Yuanzhi Xia

Computational Elucidation of the Internal Oxidant-Controlled Reaction Pathways in Rh(III)-Catalyzed Aromatic C–H Functionalization

The Rh(III)-catalyzed C-H functionalizations of benzamide derivatives with olefin were studied by DFT calculations to elucidate the divergent pathways controlled by the N-OR internal oxidants. For substrates of N-OMe and N-OPiv internal oxidants, the energy profiles for consecutive N-H deprotonation/C-H activation/olefin insertion sequences were similar, and different properties and reactivities of the generated 7-membered rhodacycles were predicted. When N-OMe is involved, this intermediate is generally unstable, and the olefination occurs easily via a β-H elimination/reductive elimination (RE) sequence to generate the Rh(I) intermediate, which is then oxidized to the active Rh(III) via MeOH elimination from the N-OMe reduction in the presence of a HOAc. However, for a 7-membered rhodacycle containing a N-OPiv moiety, the coordination of the acyloxy carbonyl oxygen stabilizes this intermediate and increases the barrier of the olefination pathway. Instead, the migration of the acyloxy from N to Rh(III) via a 5-membered ring TS to form a cyclic Rh(V) nitrene intermediate is more kinetically favorable, then the facile RE of this Rh(V) species forms the heterocycle product and regenerates Rh(III). Notably, for both reactions, the direct C-N formation from intermediates containing a C(sp(3))-Rh(III)-N(sp(3)) unit would be very difficult with barriers over 40 kcal/mol.

RhV‐Nitrenoid as a Key Intermediate in RhIII‐Catalyzed Heterocyclization by CH Activation: A Computational Perspective on the Cycloaddition of Benzamide and Diazo Compounds

A mechanistic study of the substituent-dependent ring formations in Rh(III) -catalyzed C-H activation/cycloaddition of benzamide and diazo compounds was carried out by using DFT calculations. The results indicated that the decomposition of the diazo is facilitated upon the formation of the five-membered rhodacycle, in which the Rh(III) center is more electrophilic. The insertion of carbenoid into Rh-C(phenyl) bond occurs readily and forms a 6-membered rhodacycle, however, the following C-N bond formation is difficult both kinetically and thermodynamically by reductive elimination from the Rh(III) species. Instead, the Rh(V) -nitrenoid intermediate could be formed by migration of the pivalate from N to Rh, which undergoes the heterocyclization much more easily and complementary ring-formations could be modulated by the nature of the substituent at the α-carbon. When a vinyl is attached, the stepwise 1,3-allylic migration occurs prior to the pivalate migration and the 8-membered ring product will be formed. On the other hand, the pivalate migration becomes more favorable for the phenyl-contained intermediate because of the difficult 1,3-allylic migration accompanied by dearomatization, thus the 5-membered ring product was formed selectively.

Mechanism of the Transition‐Metal‐Catalyzed Hydroarylation of Bromo‐Alkynes Revisited: Hydrogen versus Bromine Migration

A comprehensive mechanistic study of the InCl(3)-, AuCl-, and PtCl(2)-catalyzed cycloisomerization of the 2-(haloethynyl)biphenyl derivatives of Fürstner et al. was carried out by DFT/M06 calculations to uncover the catalyst-dependent selectivity of the reactions. The results revealed that the 6-endo-dig cyclization is the most favorable pathway in both InCl(3)- and AuCl-catalyzed reactions. When AuCl is used, the 9-bromophenanthrene product could be formed by consecutive 1,2-H/1,2-Br migrations from the Wheland-type intermediate of the 6-endo-dig cyclization. However, in the InCl(3)-catalyzed reactions, the chloride-assisted intermolecular H-migrations between two Wheland-type intermediates are more favorable. These Cl-assisted H-migrations would eventually lead to 10-bromophenanthrene through proto-demetalation of the aryl indium intermediate with HCl. The cause of the poor selectivity of the PtCl(2) catalyst in the experiments by the Fürstner group was predicted. It was found that both the PtCl(2)-catalyzed alkyne-vinylidene rearrangement and the 5-exo-dig cyclization pathways have very close activation energies. Further calculations found the former pathway would lead eventually to both 9- and 10-bromophenanthrene products, as a result of the Cl-assisted H-migrations after the cyclization of the Pt-vinylidene intermediate. Alternatively, the intermediate from the 5-exo-dig cyclization would be transformed into a relatively stable Pt-carbene intermediate irreversibly, which could give rise to the 9-alkylidene fluorene product through a 1,2-H shift with a 28.1 kcal mol(-1) activation barrier. These findings shed new light on the complex product mixtures of the PtCl(2)-catalyzed reaction.

Hydroarylation of arynes catalyzed by silver for biaryl synthesis

A new biaryl synthesis via silver-catalyzed hydroarylation of arynes from acyclic building blocks with unactivated arenes in intra- and intermolecular manners has been developed. The previously observed Diels-Alder reactions of arynes with arene were not observed under the current silver-catalyzed conditions. Deuterium scrambling and DFT calculations suggest a stepwise electrophilic aromatic substitution mechanism through the formation of a Wheland-type intermediate followed by a water-catalyzed proton transfer in the final step of the hydroarylation.

Benzannulation of Triynes to Generate Functionalized Arenes by Spontaneous Incorporation of Nucleophiles

The thermal reaction of ester-tethered 1,3,8-triynes provides novel benzannulation products with concomitant incorporation of a nucleophile. Evidence suggests that this reaction proceeds via an allene-enyne intermediate generated by an Alder-ene reaction in the first step. Depending on the substituent of the alkyne moiety on the allene-enyne intermediate, the subsequent transformation can take one of two different paths, each leading to discrete aromatization products. The benzannulation of a silane-substituted 1,3,8-triynes provides arene products with a nucleophile incorporated onto the newly formed benzene core, whereas an aryl substituent leads to nucleophile trapping at the benzylic carbon atom connected to the aryl substituent. The formation of these two different products results from the involvement of two regioisomeric allene-enyne intermediates.

Subtle Electronic Effects in Metal-Free Rearrangement of Allenic Alcohols

A general and stereoselective rearrangement of allenic alcohols to (E,E)-1,3-dien-2-yl triflates and chlorides was developed under metal-free conditions. Subtle electronic effects of the alkyl and aryl substituents on the carbon bearing the hydroxyl group has a profound impact on the reaction rate and efficiency such that vinyl triflates were obtained from electron-deficient substrates and trimethylsilyl triflate whereas vinyl chlorides were generated with an electron-rich substrate and trimethylsilyl chloride.

Noninnocent counterion effect on the rearrangements of cationic intermediates in a gold(I)-catalyzed alkenylsilylation reaction.

A mechanistic DFT study of the gold(I)-catalyzed alkenylsilylation reaction of a silyl-tethered 1,6-enyne system is reported. A novel pathway involving bistriflimide counterion-assisted rearrangements of carbocation and silyl cation intermediates corroborates the experimental observations. The results suggest the important role of the counterion in modulating the reactivity of cationic intermediates in gold catalysis.

Mechanism of the N-protecting group dependent annulations of 3-aryloxy alkynyl indoles under gold catalysis: a computational study

The mechanism of the gold-catalyzed annulations of 3-aryloxy alkynyl indoles developed by Tu et al. was studied by DFT calculations. It was found that both indole derivatives of electron-donating and electron-withdrawing protective groups would first undergo the 5-exo-dig cyclization simultaneously upon activation by cationic [PR(3)Au(+)] species. However, divergent reactivity of the resulting spirocyclic intermediate in competitive 1,2-alkenyl migration and nucleophilic water addition reactions towards C3 was predicted. When protected by electron-donating group, the 1,2-alkenyl migration occurs to generate a tricyclic intermediate, from which an aromatic Claisen rearrangement/nucleophilic addition sequence results in the observed 1,2-phenoxy migration. In case of electron-withdrawing group, the 1,2-alkenyl migration would be unfavorable. Instead, the nucleophilic addition of water oxygen to C3 is more facile, and leads to the hemiketal intermediate. The possible roles of water-cluster and OTf anion as proton shuttles in both reactions were also evaluated.

Computational Revisit to the β-Carbon Elimination Step in Rh(III)-Catalyzed C-H Activation/Cycloaddition Reactions of N-Phenoxyacetamide and Cyclopropenes.

This computational study uncovered the origin of the contradicting results in two recent DFT studies of the Rh(III)-catalyzed C-H activation/cycloaddition reactions between N-phenoxyacetamide and cyclopropenes. It was found that the β-carbon elimination of the tricyclic intermediate occurs very faciely via a conformer in which the opening of the three-membered ring is trans to the Cp* ligand so that the steric repulsion between the two moieties is avoided. Thus, the conclusions of our previous study were reconfirmed.

Theoretical Studies on the Mechanism of the C–H Amination of Silyl Cyclopropenes by Azodicarboxylates

DFT/M06 calculations were carried out to better understand the mechanism and regio- and chemoselectivities of our previously discovered formal C-H amination of silyl cyclopropenes by azodicarboxylates (Chem. Commun. 2012, 48, 10990). The results revealed that the initial Alder-ene reaction between the two reactants follows a stepwise mechanism and the subsequent allylic transposition proceeds via a concerted [1,3]-migration of hydrazodicarboxylate. For the Alder-ene process of 1-silyl-2-methylcyclopropene, different electronic effects of the substituents make the C1 much more negatively charged and thus more reactive than C2 in the regiochemistry-determining electrophilic azodicarboxylate addition step. In addition, the poor regioselectivity caused by a C2 ether linkage and the lower reactivity of ene donors other than cyclopropenes with azodicarboxylate were well explained by the computational results. Furthermore, the divergent allylic transposition of the Alder-ene intermediates was rationalized, and the steric repulsion between the silyl group and the hydrazodicarboxylate moiety was suggested as the driving force in promoting the allylic transposition. The barrier for the rate-controlling [1,3]-migration of hydrazodicarboxylate from an intermediate containing the C1-N bond is 21.1 kcal/mol, whereas a higher barrier of 27.5 kcal/mol is required for the similar rearrangement of the thermodynamically more stable intermediate containing the C2-N bond.