxane at 65 °C, provided a variety of hydroacylated bicyclic adducts in up to a 95% yield with complete stereo- and regioselectivity. The mechanism and origins of selectivity in the iridium-catalyzed hydroacylation reaction has been examined at the M06/Def2TZVP level of theory. The catalytic cycle consists of three key steps including oxidative addition into the aldehyde C–H bond, insertion of the olefin into the iridium hydride, and C–C bond-forming reductive elimination. Computational results indicate the origin of regioselectivity is involved in the reductive elimination step.

Allylic C(sp3)–H arylation of olefins via ternary catalysis

Transforming C(sp3)–H bonds efficiently and selectively into C(sp3)–C(sp3) or C(sp3)–X bonds is a highly relevant task. The direct arylation of allylic C(sp3)–H bonds provides an elegant method for the formation of unconjugated aryl-substituted olefins. Although both ionic- and radical-based transition metal catalysis has been applied to achieve this transformation, numerous challenges remain. The requirement for persistent radical coupling partners, moderate selectivity and the need for tri- or tetrasubstituted olefins have limited the generality of existing methods. Now we report a ternary catalytic method that combines organic photoredox, hydrogen atom transfer and nickel catalysis, and can directly arylate allylic C(sp3)–H bonds of readily available olefins. This process operates under mild conditions and exhibits a remarkable reaction scope in both aryl halide and olefin coupling partners. Mechanistic experiments, coupled with density functional theory calculations of Ni-oxidation states and reaction energetics allowed the elucidation of a ternary catalytic cycle and the origin of regioselectivity. A ternary catalytic method combining organic photoredox, hydrogen atom transfer and nickel catalysis is reported. This combination can directly arylate the allylic C(sp3)–H bonds of a broad range of readily available olefins. Mechanistic experiments, coupled with density functional theory calculations aid the elucidation of the ternary catalytic cycle and the origin of regioselectivity.

Investigations into mechanism and origin of regioselectivity in the metallaphotoredox-catalyzed α-arylation of N-alkylbenzamides.

A mechanistic study on the α-arylation of N-alkylbenzamides catalyzed by a dual nickel/photoredox system using aryl bromides is reported herein. This study elucidates the origins of site-selectivity of the transformation, which is controlled by the generation of a hydrogen atom transfer (HAT) agent by a photocatalyst and bromide ions in solution. Tetrabutylammonium bromide was identified as a crucial additive and source of a potent HAT agent, which led to increases in yields and a lowering of the stoichiometries of the aryl bromide coupling partner. NMR titration experiments and Stern–Volmer quenching studies provide evidence for complexation to and oxidation of bromide by the photocatalyst, while elementary steps involving deprotonation of the N-alkylbenzamide or 1,5-HAT were ruled out through mechanistic probes and kinetic isotope effect analysis. This study serves as a valuable tool to better understand the α-arylation of N-alkylbenzamides, and has broader implications in halide-mediated C–H functionalization reactions.

Mechanism and origin of regioselectivity in Rh-catalyzed desymmetric [2 + 2 + 2] cycloaddition: charge versus π–π stacking interaction

Competition between different types of electronic effects (charge versus π–π stacking) controls the regioselectivity of Rh-catalyzed [2 + 2 + 2] cycloaddition.

Regioselectivity in metalloradical catalyzed C[sbnd]H bond activation: A theoretical study

Pure quantum mechanical calculations were performed to find out the origin of regioselectivity under the metalloradical catalysis (MRC) by Co(II) -porphyrin, which showed regioselectivity is the inherent property of the aminyl radical generated from the sulfamoyl azide substrate. Different conformational analysis for the transition state from α- CoIII-aminyl radical to ζ-CoIII-alkyl radical formation have been studied to find out the most stable conformation for the preferable selectivity. The outcome of our study completely agrees with the reported experimental results.

Nickel-Catalyzed Dearomative Arylboration of Indoles: Regioselective Synthesis of C2- and C3-Borylated Indolines.

Indole dearomatization is an important strategy to access indolines: a motif present in a variety of natural products and biologically active molecules. Herein, a method for transition-metal catalyzed regioselective dearomative arylboration of indoles to generate diverse indolines is presented. The method accomplishes intermolecular dearomatization of simple indoles through a migratory insertion pathway on substrates that lack activating or directing groups on the C2- or C3-positions. Synthetically useful C2- and C3-borylated indolines can be accessed through a simple change in N-protecting group in high regio- and diastereoselectivities (up to >40:1 rr and >40:1 dr) from readily available starting materials. Additionally, the origin of regioselectivity was explored experimentally and computationally to uncover the remarkable interplay between carbonyl orientation of the N-protecting group on indole, electronics of the C2-C3 π-bond, and sterics. The method enabled the first enantioselective synthesis of (-)-azamedicarpin.

Origin of Regioselectivity in the Dehydrogenation of Alkanes by Pincer–Iridium Complexes: A Combined Experimental and Computational Study

Origin of Regioselectivity in the Dehydrogenation of Alkanes by Pincer–Iridium Complexes: A Combined Experimental and Computational Study

Double-Regiodetermining-Stages Mechanistic Model Explaining the Regioselectivity of Pd-Catalyzed Hydroaminocarbonylation of Alkenes with Carbon Monoxide and Ammonium Chloride.

Pd-catalyzed hydroaminocarbonylation (HAC) of alkenes with CO and NH4Cl enables atom-economic and regiodivergent synthesis of primary amides, but the origin of regioselectivity was incorrectly interpreted in previous computational studies. A density functional theory study was performed herein to investigate the mechanism. Different from the previous proposals, both alkene insertion and aminolysis were found to be potential regioselectivity-determining stages. In the alkene insertion stage, 2,1-insertion is generally faster than 1,2-insertion irrespective of neutral or cationic pathways for both P(tBu)3 and xantphos. Such selectivity results from the unconventional proton-like hydrogen of the Pd-H bond in alkene insertion transition states. For less bulky alkenes, aminolysis with P(tBu)3 shows low selectivity, while linear selectivity dominates in this stage with xantphos due to a stronger repulsion between xantphos and branched acyl ligands. It was further revealed that the less-mentioned CO concentration and solvents also influence the regioselectivity by adjusting the relative feasibilities of CO-involved steps and NH3 release from ammonium chloride, respectively. The presented double-regiodetermining-stages mechanistic model associated with the effects of ligands, CO concentration, and solvents well reproduced the experimental selectivity to prove its validity and illuminated new perspectives for the regioselectivity control of HAC reactions.

A Computational Mechanistic Study of Cp*Co(III)-Catalyzed Three-Component C-H Bond Addition to Terpenes and Formaldehydes: Insights into the Origins of Regioselectivity.

Transition metal-catalyzed three-component reactions of arenes, dienes, and carbonyls enable the convergent synthesis of homoallylic alcohols. Controlling regioselectivity is a central challenge for the difunctionalization of substituted 1,3-dienes in which multiple unbiased C═C bonds exist. Here, the mechanisms of Cp*Co(III)-catalyzed three-component C-H bond addition to terpenes and formaldehydes were investigated by density functional theory calculations. The reaction proceeds via sequential C(sp2)-H activation, migratory insertion, β-hydride elimination, hydride reinsertion, and C-C bond formation to yield the final product. The migratory insertion is the rate- and regioselectivity-determining step of the overall reaction. We employed an energy decomposition approach to quantitatively dissect the contributions of different types of interactions to regioselectivity. For the 2-alkyl substituted 1,3-dienes, the orbital interactions in the 3,4-insertion are intrinsically more favorable as compared to that in the 4,3-insertion, while the stronger steric effects between metallacycle and 1,3-diene override the intrinsic electronic preference. However, the steric effects failed to rationalize the unfavorable 1,2-insertion that is analogous to 4,3-insertion and even bears smaller steric effects. The donor-acceptor interaction analysis indicates that orbital interactions between σCo-C and πC═C decreased significantly in the 1,2-insertion transition state, which leads to higher activation energy barriers. These insights into the dominant effects controlling regioselectivity will enable rational design of new catalysts for selective functionalization of dienes.

Radical Mechanism of Ir III /Ni II -Metallaphotoredox-Catalyzed C(sp 3 )–H Functionalization Triggered by Proton-Coupled Electron Transfer: Theoretical Insight

Photoredox catalysis can be induced to activate organic substrates or to modulate the oxidation state of transition-metal catalysts via unique single-electron transfer processes, so as to achieve c...