Oxidative Addition Transition State Research Articles

Synthesis and Mechanistic Study of Naphthalimide Derivative Formation via Cu-Mediated Ullmann-Type Reactions.

Cu-mediated Ullmann-type coupling reactions are fundamental to organic synthesis, garnering significant academic and industrial interest since their inception. Optimizing reaction parameters, particularly temperature control, is crucial for maximizing efficiency while maintaining high yields. Bidentate ligands, such as amino acids, have demonstrated potential in facilitating these reactions at lower temperatures (<100 °C). This study explores the Cu-catalyzed Ullmann-type coupling of naphthalimide derivatives with amino acid substitutions. Naphthalimide dyes, known for their diverse applications in bioimaging, solar cells, medicine, and sensors, were selected for their potent anticancer properties. The synthesized compounds were characterized by using 1H NMR, ESI-MS, and melting point analyses. Compounds with significant steric hindrance exhibited lower yields, leading to the development of a novel catalytic system employing l-carnosine as a bidentate ligand, which significantly improved yields. Mechanistic insights, derived from density functional theory calculations, identified "L-complex 3" as the most stable and reactive intermediate during oxidative addition to aryl halides. The oxidative addition transition state "OX1-TS" was found to be the most favorable, with a relatively low energy barrier of 6.13 kcal/mol, suggesting that this step, despite being the rate-limiting stage, is energetically accessible. In contrast, reductive elimination was facilitated by a Cu(III) penta-coordinated intermediate, with a barrier of just 8.34 kcal/mol, making it a more straightforward process. Theoretical findings aligned closely with experimental data, reinforcing the oxidative addition/reductive elimination pathway as the operative mechanism for this reaction.

Iridium-Catalyzed Regioselective Borylation through C–H Activation and the Origin of Ligand-Dependent Regioselectivity Switching

Research efforts in catalytic regioselective borylation using C-H bond activation of arenes have gained considerable recent attention. The ligand-enabled regiocontrol, such as in the borylation of benzaldehyde, the selectivity could be switched from the ortho to meta position, under identical conditions, by just changing the external ligand (L) from 8-aminoquinoline (8-AQ) to tetramethylphenanthroline (TMP). The DFT(B3LYP-D3) computations helped us learn that the energetically preferred catalytic pathway includes the formation of an Ir-π-complex between the active catalyst [Ir(L)(Bpin)3] and benzaldimine, a C-H bond oxidative addition (OA) to form an Ir(V)aryl-hydride intermediate, and a reductive elimination to furnish the borylated benzaldehyde as the final product. The lowest energetic span (δEortho = 26 kcal/mol with 8-AQ) is noted in the ortho borylation pathway, with the OA transition state (TS) as the turnover-determining TS. The change in regiochemical preference to the meta borylation (δEmeta = 26) with TMP is identified. A hemilabile mode of 8-AQ participation is found to exhibit a δEortho of 24 kcal/mol for the ortho borylation, relative to that in the chelate mode (δEortho = 26 kcal/mol). The predicted regioselectivity switching is in good agreement with the earlier experimental observations.

Kinetic Resolution via Rh-Catalyzed C-C Activation of Cyclobutanones at Room Temperature.

Herein we describe the development of a highly selective kinetic resolution of cyclobutanones via a Rh-catalyzed "cut-and-sew" reaction with selectivity factor up to 785. This reaction takes place at room temperature with excellent efficiency. Various trans-5,6-fused bicycles and C2-substituted cyclobutanones were obtained with excellent ee's that can be further used as chiral building blocks. DFT calculations reveal the crucial roles of the DTBM-segphos ligand in stabilizing the rate- and enantioselectivity-determining C-C oxidative addition transition state via favorable ligand-substrate dispersion interactions.

Solvent Effects on the Selectivity of Palladium-Catalyzed Suzuki-Miyaura Couplings.

The use of polar solvents MeCN or dimethylformamide (DMF) was previously shown to induce a selectivity switch in the Pd/P t Bu3-catalyzed Suzuki-Miyaura coupling of chloroaryl triflates. This phenomenon was attributed to the ability of polar solvents to stabilize anionic transition states for oxidative addition. However, we demonstrate that selectivity in this reaction does not trend with solvent dielectic constant. Unlike MeCN and DMF, water, alcohols, and several polar aprotic solvents such as MeNO2, acetone, and propylene carbonate provide the same selectivity as nonpolar solvents. These results indicate that the role of solvent on the selectivity of Suzuki-Miyaura couplings may be more complex than previously envisioned. Furthermore, this observation has the potential for synthetic value as it greatly broadens the scope of solvents that can be used for chloride-selective cross coupling of chloroaryl triflates.

Direct dynamics analysis of the cationic Cp*(PMe3)Ir(CH3) methane C-H activation mechanism.

For the σ-bond metathesis reaction between methane and cationic Cp*(PMe3)IrIII(CH3), previous static DFT calculations revealed a two-step oxidative addition/reductive elimination mechanism with an intervening IrV-H intermediate. We recently reported quasiclassical direct molecular dynamics simulations where starting from the vibrationally-averaged oxidative addition transition state a minor, but significant, amount of trajectories bypassed the IrV-H intermediate in a dynamical one-step mechanism. These trajectories also revealed that after the reductive coupling transition state is passed methane always dissociates and the C-H σ-complex is skipped. Here we report direct dynamics simulations using a microcanonical temperature sampling method with trajectories initialized and propagated using the Gaussian program. Sets of 30 trajectories were examined with average time steps ranging from 1.5 to 0.25 femtoseconds (fs). These results showed that a step size of ∼1.5 fs is too large and likely overestimates the amount of trajectories skipping the IrV-H intermediate. Trajectories with 0.75 and 0.25 fs time steps gave qualitatively similar profiles compared to our previous results using our program DynSuite with a 1 fs time step. Reverse trajectories with an average time step of 0.25 fs showed complete skipping of the methane σ complex. 30 trajectories were also propagated using a SMD continuum dichloromethane solvent model. These trajectories showed very similar behavior to gas-phase trajectories.

Mechanistic Study on Nickel-Catalyzed Silylation of Aryl Methyl Ethers.

The mechanism of the nickel-catalyzed silylation of aryl methyl ethers has been systematically investigated by using DFT methods. This theoretical study supports a catalytic cycle that involves the formation of a nickel-silyl complex, C-O bond cleavage, C-Si reductive elimination, the addition of methoxide to boron, and finally regeneration of the catalyst. Notably, it was found that activation of the C-O bond proceeded through an oxidative addition pathway with a three-centered transition state. The silyl anion generated in situ works as a ligand to the nickel center and promotes this process. Meanwhile, the role of the base added (KOtBu) is also elucidated. The potassium cation helps to stabilize the oxidative addition transition state through noncovalent interactions, while the resting state is destabilized due to steric repulsion introduced by the tert-butoxide anion. This is further confirmed by a comparison made computationally between the reaction with KOtBu and that with KOMe or NaOtBu as the base.

DFT Investigation of Suzuki-Miyaura Reactions with Aryl Sulfamates Using a Dialkylbiarylphosphine-Ligated Palladium Catalyst.

Aryl sulfamates are valuable electrophiles for cross-coupling reactions because they can easily be synthesized from phenols and can act as directing groups for C-H bond functionalization prior to cross-coupling. Recently, it was demonstrated that (1-tBu-Indenyl)Pd(XPhos)Cl (XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) is a highly active precatalyst for room-temperature Suzuki-Miyaura couplings of a variety of aryl sulfamates. Herein, we report an in-depth computational investigation into the mechanism of Suzuki-Miyaura reactions with aryl sulfamates using an XPhos-ligated palladium catalyst. Particular emphasis is placed on the turnover-limiting oxidative addition of the aryl sulfamate C-O bond, which has not been studied in detail previously. We show that bidentate coordination of the XPhos ligand via an additional interaction between the biaryl ring and palladium plays a key role in lowering the barrier to oxidative addition. This result is supported by NBO and NCI-Plot analysis on the transition states for oxidative addition. After oxidative addition, the catalytic cycle is completed by transmetalation and reductive elimination, which are both calculated to be facile processes. Our computational findings explain a number of experimental results, including why elevated temperatures are required for the coupling of phenyl sulfamates without electron-withdrawing groups and why aryl carbamate electrophiles are not reactive with this catalyst.

Mechanism and Origins of Ligand-Controlled Stereoselectivity of Ni-Catalyzed Suzuki-Miyaura Coupling with Benzylic Esters: AComputational Study.

Nickel catalysts have shown unique ligand control of stereoselectivity in the Suzuki-Miyaura cross-coupling of boronates with benzylic pivalates and derivatives involving C(sp3)-O cleavage. The SIMes ligand (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) produces the stereochemically inverted C-C coupling product, while the tricyclohexylphosphine (PCy3) ligand delivers the retained stereochemistry. We have explored the mechanism and origins of the ligand-controlled stereoselectivity with density functional theory (DFT) calculations. The oxidative addition determines the stereoselectivity with two competing transition states, an SN2 back-side attack type transition state that inverts the benzylic stereogenic center and a concerted oxidative addition through a cyclic transition state, which provides stereoretention. The key difference between the two transition states is the substrate-nickel-ligand angle distortion; the ligand controls the selectivity by differentiating the ease of this angle distortion. For the PCy3 ligand, the nickel-ligand interaction involves mainly σ-donation, which does not require a significant energy penalty for the angle distortion. The facile angle distortion with PCy3 ligand allows the favorable cyclic oxidative addition transition state, leading to the stereoretention. For the SIMes ligand, the extra d-p back-donation from nickel to the coordinating carbene increases the rigidity of the nickel-ligand bond, and the corresponding angle distortion is more difficult. This makes the concerted cyclic oxidative addition unfavorable with SIMes ligand, and the back-side SN2-type oxidative addition delivers the stereoinversion.

Oxidative addition transition states of Pd(0) complexes in polar solvent—a DFT study involving implicit and explicit solvation

Previous reports in the literature have suggested that concerted transition states for oxidative addition would not exist in solution. By contrast, this report describes the successful location of transition states for the oxidative addition of monoligated Pd(PtBu3), bisligated Pd(PtBu3)(MeCN), and anionic Pd(PtBu3)F− complexes to C–Cl and C–OTf of an aryl chloro triflate in polar solvent (MeCN). Optimizations were done with implicit solvation and a combined implicit/explicit solvation approach in which six acetonitrile molecules were additionally involved in the optimization. The geometries obtained from optimizations employing an implicit solvation model are structurally largely analogous to those found using a combination of implicit and explicit solvation.

ChemInform Abstract: Highly Selective Activation of Vinyl C—S Bonds over Aryl C—S Bonds in the Pd‐Catalyzed Coupling of (E)‐(β‐Trifluoromethyl)vinyldiphenylsulfonium Salts: Preparation of Trifluoromethylated Alkenes and Dienes.

We describe the Suzuki coupling reaction of (E)-(beta-trifluoromethyl)vinyldiphenylsulfonium salts with arylboronic acid. The highly efficient and selective reaction provides a useful and mild method for the synthesis of trifluoromethylated alkenes and dienes. Subsequent DFT studies showed that the oxidative addition transition state of the vinyl CS bond is much more favorable (11.7 kcal?mol1) than that of the aryl CS bond.

Highly Selective Activation of Vinyl C–S Bonds Over Aryl C–S Bonds in the Pd‐Catalyzed Coupling of (E)‐(β‐Trifluoromethyl)vinyldiphenylsulfonium Salts: Preparation of Trifluoromethylated Alkenes and Dienes

AbstractWe describe the Suzuki coupling reaction of (E)‐(β‐trifluoromethyl)vinyldiphenylsulfonium salts with arylboronic acid. The highly efficient and selective reaction provides a useful and mild method for the synthesis of trifluoromethylated alkenes and dienes. Subsequent DFT studies showed that the oxidative addition transition state of the vinyl C–S bond is much more favorable (11.7 kcal mol–1) than that of the aryl C–S bond.

Alternative Mechanistic Explanation for Ligand-Dependent Selectivities in Copper-Catalyzed N- and O-Arylation Reactions

The ligand-dependent selectivities in Ullmann-type reactions of amino alcohols with iodobenzene by β-diketone- and 1,10-phenanthroline-ligated Cu(I) complexes were recently explained by the single-electron transfer and iodine atom transfer mechanisms (Jones, G. O., Liu, P., Houk, K. N., and Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 6205.). The present study shows that an alternative, oxidative addition/reductive elimination mechanism may also explain the selectivities. Calculations indicate that a Cu(I) complex with a negatively charged β-diketone ligand is electronically neutral, so that oxidative addition of ArI to a β-diketone-ligated Cu(I) prefers to occur (and occur readily) in the absence of the amino alcohol. Thus, coordination of the amino alcohol in its neutral form can only occur at the Cu(III) stage where N-coordination is favored over O-coordination. The coordination step is the rate-limiting step and the outcome is that N-arylation is favored with the β-diketone ligand. On the other hand, a Cu(I) complex with a neutral 1,10-phenanthroline ligand is positively charged, so that oxidative addition of ArI to a 1,10-phenanthroline-ligated Cu(I) has to get assistance from a deprotonated amino alcohol substrate. This causes oxidative addition to become the rate-limiting step in the 1,10-phenanthroline-mediated reaction. The immediate product of the oxidative addition step is found to undergo facile reductive elimination to provide the arylation product. Because O-coordination of a deprotonated amino alcohol is favored over N-coordination in the oxidative addition transition state, O-arylation is favored with the 1,10-phenanthroline ligand.

Carbon–hydrogen and carbon–heteroatom bond activation using iridium(I) complexes

In this research, the B3LYP density functional and Stevens effective core potentials are used to compare carbon–hydrogen and carbon–heteroatom bond activation by an iridium(I) complex. Of particular importance is to address the kinetic (transition state) and thermodynamic (ground state) selectivity. The complex Ir(PH 3) 2(H) with CH 3–X (X=F, Cl, OH, SH, NH 2, PH 2) as the substrate has been used as a model. Good agreement in geometries is obtained between the target molecules and experimental models. The resultant products of C–H and C–X oxidative addition are Y-shaped minima (i.e., a distorted trigonal bipyramid with one acute and two obtuse angles among the equatorial ligands). Oxidative addition of the C–X bond to the substrate is exothermic for groups 16 and 17, but endothermic for group 15. A significant thermodynamic preference for C–X activation over C–H activation is observed for these Ir(I) complexes. However, analysis of the transition states for oxidative addition suggests that there is a kinetic preference for C–H activation.

Electronic and medium effects on the rate of arene C [bond] H activation by cationic Ir(III) complexes.

A detailed mechanistic study of arene C [bond] H activation in CH(2)Cl(2) solution by Cp(L)IrMe(X) [L = PMe(3), P(OMe)(3); X = OTf, (CH(2)Cl(2))BAr(f); (BAr(f) = B[3,5-C(6)H(3)(CF(3))(2)](4))(-)] is presented. It was determined that triflate dissociation in Cp(L)IrMe(OTf), to generate tight and/or solvent-separated ion pairs containing a cationic iridium complex, precedes C [bond] H activation. Consistent with the ion-pair hypothesis, the rate of arene activation by Cp(L)IrMe(OTf) is unaffected by added external triflate salts, but the rate is strongly dependent upon the medium. Thus the reactivity of Cp(PMe(3))IrMe(OTf) can be increased by almost 3 orders of magnitude by addition of (n-Hex)(4)NBAr(f), presumably because the added BAr(f) anion exchanges with the OTf anion in the initially formed ion pair, transiently forming a cation/borate ion pair in solution (special salt effect). In contrast, addition of (n-Hex)(4)NBAr(f) to [CpPMe(3)Ir(Me)CH(2)Cl(2)][BAr(f)] does not affect the rate of benzene activation; here there is no initial covalent/ionic pre-equilibrium that can be perturbed with added (n-Hex)(4)NBAr(f). An analysis of the reaction between Cp(PMe(3))IrMe(OTf) and various substituted arenes demonstrated that electron-donating substituents on the arene increase the rate of the C [bond] H activation reaction. The rate of C(6)H(6) activation by [Cp(PMe(3))Ir(Me)CH(2)Cl(2)][BAr(f)] is substantially faster than [Cp(P(OMe)(3))Ir(Me)CH(2)Cl(2)][BAr(f)]. Density functional theory computations suggest that this is due to a less favorable pre-equilibrium for dissociation of the dichloromethane ligand in the trimethyl phosphite complex, rather than to a large electronic effect on the C [bond] H oxidative addition transition state. Because of these combined effects, the overall rate of arene activation is increased by electron-donating substituents on both the substrate and the iridium complex.

ChemInform Abstract: Transition States for Oxidative Addition to Three‐Coordinate Ir(I): H—H, C—H, C—C, and C—F Bond Activation Processes

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