Xinhao Zhang

Palladium-catalyzed meta-selective C-H bond activation with a nitrile-containing template: computational study on mechanism and origins of selectivity.

Density functional theory investigations have elucidated the mechanism and origins of meta-regioselectivity of Pd(II)-catalyzed C-H olefinations of toluene derivatives that employ a nitrile-containing template. The reaction proceeds through four major steps: C-H activation, alkene insertion, β-hydride elimination, and reductive elimination. The C-H activation step, which proceeds via a concerted metalation-deprotonation (CMD) pathway, is found to be the rate- and regioselectivity-determining step. For the crucial C-H activation, four possible active catalytic species-monomeric Pd(OAc)2, dimeric Pd2(OAc)4, heterodimeric PdAg(OAc)3, and trimeric Pd3(OAc)6-have been investigated. The computations indicated that the C-H activation with the nitrile-containing template occurs via a Pd-Ag heterodimeric transition state. The nitrile directing group coordinates with Ag while the Pd is placed adjacent to the meta-C-H bond in the transition state, leading to the observed high meta-selectivity. The Pd2(OAc)4 dimeric mechanism also leads to the meta-C-H activation product but with higher activation energies than the Pd-Ag heterodimeric mechanism. The Pd monomeric and trimeric mechanisms require much higher activation free energies and are predicted to give ortho products. Structural and distortion energy analysis of the transition states revealed significant effects of distortions of the template on mechanism and regioselectivity, which provided hints for further developments of new templates.

Role of N-acyl amino acid ligands in Pd(II)-catalyzed remote C-H activation of tethered arenes.

A combined experimental/computational study on the amino acid ligand-assisted Pd-catalyzed C-H bond activation reveals a mechanism in which the amino acid acts as both a dianionic bidentate ligand and a proton acceptor. This new model explains the effects of amino acids on reactivity and selectivity and unveils the dual roles of amino acids: stabilizing monomeric Pd complexes and serving as the internal base for proton abstraction.

Computational Organic Chemistry: Bridging Theory and Experiment in Establishing the Mechanisms of Chemical Reactions

Understanding the mechanisms of chemical reactions, especially catalysis, has been an important and active area of computational organic chemistry, and close collaborations between experimentalists and theorists represent a growing trend. This Perspective provides examples of such productive collaborations. The understanding of various reaction mechanisms and the insight gained from these studies are emphasized. The applications of various experimental techniques in elucidation of reaction details as well as the development of various computational techniques to meet the demand of emerging synthetic methods, e.g., C-H activation, organocatalysis, and single electron transfer, are presented along with some conventional developments of mechanistic aspects. Examples of applications are selected to demonstrate the advantages and limitations of these techniques. Some challenges in the mechanistic studies and predictions of reactions are also analyzed.

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.

Ligand-Controlled Remarkable Regio- and Stereodivergence in Intermolecular Hydrosilylation of Internal Alkynes: Experimental and Theoretical Studies

The first highly efficient ligand-controlled regio- and stereodivergent intermolecular hydrosilylations of internal alkynes have been disclosed. Cationic ruthenium complexes [Cp*Ru(MeCN)3](+) and [CpRu(MeCN)3](+) have been demonstrated to catalyze intermolecular hydrosilylations of silyl alkynes to form a range of vinyldisilanes with excellent but opposite regio- and stereoselectivity, with the former being α anti addition and the latter β syn addition. The use of a silyl masking group not only provides sufficient steric bulk for high selectivity but also leads to versatile product derivatizations toward a variety of useful building blocks. DFT calculations suggest that the reactions proceed by a mechanism that involves oxidative hydrometalation, isomerization, and reductive silyl migration. The energetics of the transition states and intermediates varies dramatically with the catalyst ligand (Cp* and Cp). Theoretical studies combined with experimental evidence confirm that steric effect plays a critical role in governing the regio- and stereoselectivity, and the interplay between the substituent in the alkyne (e.g., silyl group) and the ligand ultimately determines the observed remarkable regio- and stereodivergence.

Conversion of Methane to Methanol: Nickel, Palladium, and Platinum (d9) Cations as Catalysts for the Oxidation of Methane by Ozone at Room Temperature

The room-temperature chemical kinetics has been measured for the catalytic activity of Group 10 atomic cations in the oxidation of methane to methanol by ozone. Ni(+) is observed to be the most efficient catalyst. The complete catalytic cycle with Ni(+) is interpreted with a computed potential energy landscape and, in principle, has an infinite turnover number for the oxidation of methane, without poisoning side reactions. The somewhat lower catalytic activity of Pd(+) is reported for the first time and also explored with DFT calculations. Pt(+) is seen to be ineffective as a catalyst because of the observed failure of PtO(+) to convert methane to methanol.

Bonding in Cationic MCH2+ (M=K–La, Hf–Rn): A Theoretical Study on Periodic Trends

DFT and CCSD(T) calculations have been performed to investigate the bonding situation of 54 cationic methylene complexes, MCH(2)(+) (M=K-La, Hf-Rn). A comparison of the computed results with experimentally and CBS-QB3-derived data demonstrates the reliability of B3LYP/def2-QZVP with regard to the bond dissociation energies. Further, the bonding character of the MCH(2)(+) complexes is revealed by geometrical and molecular-orbital (MO) analysis. The comparison of the periodic trends within the s-, p-, and d-block MCH(2)(+) carbenes shows a pattern different for main-group versus transition-metal complexes. By combining this work with the recently reported trends for the f-block lanthanide carbenes MCH(2)(+), a systematic and comprehensive overview can be obtained.

Synthesis of Indolo(2,1‑a)isoquinolines via a Triazene-Directed C−H Annulation Cascade

Indole-containing polyaromatic scaffolds are widely found in natural products, pharmaceutical agents, and π-conjugated functional materials. Often, the synthesis of these highly valuable molecules requires a multistep sequence. Therefore, a simple, one-step protocol to access libraries of polyaromatic indole scaffolds is highly desirable. Herein we describe the direct synthesis of polysubstituted indolo[2,1-a]isoquinoline analogues via a double C-H annulation cascade using triazene as an internally cleavable directing group. Evidence from HRMS and theoretical calculations suggests that an unprecedented 1,2-alkyl migration might be responsible for the in situ cleavage of the directing group. Both kinetic isotope effects and DFT calculations suggested that the alkyne insertion step is rate-limiting for the second C,N annulation reaction.

Structure and chemistry of the heteronuclear oxo-cluster [VPO4]•+: a model system for the gas-phase oxidation of small hydrocarbons.

The heteronuclear oxo-cluster [VPO4](•+) is generated via electrospray ionization and investigated with respect to both its electronic structure as well as its gas-phase reactivity toward small hydrocarbons, thus permitting a comparison to the well-known vanadium-oxide cation [V2O4](•+). As described in previous studies, the latter oxide exhibits no or just minor reactivity toward small hydrocarbons, such as CH4, C2H6, C3H8, n-C4H10, and C2H4, while substitution of one vanadium by a phosphorus atom yields the reactive [VPO4](•+) ion; the latter brings about oxidative dehydrogenation (ODH) of saturated hydrocarbons, e.g., propane and butane as well as oxygen-atom transfer (OAT) to unsaturated hydrocarbons, e.g. ethene, at thermal conditions. Further, the gas-phase structure of [VPO4](•+) is determined by IR photodissociation spectroscopy and compared to that of [V2O4](•+). DFT calculations help to elucidate the reaction mechanism. The results underline the crucial role of phosphorus in terms of C-H bond activation of hydrocarbons by mixed VPO clusters.

Metal-Free [2+2+2] Cycloaddition of Ynamides and Nitriles: Mild and Regioselective Synthesis of Fully Substituted Pyridines

A metal-free trimolecular [2+2+2] cycloaddition of internal ynamides and nitriles for de novo synthesis of fully substituted pyridines is disclosed. With the versatile Brønsted acid catalyst HNTf2 , the mild intermolecular cyclotrimerization process proceeds with complementary chemoselectivity and excellent regioselectivity.