Ruthenium-Catalyzed Alkyne trans-Hydrometalation: Mechanistic Insights and Preparative Implications.

[Cp*RuCl]4 (1) has previously been shown to be the precatalyst of choice for stereochemically unorthodox trans-hydrometalations of internal alkynes. Experimental and computational data now prove that the alkyne primarily acts as a four-electron donor ligand to the catalytically active metal fragment [Cp*RuCl] but switches to adopt a two-electron donor character once the reagent R3MH (M = Si, Ge, Sn) enters the ligand sphere. In the stereodetermining step the resulting loaded complex evolves via an inner-sphere mechanism into a ruthenacyclopropene which swiftly transforms into the product. In accord with the low computed barriers, spectral and preparative data show that the reaction is not only possible but sometimes even favored at low temperatures. Importantly, such trans-hydrometalations are distinguished by excellent levels of regioselectivity when unsymmetrical alkynes are used that carry an -OH or -NHR group in vicinity of the triple bond. A nascent hydrogen bridge between the protic substituent and the polarized [Ru-Cl] unit imposes directionality onto the ligand sphere of the relevant intermediates, which ultimately accounts for the selective delivery of the R3M- group to the acetylene C-atom proximal to the steering substituent. The interligand hydrogen bonding also allows site-selectivity to be harnessed in reactions of polyunsaturated compounds, since propargylic substrates bind more tightly than ordinary alkynes; even the electronically coupled triple bonds of conjugated 1,3-diynes can be faithfully discriminated as long as one of them is propargylic. Finally, properly positioned protic sites lead to a substantially increased substrate scope in that they render even 1,3-enynes, arylalkynes, and electron-rich alkynylated heterocycles amenable to trans-hydrometalation which are otherwise catalyst poisons.

A Striking Case of Enantioinversion in Gold Catalysis and Its Probable Origins.

The cyclization of the hydroxy-allene 2 to the tetrahydrofuran 3 catalyzed by the gold-phosphoramidite complex 1, after ionization with an appropriate silver salt AgX, is one of the most striking cases of enantioinversion known to date. The major reason why the sense of induction can be switched from (S) to (R) solely by changing either the solvent or the temperature or the nature of the counterion X is likely found in the bias of the organogold intermediates to undergo assisted proto-deauration. Such assistance can be provided by a protic solvent, a reasonably coordinating counterion or even by a second substrate molecule itself; in this case, the reaction free energy profile gains a strong entropic component that can ultimately dictate the stereochemical course.

Formation of ruthenium carbenes by gem-hydrogen transfer to internal alkynes: implications for alkyne trans-hydrogenation.

Insights into the mechanism of the unusual trans-hydrogenation of internal alkynes catalyzed by {Cp*Ru} complexes were gained by para-hydrogen (p-H2 ) induced polarization (PHIP) transfer NMR spectroscopy. It was found that the productive trans-reduction competes with a pathway in which both H atoms of H2 are delivered to a single alkyne C atom of the substrate while the second alkyne C atom is converted into a metal carbene. This "geminal hydrogenation" mode seems unprecedented; it was independently confirmed by the isolation and structural characterization of a ruthenium carbene complex stabilized by secondary inter-ligand interactions. A detailed DFT study shows that the trans alkene and the carbene complex originate from a common metallacyclopropene intermediate. Furthermore, the computational analysis and the PHIP NMR data concur in that the metal carbene is the major gateway to olefin isomerization and over-reduction, which frequently interfere with regular alkyne trans-hydrogenation.

Origin of inversion versus retention in the oxidative addition of 3-chloro-cyclopentene to Pd(0)L(n).

The preference for syn versus anti oxidative addition of 3-chloro-cyclopentene to Pd(0)L(n) was investigated using density functional theory (L = PH3, PMe3, PF3, ethylene, maleic anhydride, pyridine, imidazol-2-ylidene). Both mono- and bis-ligation modes were studied (n = 1 and 2). The pathways were analyzed at the B2PLYP-D3/def2-TZVPP//TPSS-D3/def2-TZVP level, and an interaction/distortion analysis was performed at the ZORA-TPSS-D3/TZ2P level for elucidating the origin of the selectivity preferences. Mechanistically, the anti addition follows an S(N)2 type mechanism, whereas the syn addition has partial S(N)1 and S(N)2' character. Contrary to the traditional rationale that orbital interactions are dominant in the anti pathway, analysis of the variation of the interaction components along the intrinsic reaction coordinate shows that the syn pathway exhibits stronger overall orbital interactions. This orbital preference for the syn pathway diminishes with increasing donor capacity of the ligand. It is caused by the donation of the isolated p orbitals on the migrating chlorine atom to the PdL(n) fragment, which is lacking in the anti pathway, whereas the HOMO-LUMO overlap between the fragments is greater for the anti pathway. Electrostatically, the syn pathway is preferred for weakly donating and withdrawing ligands, whereas the anti pathway is favored with strongly donating ligands.

A theoretical investigation on the mechanism and stereochemical course of the addition of (E)-2-butenyltrimethylsilane to acetaldehyde by electrophilic and nucleophilic activation.

The diastereoselectivity of the addition of (E)-2-butenyltrimethylsilane to acetaldehyde under electrophilic (BF3, H3O(+)) and nucleophilic (F(-)) activation is investigated using density functional theory (M06-2X). The interaction-distortion/activation-strain model of reactivity is used to rationalize the origin of the selectivity. Consistent with experimental model systems, the synclinal transition states are determined to be preferred over the antiperiplanar transition states in the electrophilic-activated manifolds and vice versa for the fluoride-activated manifold. The selectivity for the syn diastereomer in the electrophilic activation manifolds is accounted for by increased electrostatic and orbital interactions for a synclinal transition state (syn-T3) at the expense of increased steric interactions relative to antiperiplanar transition states. The enhanced orbital interactions for the synclinal (syn-T3) versus antiperiplanar transition states can be attributed to increased π→π* interactions. The selectivity for the anti diastereomer in the nucleophilic manifold is explained by the lesser electrostatic repulsion in the antiperiplanar transition states which are favored relative to the synclinal transition states. Additionally, the diastereoselectivity is partly attributed to variation in the distortion of the crotylsilane.

A systematic investigation of quaternary ammonium ions as asymmetric phase-transfer catalysts. Synthesis of catalyst libraries and evaluation of catalyst activity.

Despite over three decades of research into asymmetric phase-transfer catalysis (APTC), a fundamental understanding of the factors that affect the rate and stereoselectivity of this important process are still obscure. This paper describes the initial stages of a long-term program aimed at elucidating the physical organic foundations of APTC employing a chemoinformatic analysis of the alkylation of a protected glycine imine with libraries of enantiomerically enriched quaternary ammonium ions. The synthesis of the quaternary ammonium ions follows a diversity-oriented approach wherein the tandem inter[4 + 2]/intra[3 + 2] cycloaddition of nitroalkenes serves as the key transformation. A two-part synthetic strategy comprised of (1) preparation of enantioenriched scaffolds and (2) development of parallel synthesis procedures is described. The strategy allows for the facile introduction of four variable groups in the vicinity of a stereogenic quaternary ammonium ion. The quaternary ammonium ions exhibited a wide range of activity and to a lesser degree enantioselectivity. Catalyst activity and selectivity are rationalized in a qualitative way on the basis of the effective positive potential of the ammonium ion.

A systematic investigation of quaternary ammonium ions as asymmetric phase-transfer catalysts. Application of quantitative structure activity/selectivity relationships.

Although the synthetic utility of asymmetric phase-transfer catalysis continues to expand, the number of proven catalyst types and design criteria remains limited. At the origin of this scarcity is a lack in understanding of how catalyst structural features affect the rate and enantioselectivity of phase transfer catalyzed reactions. Described in this paper is the development of quantitative structure-activity relationships (QSAR) and -selectivity relationships (QSSR) for the alkylation of a protected glycine imine with libraries of quaternary ammonium ion catalysts. Catalyst descriptors including ammonium ion accessibility, interfacial adsorption affinity, and partition coefficient were found to correlate meaningfully with catalyst activity. The physical nature of the descriptors was rationalized through differing contributions of the interfacial and extraction mechanisms to the reaction under study. The variation in the observed enantioselectivity was rationalized employing a comparative molecular field analysis (CoMFA) using both the steric and electrostatic fields of the catalysts. A qualitative analysis of the developed model reveals preferred regions for catalyst binding to afford both configurations of the alkylated product.

Formation of Ruthenium Carbenes by gem-Hydrogen Transfer to Internal Alkynes: Implications for Alkyne trans-Hydrogenation.

Insights into the mechanism of the unusual trans-hydrogenation of internal alkynes catalyzed by {Cp*Ru} complexes were gained by para-hydrogen (p-H2) induced polarization (PHIP) transfer NMR spectroscopy. It was found that the productive trans-reduction competes with a pathway in which both H atoms of H2 are delivered to a single alkyne C atom of the substrate while the second alkyne C atom is converted into a metal carbene. This "geminal hydrogenation" mode seems unprecedented; it was independently confirmed by the isolation and structural characterization of a ruthenium carbene complex stabilized by secondary inter-ligand interactions. A detailed DFT study shows that the trans alkene and the carbene complex originate from a common metallacyclopropene intermediate. Furthermore, the computational analysis and the PHIP NMR data concur in that the metal carbene is the major gateway to olefin isomerization and over-reduction, which frequently interfere with regular alkyne trans-hydrogenation.

Dynamic behaviour of monohaptoallylpalladium species: internal coordination as a driving force in allylic alkylation chemistry.

Contemporary catalytic procedures involving alkylpalladium(ii) have enriched the arsenal of synthetic organic chemistry. Those transformations usually rely on internal coordination through "directing groups", carefully designed to maximize catalytic efficiency and regioselectivity. Herein, we report structural and reactivity studies of a series of internally coordinated monohaptoallylpalladium complexes. These species enable the direct spectroscopic observation and theoretical study of π-σ-π interconversion processes. They further display unusual dynamic behavior which should be of direct relevance to chemistries beyond catalytic allylic alkylation.