NMR chemical shift analysis decodes olefin oligo- and polymerization activity of d0 group 4 metal complexes.

d0 metal-alkyl complexes (M = Ti, Zr, and Hf) show specific activity and selectivity in olefin polymerization and oligomerization depending on their ligand set and charge. Here, we show by a combined experimental and computational study that the 13C NMR chemical shift tensors of the α-carbon of metal alkyls that undergo olefin insertion signal the presence of partial alkylidene character in the metal-carbon bond, which facilitates this reaction. The alkylidene character is traced back to the π-donating interaction of a filled orbital on the alkyl group with an empty low-lying metal d-orbital of appropriate symmetry. This molecular orbital picture establishes a connection between olefin insertion into a metal-alkyl bond and olefin metathesis and a close link between the Cossee-Arlmann and Green-Rooney polymerization mechanisms. The 13C NMR chemical shifts, the α-H agostic interaction, and the low activation barrier of ethylene insertion are, therefore, the results of the same orbital interactions, thus establishing chemical shift tensors as a descriptor for olefin insertion.

Synthesis of 2'-O-(N-methylcarbamoylethyl) 5-methyl-2-thiouridine and its application to splice-switching oligonucleotides.

The effect of 2'-O-(N-methylcarbamoyl)ethyl (MCE) modification on splice-switching oligonucleotides (SSO) was systematically evaluated. The incorporation of five MCE nucleotides at the 5'-termini of SSOs effectively improved the splice switching effect. In addition, the incorporation of 2'-O-(N-methylcarbamoylethyl)-5-methyl-2-thiouridine (s2TMCE), a duplex-stabilizing nucleotide with an MCE modification, into SSOs further improved splice switching. These SSOs may be useful for the treatment of genetic diseases associated with splicing errors.

Modification of oligonucleotides with weak basic residues via the 2'-O-carbamoylethyl linker for improving nuclease resistance without loss of duplex stability and antisense activity.

For the improvement of nuclease resistance, four kinds of new modifications through a carbamoylethyl linker were designed. Among them, the 2'-O-[2-N-{2-(benzimidazol-1-yl)ethyl}carbamoylethyl] modification showed 20-fold longer half-life when treated with a 3' to 5' exonuclease compared to the 2'-O-methoxyethyl (MOE) modification, which is used in approved drugs. In addition, this large modification did not disturb the binding affinity or RNase H-dependent antisense activity. From these findings, it could be concluded that an adequate linker, such as carbamoylethyl in this study, could extend the utility of 2'-O-modification without loss of the properties of nucleic acids. This strategy would be useful for the development of nucleic acid therapeutics.

Bridging the Gap between Industrial and Well-Defined Supported Catalysts.

Many industrial catalysts contain isolated metal sites on the surface of oxide supports. Although such catalysts have been used in a broad range of processes for more than 40 years, there is often a very limited understanding about the structure of the catalytically active sites. This Review discusses how surface organometallic chemistry (SOMC) engineers surface sites with well-defined structures and provides insight into the nature of the active sites of industrial catalysts; the Review focuses in particular on olefin production and conversion processes.

Orbital Analysis of Carbon-13 Chemical Shift Tensors Reveals Patterns to Distinguish Fischer and Schrock Carbenes.

Fischer and Schrock carbenes display highly deshielded carbon chemical shifts (>250 ppm), in particular Fischer carbenes (>300 ppm). Orbital analysis of the principal components of the chemical shift tensors determined by solid-state NMR spectroscopy and calculated by a 2-component DFT method shows specific patterns that act as fingerprints for each type of complex. The calculations highlight the role of the paramagnetic term in the shielding tensor especially in the two most deshielded components (σ11 and σ22 ). The paramagnetic term of σ11 is dominated by coupling σ(M=C) with π*(M=C) through the angular momentum operator perpendicular to the σ and π M=C bonds. The highly deshielded carbon of Fischer carbenes results from the particularly low-lying π*(M=C) associated with the CO ligand. A contribution of the coupling of π(M=C) with σ*(M=C) is found for Schrock and Ru-based carbenes, indicating similarities between them, despite their different electronic configurations (d0 vs. d6 ).

Direct Evidence for a [4+2] Cycloaddition Mechanism of Alkynes to Tantallacyclopentadiene on Dinuclear Tantalum Complexes as a Model of Alkyne Cyclotrimerization.

A dinuclear tantalum complex, [Ta2 Cl6 (µ-C4 Et4)] (2), bearing a tantallacyclopentadiene moiety, was synthesized by treating [(η(2) -EtC≡CEt)TaCl3 (DME)] (1) with AlCl3 . Complex 2 and its Lewis base adducts, [Ta2 Cl6 (µ-C4 Et4 )L] (L=THF (3 a), pyridine (3 b), THT (3 c)), served as more active catalysts for cyclotrimerization of internal alkynes than 1. During the reaction of 3 a with 3-hexyne, we isolated [Ta2 Cl4 (µ-η(4):η(4)-C6 Et6)(µ-η(2):η(2)-EtC≡CEt)] (4), sandwiched by a two-electron reduced µ-η(4):η(4) -hexaethylbenzene and a µ-η(2):η(2)-3-hexyne ligand, as a product of an intermolecular cyclization between the metallacyclopentadiene moiety and 3-hexyne. The formation of arene complexes [Ta2 Cl4 (µ-η(4):η(4)-C6 Et4 Me2)(µ-η(2):η(2)-Me3 SiC≡CSiMe3)] (7 b) and [Ta2 Cl4 (µ-η(4):η(4)-C6 Et4 RH)(µ-η(2):η(2)-Me3 SiC≡CSiMe3)] (R=nBu (8 a), p-tolyl (8 b)) by treating [Ta2 Cl4 (µ-C4 Et4)(µ-η(2):η(2) -Me3 SiC≡CSiMe3)] (6) with 2-butyne, 1-hexyne, and p-tolylacetylene without any isomers, at room temperature or low temperature were key for clarifying the [4+2] cycloaddition mechanism because of the restricted rotation behavior of the two-electron reduced arene ligands without dissociation from the dinuclear tantalum center.

Electronic Structure-Reactivity Relationship on Ruthenium Step-Edge Sites from Carbonyl 13C Chemical Shift Analysis.

Ru nanoparticles are highly active catalysts for the Fischer-Tropsch and the Haber-Bosch processes. They show various types of surface sites upon CO adsorption according to NMR spectroscopy. Compared to terminal and bridging η1 adsorption modes on terraces or edges, little is known about side-on η2 CO species coordinated to B5 or B6 step-edges, the proposed active sites for CO and N2 cleavage. By using solid-state NMR and DFT calculations, we analyze 13C chemical shift tensors (CSTs) of carbonyl ligands on the molecular cluster model for Ru nanoparticles, Ru6(η2-µ4-CO)2(CO)13(η6-C6Me6), and show that, contrary to η1 carbonyls, the CST principal components parallel to the C-O bond are extremely deshielded in the η2 species due to the population of the C-O π* antibonding orbital, which weakens the bond prior to dissociation. The carbonyl CST is thus an indicator of the reactivity of both Ru clusters and Ru nanoparticles step-edge sites toward C-O bond cleavage.

Silica-supported isolated molybdenum di-oxo species: formation and activation with organosilicon agent for olefin metathesis.

A well-defined silica-supported molybdenum dioxo species, ([triple bond, length as m-dash]SiO)2Mo(O)2, is prepared by grafting Mo(O)2[OSi(OtBu)3]2 on partially dehydroxylated silica SiO2-700, followed by thermal treatment under high-vaccum and calcination. Activated by an organosilicon agent the resulting material is active for olefin metathesis at 30 °C.

Metal alkyls programmed to generate metal alkylidenes by α-H abstraction: prognosis from NMR chemical shift.

Metal alkylidenes, which are key organometallic intermediates in reactions such as olefination or alkene and alkane metathesis, are typically generated from metal dialkyl compounds [M](CH2R)2 that show distinctively deshielded chemical shifts for their α-carbons. Experimental solid-state NMR measurements combined with DFT/ZORA calculations and a chemical shift tensor analysis reveal that this remarkable deshielding originates from an empty metal d-orbital oriented in the M-Cα-Cα' plane, interacting with the Cα p-orbital lying in the same plane. This π-type interaction inscribes some alkylidene character into Cα that favors alkylidene generation via α-H abstraction. The extent of the deshielding and the anisotropy of the alkyl chemical shift tensors distinguishes [M](CH2R)2 compounds that form alkylidenes from those that do not, relating the reactivity to molecular orbitals of the respective molecules. The α-carbon chemical shifts and tensor orientations thus predict the reactivity of metal alkyl compounds towards alkylidene generation.

Tantallacyclopentadiene as a unique metal-containing diene ligand coordinated to nickel for preparing tantalum-nickel heterobimetallic complexes.

A mononuclear tantallacyclopentadiene complex, TaCl3(C4H2tBu2) (3), serves as a unique ligand to nickel: the addition of Ni(COD)2 to 3 selectively afforded heterobimetallic Ta-Ni complex 4. The cyclooctadiene ligand bound to the nickel center in complex 4 was readily substituted by monodentate and bidentate phosphine ligands, such as dimethylphenylphosphine, 1,2-bis(diphenylphosphino)ethane, and 1,2-bis(diethylphosphino)ethane, to give the corresponding phosphine complexes 5, 6a, and 6b. We also examined a ligand substitution reaction with 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) to produce the corresponding Ta-Ni complex 7. These newly prepared Ta-Ni heterobimetallic complexes were characterized spectroscopically together with the crystal structures of 4, 6a, and 7.

Metathesis Activity Encoded in the Metallacyclobutane Carbon-13 NMR Chemical Shift Tensors.

Metallacyclobutanes are an important class of organometallic intermediates, due to their role in olefin metathesis. They can have either planar or puckered rings associated with characteristic chemical and physical properties. Metathesis active metallacyclobutanes have short M-Cα/α' and M···Cß distances, long Cα/α'-Cß bond length, and isotropic 13C chemical shifts for both early d0 and late d4 transition metal compounds for the α- and ß-carbons appearing at ca. 100 and 0 ppm, respectively. Metallacyclobutanes that do not show metathesis activity have 13C chemical shifts of the α- and ß-carbons at typically 40 and 30 ppm, respectively, for d0 systems, with upfield shifts to ca. -30 ppm for the α-carbon of metallacycles with higher d n electron counts (n = 2 and 6). Measurements of the chemical shift tensor by solid-state NMR combined with an orbital (natural chemical shift, NCS) analysis of its principal components (δ11 ≥ δ22 ≥ δ33) with two-component calculations show that the specific chemical shift of metathesis active metallacyclobutanes originates from a low-lying empty orbital lying in the plane of the metallacyclobutane with local π*(M-Cα/α') character. Thus, in the metathesis active metallacyclobutanes, the α-carbons retain some residual alkylidene character, while their ß-carbon is shielded, especially in the direction perpendicular to the ring. Overall, the chemical shift tensors directly provide information on the predictive value about the ability of metallacyclobutanes to be olefin metathesis intermediates.

[Changing behavior of estrogen and progesterone receptors with metastasis or recurrence of breast cancer].

Changes in level of estrogen receptor (ER) and progesterone receptor (PgR) and their affecting factors were studied with metastasis or recurrence of breast cancer. Since 1983, from 177 patients, 443 specimens were obtained and 244 simultaneous and 122 sequential pairs were compared. The consistency rate was 81% for both ER and PgR with simultaneous comparison,and 69% for ER and 71% for PgR with sequential comparison, mainly due to positive-to-negative change, and less than 10% of negative-to-positive change. Positive-to-negative change was prominent with intervening endocrine treatment, and it was significant (p=0.015) for ER by multiple regression analysis of age, interval of sampling and from prior surgery, intervening chemotherapy, endocrine therapy and human epidermal growth factor receptor 2 (HER 2). Based on recent data of ER and PgR, feasible treatment seems to be planned, because about 30% of them are different from that of primary lesion.

Mechanistic understanding of alkyne cyclotrimerization on mononuclear and dinuclear scaffolds: [4 + 2] cycloaddition of the third alkyne onto metallacyclopentadienes and dimetallacyclopentadienes.

Cyclotrimerization of alkynes catalyzed by transition metal complexes is a straightforward synthetic method for constructing a benzene skeleton in organic synthesis. Not only mononuclear complexes, but also multinuclear complexes act as catalysts for alkyne cyclotrimerization, and their reaction mechanisms have been intensively investigated toward developing highly efficient and regio- and chemo-selective catalysts. In this review, we summarize stoichiometric and catalytic alkyne coupling reactions on mononuclear and dinuclear scaffolds in relation to the reaction mechanism of alkyne cyclotrimerization, including our recent mechanistic approaches using dinuclear tantalum motifs.

Isospecific polymerization of 1-hexene by C1-symmetric half-metallocene dimethyl complexes of group 4 metals with bidentate N-substituted iminomethylpyrrolyl ligands.

Non-bridged half-metallocene dimethyl complexes of group 4 metals 2a-4a with an N-4-methoxyphenyl(iminomethyl)pyrrolyl ligand 1a were synthesized and characterized by NMR spectroscopy and X-ray analysis. Upon activation with [Ph3C][B(C6F5)4], these complexes became active catalysts for the polymerization of 1-hexene. A series of hafnium complexes with various N-substituents on the imine group of ligands 1b-1g were also prepared and applied as catalysts for 1-hexene polymerization. The activation parameters for the exchange process between the two methyl groups bound to the metal for Cp*MMe2(R-pyr) complexes were estimated by NMR shape analysis at various temperatures. The findings indicated that the transition state of the ligand flipping process might be associated with the isoselectivity of the polymerization reaction.