Β-hydride Elimination Step Research Articles

Palladium-Catalyzed Regiodivergent C-H Olefination of Imidazo[1,2a]pyridine Carboxamide and Unactivated Alkenes.

Despite remarkable successes in linear and branched vinyl (hetero) arene synthesis, regiodivergent C-H olefination with a single catalytic system has remained underdeveloped. Overcoming this limitation, a Pd/MPAA-catalyzed regiodivergent C-H olefination of imidazo[1,2a] pyridine carboxamides with unactivated terminal alkenes to generate branched and linear olefinated products depending upon the electronic nature of alkenes is reported herein. Moreover, this protocol can be applied for C-H deuteriation of the corresponding heteroarenes with D2 O as deuterium source. Preliminary experimental studies combined with computational investigations (DFT studies) suggest that regiodivergent olefination can be controlled by olefin insertion and β-hydride elimination steps.

Oxidative rearrangement of 1,1-disubstituted alkenes to ketones.

The Wacker process, which is widely used to convert monosubstituted alkenes into the corresponding methyl ketones, is thought to proceed through a PdII/Pd0 catalytic cycle involving a β-hydride elimination step. This mechanistic scenario is inapplicable to the synthesis of ketones from the 1,1-disubstituted alkenes. Current approaches based on semi-pinacol rearrangement of PdII intermediates are limited to the ring expansion of highly strained methylene cyclobutane derivatives. Herein, we report a solution to this synthetic challenge by designing a PdII/PdIV catalytic cycle incorporating a 1,2-alkyl/PdIV dyotropic rearrangement as a key step. This reaction, compatible with a broad range of functional groups, is applicable to both linear olefins and methylene cycloalkanes, including macrocycles. Regioselectivity favors the migration of the more substituted carbon, and a strong directing effect of the β-carboxyl group was also observed.

Synthesis of Bio-Inspired 1,3-Diarylpropene Derivatives via Heck Cross-Coupling and Cytotoxic Evaluation on Breast Cancer Cells.

The Heck cross-coupling reaction is a well-established chemical tool for the synthesis of unsaturated compounds by formation of a new C-C bond. In this study, 1,3-diarylpropene derivatives, designed as structural analogues of stilbenoids and dihydrostilbenoids, were synthesised by the palladium-catalysed reactions of 2-amidoiodobenzene derivatives with either estragole or eugenol. The products were obtained with high (E) stereoselectivity but as two regioisomers. The ratios of isomers were found to be dependent on the nature of the allylbenzene partner and were rationalised by electronic effects exercising a determining influence in the β-hydride elimination step. In addition, the cytotoxic effects of all the Heck reaction products were evaluated against MCF-7 and MDA-MB-231 human breast cancer cells, with unpromising results. Among all, compound 7d exhibited weak cytotoxic activity towards MCF-7 cell lines with IC50 values of 47.92 µM in comparison with tamoxifen and was considered to have general toxicity (SI value < 2).

Unveiling the mechanistic landscape of formic acid dehydrogenation catalyzed by Cp∗M(III) catalysts (M = Co or Rh or Ir) with bis(pyrazol-1-yl)methane ligand architecture: A DFT investigation

The production of dihydrogen via formic acid dehydrogenation (FAD) has been gaining remarkable attention and advancement as an alternative, sustainable and clean energy source. Density functional theory (DFT) calculations have been utilized to probe the reaction mechanism of FAD catalyzed by a Cp∗Rh(III) complex reported by Fink and Laurenczy with bis(pyrazol-1-yl)methane ligand system. The calculated energetics show that the rate-limiting step is the β-hydride elimination step and protonation by hydronium ion was calculated to be the most favourable route requiring relatively less activation energy than the conventional process which entails formic acid as the proton source. The Co and Ir congeners of the chosen Rh catalyst were computationally designed and they were also found to follow the same mechanism. Interestingly, the three metal centres (Co, Rh and Ir) were estimated to possess nearly the same activation barrier of c.a. 14 kcal/mol at the rate determining step. Thus, the proposed Co complex with such a small rate determining activation barrier, could be considered as a cheap and propitious earth-abundant transition metal-based catalyst for FAD.

Theoretical study of nickel-catalyzed hydroalkylation of 3-pyrrolines: Origin of ligand-controlled regioselectivity

Nickel catalysts have shown unique ligand control of regioselectivity in the hydroalkylation of 3-pyrrolines. The (2-(5-bromopyridin-2-yl)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole) ligand (L1) produces a C2-alkylated pyrrolidine, while the (4-benzyl-2-(6-methylpyridin-2-yl)-4,5-dihydrooxazole) ligand (L2) delivers a C3-alkylated pyrrolidine. We have explored the mechanism and origin of the ligand-controlled regioselectivity with density functional theory (DFT) calculations. The calculation results show good agreement with the experimental results for the regioselectivity. The hydroalkylation reactions of 3-pyrrolines with the two different ligands occur via completely different mechanisms, neither of which is via the traditional route proposed by experimental research. These mechanistic rationales are supported by several related experimental observations in ref. 40. For the L1 ligand, the regioselectivity is determined by two competing transition states, a β-hydride elimination transition state and a C–C reductive elimination transition state. For the L2 ligand, radical coupling and β-H elimination steps are responsible for the regioselectivity. The bulky L1 ligand facilitates the β-hydride elimination step and thus leads to the C2-alkylated pyrrolidine product. The less bulky L2 ligand prefers radical coupling step and thus results in the C3-alkylated pyrrolidine product.

Dinickel Catalyzed Vinylidene-Alkene Cyclization Reactions.

A dinickel catalyst promotes reductive cyclization reactions of 1,1-dichloroalkenes containing pendant olefins. The reactions can be conducted with a Zn reductant or electrocatalytically using a carbon working electrode. Mechanistic studies are consistent with the intermediacy of a Ni2(vinylidene) species, which adds to the alkene and generates a metallacyclic intermediate. β-Hydride elimination followed by C-H reductive elimination forms the cyclization product. The proposed dinickel metallacycle is structurally characterized and its stoichiometric conversion to product is demonstrated. Spin polarized, unrestricted DFT calculations are used to further examine the cyclization mechanism. These computational models reveal that both nickel centers function cooperatively to mediate the key oxidative addition, migratory insertion, β-hydride elimination, and reductive elimination steps.

DFT Probe into the Mechanism of Formic Acid Dehydrogenation Catalyzed by Cp*Co, Cp*Rh, and Cp*Ir Catalysts with 4,4'-Amino-/Alkylamino-Functionalized 2,2'-Bipyridine Ligands.

The mechanistic landscape of H2 generation from formic acid catalyzed by Cp*M(III) complexes (M = Co or Rh or Ir) with diamino-/dialkylamino-substituted 2,2'-bipyridine ligand architectures have been unveiled computationally. The calculations indicate that the β-hydride elimination process is the rate-determining step for all the investigated catalysts. The dialkylamino moieties on the 2,2'-bipyridine ligand were found to reduce the activation free energy required for the rate-limiting β-hydride elimination step and increase the hydridic nature of the Ir-hydride bond, which accounts for the experimentally observed enhanced catalytic activity. Furthermore, the protonation by H3O+ ion was found to be the kinetically most favorable route than the conventional protonation by formic acid. The origin for this preference lies in the increased electrophilicity of the proton from hydronium ion which facilitates easy protonation of the metal-hydride with low activation energy barrier. The Co and Rh analogues of the chosen iridium catalyst were computationally designed and were estimated to possess a rate-determining activation barrier of 16.9 and 14.5 kcal/mol, respectively. This illustrates that these catalysts are potential candidates for FAD. The insights derived in this work might serve as a vital knowledge that could be capitalized upon for designing cost-effective catalyst for FAD in future.

Synthesis of Arylidene-β-lactams via exo-Selective Matsuda-Heck Arylation of Methylene-β-lactams.

exo-Methylene-β-lactams were synthesized in two steps from commercially available 3-bromo-2-(bromomethyl)propionic acid and reacted with arene diazonium salts in a Heck-type arylation in the presence of catalytic amounts of Pd(OAc)2 under ligand-free conditions. The products, arylidene-β-lactams, were obtained in high yields as single isomers. The β-hydride elimination step of the Pd-catalyzed coupling reaction proceeds with high exo-regioselectivity and E-stereoselectivity. With aryl iodides, triflates, or bromides, the coupling products were isolated only in low yields, due to extensive decomposition of the starting material at elevated temperatures. This underlines that arene diazonium salts can be superior arylating reagents in Heck-type reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail.

Efficient Iridium Catalysts for Formic Acid Dehydrogenation: Investigating the Electronic Effect on the Elementary β-Hydride Elimination and Hydrogen Formation Steps

We report herein a series of Cp*Ir complexes containing a rigid 8-aminoquinolinesulfonamide moiety as highly efficient catalysts for the dehydrogenation of formic acid (FA). The complex [Cp*Ir(L)Cl] (HL = N-(quinolin-8-yl)benzenesulfonamide) displayed a high turnover frequency (TOF) of 2.97 × 104 h-1 and a good stability (>100 h) at 60 °C. Comparative studies of [Cp*Ir(L)Cl] with the rigid ligand and [Cp*Ir(L')Cl] (HL' = N-propylpypridine-2-sulfonamide) without the rigid aminoquinoline moiety demonstrated that the 8-aminoquinoline moiety could dramatically enhance the stability of the catalyst. The electron-donating ability of the N,N'-chelating ligand was tuned by functionalizing the phenyl group of the L ligand with OMe, Cl, and CF3 to have a systematical perturbation of the electronic structure of [Cp*Ir(L)Cl]. Experimental kinetic studies and density functional theory (DFT) calculations on this series of Cp*Ir complexes revealed that (i) the electron-donating groups enhance the hydrogen formation step while slowing down the β-hydride elimination and (ii) the electron-withdrawing groups display the opposite effect on these reaction steps, which in turn leads to lower optimum pH for catalytic activity compared to the electron-donating groups.

Walking metals: catalytic difunctionalization of alkenes at nonclassical sites.

Migration of metals along a carbon chain is triggered by two of the most common organometallic elementary steps – β-hydride (β-H) elimination and alkene hydrometallation. This process heralds a new future for creating bonds at carbon sites that fall outside the tenets of the conventional wisdom for reactivity and bond formation, and provides an opportunity to leverage β-H elimination to advance the very reaction of alkene difunctionalization it is intrinsically predestined to disrupt. Almost four decades since its genesis, the early adventure for alkene difunctionalization by metal migration was sporadic, and its later development went on a hiatus primarily due to original impetus on arresting β-H elimination for vicinal alkene difunctionalization. With the recent surge on alkene difunctionalization, efforts have been gradually shifting to harnessing the process of β-H elimination to difunctionalize alkenes at sites other than the classical vicinal carbons, termed henceforth nonclassical reaction sites for pedagogical simplicity. In this review article, we extricate and examine the origin and the development of such reactions over the years. This review covers a wide range of reactions for the difunctionalization of alkenes at geminal (1,1), allylic (1,3) and remote (1,n) carbon sites with a variety of coupling partners. These reactions have enabled engineering of complex molecular frameworks with the generation of new carbon–carbon (C–C)/C–C, C–C/C–heteroatom (halogens, O, N, B) and C–B/C–B bonds. The development of these unique transformations is also presented with mechanistic hypotheses and experimental evidences put forward by researchers. Judged by the number of reports emerging recently, it is now strikingly evident that the field of alkene difunctionalization by metal migration has begun to gain momentum, which holds a great future prospect to develop into a synthetic method of enormous potential.

Unravelling the Reaction Mechanism of Formic Acid Dehydrogenation by Cp*Rh(III) and Cp*Co(III) Catalysts with Proton-Responsive 4,4′- and 6,6′-Dihydroxy-2,2′-Bipyridine Ligands: A DFT Study

The catalytic mechanism of hydrogen production via formic acid decomposition by pentamethylcyclopentadienyl (Cp*) rhodium(III) and cobalt(III) catalysts with proton-responsive 4,4′-dihydroxy-2,2′-bipyridine (4L) and 6,6′-dihydroxy-2,2′-bipyridine (6L) ligands ([Cp*M(4L)(H2O)]2+ and [Cp*M(6L)(H2O)]2+; M = Rh and Co) were explored using density functional theory calculations. The effect of pH on the protonation state of M(4L) and M(6L) ligands was studied using the speciation approach, and the fully protonated dihydroxy-2,2′-bipyridine ligand was found to be the dominated species throughout the catalytic mechanism of formic acid decomposition at pH 2.5. For both Cp*Rh(III) and Cp*Co(III) catalysts with 4L or 6L ligands, the β-hydride elimination step was found to be the rate-determining step irrespective of the position of the hydroxyl group on the bipyridine ligand. In the case of M(6L), both formic acid- and water-assisted hydrogen evolution transition states were considered, and from the computed free en...

Effect of Coverage on Catalytic Selectivity and Activity on Metallic and Alloy Catalysts; Vinyl Acetate Monomer Synthesis

The repulsive lateral interactions that occur at the high coverages present on catalysts under reaction conditions are likely to exert a significant influence on the reaction energetics. The effect of such lateral interactions are explored for the synthesis of vinyl acetate monomer (VAM) on Pd(111) and Au/Pd(111) alloy model single-crystal catalysts, where the reaction kinetics are monitored by reflection–absorption infrared spectroscopy (RAIRS). It is shown by comparing the reactivity of ethylene and its deuterated isotopomers, and by trapping reaction intermediates, that VAM is formed on Pd(111) by a mechanism first proposed by Samanos, where the reaction is initiated by coupling between ethylene and adsorbed acetate species to form an acetoxyethyl intermediate, followed by a rate-limiting β-hydride elimination step to produce VAM. The reaction comprises two sequential steps; a bond-forming reaction, followed by a bond-breaking step. Repulsive lateral interactions are expected to facilitate bond-forming reactions that reduce the total coverage, but inhibit bond-breaking steps, so that VAM formation provides an ideal reaction to explore these effects. Density functional theory (DFT) calculations confirm the proposed coverage effects and yield energy barriers for the reaction of ethylene with acetate-saturated Pd(111) surfaces that are in excellent agreement with experiment. It is also found that bond-breaking in VAM decomposition is inhibited on a crowded Pd(111) surface, indicating that high adsorbate coverages influence both reactivity and selectivity. VAM formation is also explored on Au/Pd(111) alloys. The catalytic activity of alloys is conventionally discussed by invoking ensemble (geometric) and electronic (ligand) effects. However, the acetate coverage also decreases with increasing gold content of the Au/Pd(111) alloy, thereby decreasing the repulsive lateral interactions. The coverage effects on alloys are found to be as large as the ensemble + electronic effects and induce a change in the rate-limiting step for VAM formation from β-hydride elimination to the ethylene-acetate coupling step.

General, Mild, and Selective Method for Desaturation of Aliphatic Amines.

A novel method for desaturation of aliphatic amines into enamines as well as allylic and homoallylic amines has been developed. This general protocol operates via putative aryl hybrid Pd-radical intermediates, which combine the signature features of radical chemistry, a hydrogen atom transfer (HAT) process, and transition metal chemistry, a selective β-hydride elimination step, to achieve efficient and selective desaturation of amines. These hybrid Pd-radical intermediates are efficiently generated under mild photoinduced conditions and are capable of a 1,n-HAT (n = 5-7) event at C(sp3)-H sites. The selectivity of HAT is tunable by varying different auxiliaries, which highlight the generality of this method. Remarkably, this desaturation method, which operates under mild conditions and does not require employment of exogenous photosensitizers or oxidants, can be performed in a practical scalable fashion from simple amines.

Photochemical Heck benzylation of styrenes catalyzed by Na[FeCp(CO)2

Iron-catalyzed Heck coupling of benzyl chlorides and styrenes proceeds under photochemical conditions using the well-known anionic complex, [FeCp(CO)2]- (Fp−), as a catalyst. The reaction likely proceeds through the established SN2 mechanism for Fp− alkylation, followed by styrene migratory insertion and β-hydride elimination steps that are enabled by photochemical CO dissociation.

ChemInform Abstract: The Strategic Generation and Interception of Palladium‐Hydrides for Use in Alkene Functionalization Reactions

We review methods that our lab has developed for the generation of Pd-hydrides and the manipula- tion of these useful intermediates via β-hydride elimination and migratory insertion steps. For a given alkene functionalization reaction, careful understanding of the dynamics of β-hydride elimination, migratory inser- tion, and transmetallation have allowed for the selective functionalization of Pd-alkyl intermediates. This has afforded us a means by which to transpose palladium to a desired position on a substrate for subsequent functionalization, empowering a number of useful C-H, C-O, and C-C bond-forming reactions.

The strategic generation and interception of palladium-hydrides for use in alkene functionalization reactions

Abstract We review methods that our lab has developed for the generation of Pd-hydrides and the manipulation of these useful intermediates via β-hydride elimination and migratory insertion steps. For a given alkene functionalization reaction, careful understanding of the dynamics of β-hydride elimination, migratory insertion, and transmetallation have allowed for the selective functionalization of Pd-alkyl intermediates. This has afforded us a means by which to transpose palladium to a desired position on a substrate for subsequent functionalization, empowering a number of useful C–H, C–O, and C–C bond-forming reactions.

Effect of Sodium Cation on Metallacycle β‐Hydride Elimination in CO2–Ethylene Coupling to Acrylates

The catalytic conversion of carbon dioxide and olefins into acrylates has been a long standing target, because society attempts to synthesize commodity chemicals in a more economical and sustainable fashion. Although nickel complexes have been known to successfully couple CO2 and ethylene for decades, a key β-hydride elimination step has proven a major obstacle to the development of a catalytic process. Recent studies have shown that Lewis acid additives can be used to create a lower-energy pathway for β-hydride elimination and facilitate a low number of catalytic turnovers. However, the exact manner, in which the Lewis acid promotes β-hydride elimination remains to be elucidated. Herein, we describe the kinetic and thermodynamic role that commercially relevant and weakly Lewis acidic sodium salts play in promoting β-hydride elimination from nickelalactones synthesized from CO2 and ethylene. This process is compared to a non-Lewis acid promoted pathway, and DFT calculations were used to identify differences between the two systems. The sodium-free isomerization reaction gave a rare CO2 -derived β-nickelalactone complex, which was structurally characterized.

Mechanism, Reactivity, and Selectivity in Palladium-Catalyzed Redox-Relay Heck Arylations of Alkenyl Alcohols

The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG⧧ of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C–O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.

Thermal Chemistry of Cu(I)-Iminopyrrolidinate and Cu(I)-Guanidinate Atomic Layer Deposition (ALD) Precursors on Ni(110) Single-Crystal Surfaces

The thermal chemistry of tetrakis[Cu(I)-N-sec-butyl-iminopyrrolidinate] and bis[Cu(I)-N,N-dimethyl-N′,N″-di-iso-propyl-guanidinate], promising precursor for atomic layer deposition (ALD) applications, was investigated on a Ni(110) single-crystal under ultrahigh vacuum (UHV) conditions by using X-ray photoelectron spectroscopy (XPS) and temperature-programmed desorption (TPD). Both precursors, which exist as tetramers and dimers in the solid phase, respectively, undergo dissociative adsorption at temperatures below 200 K to produce adsorbed monomers on the surface. A β-hydride elimination step is then operative near 300 K that leads to the release of some of the ligands in dehydrogenated form. The remaining adsorbates obtained from either precursor undergo similar further decomposition between 350 K and 600 K as the Cu atoms are reduced from a Cu(I) oxidation state to metallic Cu(0). Hydrocarbons resulting from the elimination of the terminal moieties include ethene and acetonitrile from the Cu(I)-iminopyrrolidinate and propene from the Cu(I)-guanidinate, which are ejected at ∼420–490 K, and HCN in both cases at ∼570–580 K. These results shows several similarities with the surface chemistry previously reported for bis[Cu(I)-N,N′-di-sec-butyl-acetamidinate], and they suggest a common behavior in the surface reactions of these families of Cu(I)-amidinate, Cu(I)-iminopyrrolidinate, and Cu(I)-guanidinate ALD precursors.

Mechanism and Origins of Ligand-Controlled Selectivities in [Ni(NHC)]-Catalyzed Intramolecular (5 + 2) Cycloadditions and Homo-Ene Reactions: A Theoretical Study

The mechanism and origins of selectivities in [Ni(NHC)]-catalyzed intramolecular (5 + 2) cycloadditions and homo-ene reactions of vinylcyclopropanes (VCPs) and alkynes have been studied using density functional theory. The preferred mechanism involves oxidative alkyne-alkene cyclization to form a metallacyclopentene intermediate, in contrast to a cyclopropane cleavage pathway in the reaction with Rh(I) catalysts. The selectivity between the (5 + 2) and homo-ene products is determined in the subsequent competing reductive elimination and β-hydride elimination steps. Two similar-sized N-heterocyclic carbene (NHC) ligands, SIPr and ItBu, yielded reversed product selectivity, favoring the (5 + 2) and homo-ene products respectively. This is attributed to the anisotropic steric environment of these NHC ligands, which positions the bulky substituents on the ligand toward different directions and leads to distinct steric control in the reductive elimination and β-hydride elimination transition states.