ortho-Fluoro or ortho Effect? Oxidative Addition of Zerovalent Nickel into the C-CN Bond of Substituted Benzonitriles.

A recent study of the oxidative addition of zerovalent Ni to the C-CN bond of F-substituted benzonitriles showed significantly increased stabilization of the C-CN oxidative addition products with o-F groups (-6.6 kcal/mol per o-F) compared to m-F groups (-1.8 kcal/mol per m-F). To answer the question of whether this is an o-F effect or an ortho effect, in this study the effect of CF3 and CH3 groups on the oxidative addition of the [Ni(dmpe)] fragment [dmpe = 1,2-bis(dimethylphosphino)ethane] to the C-CN bond of benzonitriles has been studied. A density functional theory study of the reaction pathway between η2-CN complexes and the C-CN oxidative addition products shows stabilization of the C-CN oxidative addition product with the electron-withdrawing CF3 group and destabilization with the electron-donating CH3 group in both tetrahydrofuran and toluene. There is a slightly larger ortho effect with CF3 (-7.4 kcal/mol) than with F. However, due to steric crowding, two o-CF3 groups did not show considerably more stabilization than one o-CF3 group. There is a linear relationship between ΔG° and the number of meta groups (2.0 kcal/mol stabilization per m-CF3 and 0.8 kcal/mol destabilization per m-CH3). On the basis of natural population analysis, as the C-CN bond becomes more polarized, the stability of the C-CN oxidative addition products with respect to the η2-CN complexes increases.

Investigation on the Synthesis, Application and Structural Features of Heteroaryl 1,2-Diketones.

A set of unsymmetrical heteroaryl 1,2-diketones were synthesized by a heteroarylation/oxidation sequence with up to 65% isolated yields. Palladium catalyst XPhos Pd G4 and SeO2 were the key reagents used in this methodology, and microwave irradiation was utilized to facilitate an efficient and ecofriendly process. The application of heteroaryl 1,2-diketones is demonstrated through the synthesis of an unsymmetrical 2-phenyl-3-(pyridin-3-yl)quinoxaline (5a) from 1-phenyl-2-(pyridin-3-yl)ethane-1,2-dione (4a). The lowest energy conformations of 4a and 5a were located using Density Functional Theory (DFT) at the M06-2X/def2-TZVP level of theory. Two lowest energy conformations of 4a differ with respect to the position of the N atom in the pyridyl ring and 0.27 kcal/mol energy difference between them corresponds to 60.4 and 39.6% at 50 °C in toluene. Four lowest energy conformations for 5a have the energy differences of 0.01, 0.03 and 0.07 kcal/mol that corresponds to 26.0, 25.7, 24.9 and 23.4%, respectively. A comparison of 4a and 5a to the less hindered analogs (oxalyl chloride and oxalic acid) is used to investigate the structural features and bonding using Natural Bond Orbital (NBO) analysis.

Enantioselective palladium(0)-catalyzed Nazarov-type cyclization.

A Pd(0)-catalyzed asymmetric Nazarov-type cyclization is described. The optimized ligand for the reaction incorporates a weakly coordinating pyridine ring into a TADDOL-derived phosphoramidite (TADDOL=α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol). The reaction leads to the formation of cyclopentenones as single diastereoisomers that incorporate two contiguous asymmetric centers, one tertiary and one an all-carbon-atom quaternary stereocenter, in high yield and optical purity. It is noteworthy that the reaction does not require that substrates should be activated by aryl substituents.

Palladium-Catalyzed C8-Selective C-H Arylation of Quinoline N-Oxides: Insights into the Electronic, Steric and Solvation Effects on the Site-Selectivity by Mechanistic and DFT Computational Studies.

We report herein a palladium-catalyzed C-H arylation of quinoline N-oxides that proceeds with high selectivity in favor of the C8-isomer. This site-selectivity is unusual for palladium, since all of the hitherto described methods of palladium-catalyzed C-H functionalization of quinoline N-oxides are highly C2-selective. The reaction exhibits a broad synthetic scope with respect to quinoline N-oxides and iodoarenes and can be significantly accelerated to sub-hour reaction times under microwave irradiation. The C8-arylation method can be carried out on gram scale and has excellent functional group tolerance. Mechanistic and Density Functional Theory (DFT) computational studies provide evidence for the cyclopalladation pathway and describe key parameters influencing the site-selectivity.

Axial ligand exchange of N-heterocyclic cobalt(III) Schiff base complexes: molecular structure and NMR solution dynamics.

The kinetic and thermodynamic ligand exchange dynamics are important considerations in the rational design of metal-based therapeutics and therefore, require detailed investigation. Co(III) Schiff base complex derivatives of bis(acetylacetone)ethylenediimine [acacen] have been found to be potent enzyme and transcription factor inhibitors. These complexes undergo solution exchange of labile axial ligands. Upon dissociation, Co(III) irreversibly interacts with specific histidine residues of a protein, and consequently alters structure and causes inhibition. To guide the rational design of next generation agents, understanding the mechanism and dynamics of the ligand exchange process is essential. To investigate the lability, pH stability, and axial ligand exchange of these complexes in the absence of proteins, the pD- and temperature-dependent axial ligand substitution dynamics of a series of N-heterocyclic [Co(acacen)(X)(2)](+) complexes [where X = 2-methylimidazole (2MeIm), 4-methylimidazole (4MeIm), ammine (NH(3)), N-methylimidazole (NMeIm), and pyridine (Py)] were characterized by NMR spectroscopy. The pD stability was shown to be closely related to the nature of the axial ligand with the following trend toward aquation: 2MeIm > NH(3) ≫ 4MeIm > Py > Im > NMeIm. Reaction of each [Co(III)(acacen)(X)(2)](+) derivative with 4MeIm showed formation of a mixed ligand Co(III) intermediate via a dissociative ligand exchange mechanism. The stability of the mixed ligand adduct was directly correlated to the pD-dependent stability of the starting Co(III) Schiff base with respect to [Co(acacen)(4MeIm)(2)](+). Crystal structure analysis of the [Co(acacen)(X)(2)](+) derivatives confirmed the trends in stability observed by NMR spectroscopy. Bond distances between the Co(III) and the axial nitrogen atoms were longest in the 2MeIm derivative as a result of distortion in the planar tetradentate ligand, and this was directly correlated to axial ligand lability and propensity toward exchange.

Selectivity in the oxidative addition of C-S bonds of substituted thiophenes to the (C5Me5)Rh(PMe3) fragment: a comparison of theory with experiment.

Theoretical studies were performed on the C-S bond activation reactions of 2-/3-cyanothiophene, 2-/3-methoxythiophene, and 2-/3-methylthiophene with the [Rh(PMe3)(C5Me5)] fragment to compare with the selectivity of these reactions observed in the experimental study, with the goal of determining whether the latter represent kinetic or thermodynamic products. Density functional theory (DFT) calculations have been used to optimize the ground-state structures of the two possible insertion products and the transition state structures leading to the formation of the products arising from the above cleavage reactions to address this question. With the 2-cyano and 2-methoxy substituents, the observed formation of one product resulting from the exclusive insertion of the rhodium into the more hindered substituted C-S bond was found to be consistent with the calculated energy differences between the ground states of the two possible products (7.6 and 2.6 kcal mol(-1)). With 2-methylthiophene, the product resulting from the activation of the unsubstituted C-S bond is calculated to be favored by 5.8 kcal mol(-1), in agreement with observed results. The approximately 1:1 ratio of products with 3-cyano and 3-methyl substituted thiophenes are also found to be consistent with the small calculated energy differences (0.4 and 0.8 kcal mol(-1)) between the ground states of the two insertion products. Although the observed high selectivity in the formation of a single C-S bond activation product with 3-methoxythiophene appears to be underestimated in the calculations, the observed products for all substituted thiophenes correlate with the calculated thermodynamic products. In addition, the kinetic selectivities predicted based on the calculated C-S bond activation barriers are different from those observed experimentally. Consequently, these investigations demonstrate that DFT calculations can be used reliably to differentiate if an experimentally observed C-S bond activation reaction proceeds under thermodynamic or kinetic control.

Understanding selectivity in the oxidative addition of the carbon-sulfur bonds of 2-cyanothiophene to Pt(0).

The reaction of 2-cyanothiophene with a zerovalent platinum bisalkylphosphine fragment yields two thiaplatinacycles derived from the cleavage of the substituted and unsubstituted C-S bonds. While cleavage away from the cyano group is preferred kinetically, cleavage adjacent to the cyano group is preferred thermodynamically. Density functional theory using B3LYP level of theory on a model of this system is consistent with experimental results in that the transition state energy leading to the formation of the kinetically favored C-S bond cleavage product is lower by 5.3 kcal mol(-1) than the barrier leading to the thermodynamically favored product. There is a 6.7 kcal mol(-1) difference between these two products. The cyano substituent at the 2- position of thiophene did not substantially change the mechanism involved in the C-S bond cleavage of thiophene previously reported.

Polarizing the Nazarov cyclization: the impact of dienone substitution pattern on reactivity and selectivity.

The impact of dienone substitution on the Nazarov cyclization has been examined in detail. Substrates bearing different substituents at each of four positions on the dienone backbone were systematically probed in order to identify trends leading to higher reactivity and better selectivity. Desymmetrization of the pentadienyl cation and oxyallyl cation intermediates through placement of polarizing groups at both the C-2 and C-4 positions was found to be particularly effective. These modifications allowed cyclizations to occur in the presence of catalytic amounts of mild Lewis acids. It was also found that stereoconvergent cyclization of mixtures of E and Z isomers of alkylidene beta-ketoesters occurred via an efficient isomerization process that occurred under the reaction conditions.

Experimental and theoretical examination of C-CN and C-H bond activations of acetonitrile using zerovalent nickel.

Experimental and density functional theory show that the reaction of acetonitrile with a zerovalent nickel bis(dialkylphosphino)ethane fragment (alkyl = methyl, isopropyl) proceeds via initial exothermic formation of an eta(2)-nitrile complex. Three well-defined transition states have been found on the potential energy surface between the eta(2)-nitrile complex and the activation products. The lowest energy transition state is an eta(3)-acetonitrile complex, which connects the eta(2)-nitrile to a higher energy eta(3)-acetonitrile intermediate with an agostic C-H bond, while the other two lead to cleavage of either the C-H or the C-CN bonds. Gas-phase calculations show C-CN bond activation to be endothermic, which contradicts the observation of thermal C-CN activation in THF. Therefore, the effect of solvent was taken into consideration by using the polarizable continuum model (PCM), whereupon the activation of the C-CN bond was found to be exothermic. Furthermore the C-CN bond activation was found to be favored exclusively over C-H bond activation due to the strong thermodynamic driving force and slightly lower kinetic barrier.